Điều Trị Bỏng Toàn Diện (Bản Expert Consult)

Total Burn Care
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276.e4
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150. Wibbenmeyer LA, Mitchell MA, Newel IM, Faucher LD, Amelon
MJ, Ruffin TO, Lewis RD, Latenser BA, Kealey PG. Effect of a fish
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151. Windle EM. Glutamine supplementation in critical illness:
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153. Peng X, Yan H, You Z, Wang P, Wang S. Glutamine granule-
supplemented enteral nutrition maintains immunological
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154. Garrel D, Patenaude J, Nedelec B, Samson L, Dorais J,
Champoux J, D’Elia M, Bernier J. Decreased mortality and
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155. Wischmeyer PE, Lynch J, Liedel J, Wolfson R, Riehm J, Gottlieb
L, Kahana M. Glutamine administration reduces Gram-negative
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Crit Care Med. 2001;29:2075-2080.
156. Barret JP, Jeschke MG, Herndon DN. Selective decontamination
of the digestive tract in severely burned pediatric patients. Burns.
2001;27:439-445.
157. Mackie DP, van Hertum WA, Schumburg T, Kuijper EC, Knape P.
Prevention of infection in burns: preliminary experience with
selective decontamination of the digestive tract in patients with
extensive injuries. J Trauma. 1992;32:570-575.
158. de la Cal MA, Cerda E, Garcia-Hierro P, van Saene HK, Gomez-
Santos D, Negro E, Lorente JA. Survival benefit in critically ill
burned patients receiving selective decontamination of the
digestive tract: a randomized, placebo-controlled, double-blind
trial. Ann Surg. 2005;241:424-430.
159. Cerda E, Abella A, de la Cal MA, Lorente JA, Garcia-Hierro P,
van Saene HK, Alia I, Aranguren A. Enteral vancomycin controls
methicillin-resistant Staphylococcus aureus endemicity in an
intensive care burn unit: a 9-year prospective study. Ann Surg.
2007;245:397-407.
160. Nance FC, Hines JL, Fulton RE, Bornside GH. Treatment of
experimental burn wound sepsis by postburn immunization
with polyvalent Pseudomonas antigen. Surgery. 1970;68:248-
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161. Holder IA, Neely AN, Frank DW. PcrV immunization enhances
survival of burned Pseudomonas aeruginosa-infected mice. Infect
Immun. 2001;69:5908-5910.
162. Roe EA, Jones RJ. Active and passive immunization against
Pseudomonas aeruginosa infection of burned patients. Burns Incl
Therm Inj. 1983;9:433-439.
163. Baumann U, Mansouri E, von Specht BU. Recombinant
OprF-OprI as a vaccine against Pseudomonas aeruginosa
infections. Vaccine. 2004;22:840-847.
164. Kim DK, Kim JJ, Kim JH, Woo YM, Kim S, Yoon DW, Choi CS,
Kim I, Park WJ, Lee N, Jung SB, Ahn BY, Nam SW, Yoon SM,
Choi WJ. Comparison of two immunization schedules for a
Pseudomonas aeruginosa outer membrane proteins vaccine in
burn patients. Vaccine. 2000;19:1274-1283.
165. Lee NG, Jung SB, Ahn BY, Kim YH, Kim JJ, Kim DK, Kim IS,
Yoon SM, Nam SW, Kim HS, Park WJ. Immunization of
burn-patients with a Pseudomonas aeruginosa outer membrane
protein vaccine elicits antibodies with protective efficacy. Vaccine.
2000;18:1952-1961.
166. Mansouri E, Blome-Eberwein S, Gabelsberger J, Germann G,
von Specht BU. Clinical study to assess the immunogenicity and
safety of a recombinant Pseudomonas aeruginosa OprF-OprI
vaccine in burn patients. FEMS Immunol Med Microbiol.
2003;37:161-166.
167. Polk Jr HC, Cheadle WG, Livingston DH, Rodriguez JL, Starko
KM, Izu AE, Jaffe HS, Sonnenfeld G. A randomized prospective
clinical trial to determine the efficacy of interferon-gamma in
severely injured patients. Am J Surg. 1992;163:191-196.
168. Wasserman D, Ioannovich JD, Hinzmann RD, Deichsel G,
Steinmann GG. Interferon-gamma in the prevention of severe
burn-related infections: a European phase III multicenter trial.
The Severe Burns Study Group. Crit Care Med. 1998;26:
434-439.
169. Ami K, Kinoshita M, Yamauchi A, Nishikage T, Habu Y,
Shinomiya N, Iwai T, Hiraide H, Seki S. IFN-gamma production
from liver mononuclear cells of mice in burn injury as well as in
postburn bacterial infection models and the therapeutic effect of
IL-18. J Immunol. 2002;169:4437-4442.
170. Goebel A, Kavanagh E, Lyons A, Saporoschetz IB, Soberg C,
Lederer JA, Mannick JA, Rodrick ML. Injury induces deficient
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injury restores resistance to infection. Annals of Surgery.
2000;231:253-261.
171. O’Suilleabhain C, O’Sullivan ST, Kelly JL, Lederer J, Mannick JA,
Rodrick ML. Interleukin-12 treatment restores normal resistance
to bacterial challenge after burn injury. Surgery. 1996;120:290-
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172. Pockros PJ, Patel K, O’Brien C, Tong M, Smith C, Rustgi V,
Carithers RL, McHutchison JG, Olek E, Debruin MF. A
multicenter study of recombinant human interleukin 12 for the
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173. Wadler S, Levy D, Frederickson HL, Falkson CI, Wang Y, Weller
E, Burk R, Ho G, Kadish AS. A phase II trial of interleukin-12 in
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correlates. Eastern Cooperative Oncology Group study E1E96.
Gynecol Oncol. 2004;92:957-964.
174. Lyons A, Goebel A, Mannick JA, Lederer JA. Protective effects of
early interleukin 10 antagonism on injury-induced immune
dysfunction. Archives of Surgery. 1999;134:1317-1323.
175. O’Riordain MG, O’Riordain DS, Molloy RG, Mannick JA,
Rodrick ML. Dosage and timing of anti-TNF-alpha antibody
treatment determine its effect of resistance to sepsis after injury.
Journal of Surgical Research. 1996;64:95-101.
176. Gamelli RL, He LK, Liu H. Recombinant human granulocyte
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177. Molloy RG, Holzheimer R, Nestor M, Collins K, Mannick JA,
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modulates immune function and improves survival after
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178. Cioffi Jr WG, Burleson DG, Jordan BS, Becker WK, McManus WF,
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1991;126:74-79.
179. Bohannon J, Cui W, Cox R, Przkora R, Sherwood E, Toliver-
Kinsky T. Prophylactic treatment with fms-like tyrosine kinase-3
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183. Browder W, Williams D, Pretus H, Olivero G, Enrichens F,
Mao P, Franchello A. Beneficial effect of enhanced
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©2012 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2786-9.00023-0
Hematologic and hematopoietic
response to burn injury
Joseph A. Posluszny, Jr., Richard L. Gamelli, Ravi Shankar
Introduction
Hematopoiesis is the formation of peripheral blood cells,
including red blood cells, leukocytes and platelets. Hemat­
opoiesis occurs in a stepwise pattern in which stem cells
differentiate into cells with increasingly restricted develop­
mental potential. Growth factors and cytokines present in
the bone marrow influence the commitment patterns of
these progenitor cells, yielding the mature, fully differenti­
ated bone marrow cells that later populate the bloodstream.
These growth factors and cytokines influence transcription
factor expression, which ultimately controls cell fate. The
dramatic metabolic and physiologic stresses of other organ
systems following a severe burn injury are well recognized.
Alterations to the hematopoietic system should not be
ignored, as they contribute to immunomodulation and
anemia, which significantly affect patient morbidity and sur­
vival. This chapter provides an overview of hematopoiesis,
the blood cells formed, the growth factors and transcription
factors that control cell fate, how burn injury affects these
processes, and therapeutic strategies used to combat these
effects.
Hematopoiesis
Overview
Hematopoiesis is the formation of peripheral blood cells,
which are composed primarily of erythroid cells, leukocytes,
and megakaryocytes. Erythroid cells include erythroid pre­
cursors in the bone marrow (proerythroblast, basophilic
normoblast, polychromatic normoblast, and orthochro­
matic normoblast) and reticulocytes and erythrocytes present
in both the bone marrow and the peripheral bloodstream.
Leukocytes include both lymphoid and myeloid white blood
cells. The lymphoid lineage is composed of T and B cells.
Myeloid cells comprise the remaining leukocytes, including
monocytes, macrophages and neutrophils. Dendritic cells
and natural killer (NK) cells can develop from either the
myeloid or the lymphoid lineage. Megakaryocytes are the
bone marrow progenitors of platelets. Hematopoiesis is
essential for oxygen delivery, host defense and coagulation,
with estimates of 200 billion erythrocytes, 100 billion leu­
kocytes and 100 billion platelets made daily in an adult.
Stem cells
Hematopoiesis proceeds in a stepwise, hierarchical fashion.1,2
Hematopoietic stem cells (HSCs), which reside in the bone
marrow, are at the top of the hematopoietic hierarchy. HSCs
are able to both self-renew and differentiate, ensuring main­
tenance of their population and replenishment of all hemat­
opoietic cell lines.3–6 There are two forms of HSC, long term
(LT) and short term (ST), which differ in their self-renewal
and differentiation capacities.7–9 As suggested by their name,
LT-HSCs are the permanent self-renewing cells of the bone
marrow with minimal response to physiologic stress, whereas
ST-HSCs have the ability to increase their production and
differentiation during different pathologic states. ST-HSCs
differentiate into multipotent progenitor cells (MPPs).10
MPPs do not have the ability to reconstitute the bone
marrow, but do maintain the ability to differentiate into all
hematopoietic lineages, bridging the stem cell niche with
progressively lineage-restricted progenitor cells.11,12 The hier­
archy of hematopoiesis, from stem cell to progenitor groups
to terminally differentiated cells (Fig. 23.1), allows for the
rapid amplification of cell production by the upstream pro­
liferation of stem cells.13 There are other suggested hemat­
opoietic hierarchies14,15 which differ in the branch points at
which certain progenitor populations lose lineage potential
or suggest that some cell groups have the potential to dedif­
ferentiate and enter a different lineage. In essence, hemat­
opoiesis is controlled by a hierarchical pattern of progressive
loss of lineage potential. The expression of a limited set of
transcription factors, controlled by the growth factors and
cytokines present in the bone marrow milieu, control lineage
commitment, cell fate16,17 and, ultimately, the composition
of cells in the bloodstream.
HSCs have received extensive attention in the media both
because of their complicated ethical dilemma and also
because of their extensive potential in treating blood disor­
ders.18,19 The use of these cells as a potential therapy for the
anemia or immune dysfunction present in severely burned
patients is not currently feasible, but their use in the future
is possible.
Progenitor cells
As HSCs differentiate they lose potency and developmental
options, and become lineage-restricted progenitor cells. The
genetic programs controlling lineage restriction take place
CHAPTER 23 
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IN THIS CHAPTER
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Total Burn Care
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278
hematopoiesis, changes in ST-HSC and MPP production as
well as the lineage shift towards greater GMP production
may herald the overall erythropoietic production (anemia)
and myeloid function (immune dysfunction) problems
present after burn injury. Further work on the HSC and pro­
genitor cell response may provide avenues for early thera­
peutic intervention, which may ameliorate the negative and
deleterious hematopoietic consequences of burn injury.
For the most part, the commitment patterns of stem and
progenitor cells are a function of the growth factors and
cytokines (IL-6, TNFα, stem cell factor, etc.) to which the
cells are exposed and the transcription factors (GATA-1,
PU.1, etc.) that are expressed as a result. The intricate inter­
play of growth factors, cytokines and transcription factors,
and their influence on lineage commitment patterns, is dis­
cussed extensively later in this chapter.
Red blood cells
Sources of anemia: clinical and
laboratory findings
Red blood cells are derived from cells of the erythroid
lineage, which is a branch of MEPs. Erythroid cells progress
through several blast stages until they form reticulocytes,
which can mature in the bone marrow or periphery to form
erythrocytes. Often, a measure of the reticulocyte count can
be used to determine the degree of erythropoietic response,
as the percentage of reticulocytes should increase in states of
anemia or increased erythropoietin. Mature erythrocytes
populate the bloodstream and are responsible for oxygen
transport.
Burn patients commonly suffer from anemia. Anemia is a
reduction in red blood cells below normal laboratory limits.
Often, a mild reduction in red blood cells is of little clinical
significance.27 Only when the red blood cell concentration
over 10–15 cell divisions from the HSC stage. The traditional
hematopoietic hierarchy proposes that HSCs differentiate
into either common lymphoid progenitors (CLP) or
common myeloid progenitors (CMP), based on local
cytokine and growth factor levels2 and also on the develop­
ment of the IL-7 receptor, which prompts lymphoid but not
myeloid formation.20 CLPs can differentiate into T and B
lymphocytes, natural killer cells and antigen-presenting
dendritic cells.2,21–23 CMPs can differentiate into either
megakaryocyte–erythroid progenitors (MEP) or granulocyte–
monocyte progenitors (GMP). CMPs, MEPs and GMPs are
identified by their unique expressions of the Fcγ receptor
and CD34. As implied in their names, MEPs become either
megakaryocytes or erythroid/red blood cells and GMPs
become neutrophils, monocytes, macrophages, eosinophils,
basophils and mast cells.24 Although progenitor cells are of
the utmost importance in terms of lineage fate and the
overall composition of the bloodstream, they comprise less
than 1–2% of all bone marrow cells.
Burn injury, stem and progenitor cells
There has been very little research on the effect of burn
injury on HSCs and progenitor cells. HSC production is
amplified in a mouse model of sepsis, which is a similar
physiologic process to burn injury.25 Inflammatory cytokines
increase granulocytopoiesis while reducing lymphopoiesis
via changes in common progenitor cells.26 Preliminary work
from our laboratory has demonstrated an overall increase in
the HSC population in mice initially following burn injury,
with a gradual decrease 10–14 days post burn. Specifically,
ST-HSCs and MPPs increase, but there is no significant
change in LT-HSCs. Interestingly, in the progenitor compart­
ment there is a significant increase in GMPs, with slight
decreases in MEP, CMP, and CLP production following
burn (Fig. 23.1). Most of these changes reverse themselves
2–3 weeks post burn. Given the hierarchical nature of
Figure 23.1  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).
CLPs differentiate into T and B cells. The CMP
population can branch into GMPs (granulocyte–
monocyte progenitors) or MEPs (megakaryocyte–
erythroid progenitors), which then lead to their
respective terminally differentiated populations.
HSC
compartment
LT-HSC
HSC
ST-HSC
MPP
CLP
CMP
GMP
MEP
Monocytes
Macrophages
Neutrophils
Mega-
karyocytes
Red
blood cells
B-cells
T-cells
Progenitors
Differentiated
cells

Hematologic and hematopoietic response to burn injury
279
This insight into hematopoietic lineage commitment pat­
terns following burn injury may not only help to better
explain the dampened erythropoiesis of the anemia of
critical illness, but may also shed light on a source for the
dysfunctional leukocytes that contribute to immunomodu­
lation. Further functional studies linking the changes of
hematopoietic stem and progenitor cells with the cells
present in the bloodstream may yield findings that could
significantly benefit patient care in terms of anemia
treatment/prevention and a better understanding of the
origin of immunodysfunction.
Dampened erythropoiesis following burn injury may be
caused by proinflammatory cytokines and/or elevated levels
of catecholamines. Wallner suggested that there may be an
‘erythroid inhibitory substance’49 following burn injury, as
the sera of burn patients reduce erythroid colony production
compared to the sera of healthy patients.51 Although this
work did not identify an ‘erythroid inhibitory substance’,
later work on erythropoiesis has shown that both proinflam­
matory cytokines52–55 and catecholamines,56–60 which are
both significantly elevated following burn injury, may inhibit
erythropoiesis. In vitro, the addition of tumor necrosis
factor,61,62 β-interferon,62 interferon-γ,63,64 and interleukin-6,65
all proinflammatory cytokines, reduces erythroid colony
formation. Catecholamines are increased beyond their base­
line state in the bone marrow following burn injury,66,67 and
erythropoiesis is significantly altered with changes in cat­
echolamine levels,68–70 which may contribute to the damp­
ened erythropoiesis following burn injury. The prolonged
proinflammatory and hypermetabolic state following burn
injury may also significantly alter erythropoiesis and be a
major contributor to the anemia of critical illness.
Clinical implications and treatment
Anemia is highly prevalent in patients with severe burn
injury. Prevention of anemia mimics the sources, the
acute blood loss and the anemia of critical illness, while the
mainstay of treatment for both types of anemia remains
pRBC transfusion. Acute blood loss anemia is prevented
with innovative surgical techniques, whereas the anemia
of critical illness is prevented by reduced phlebotomy,
decreased blood loss with dressing changes, and improved
nutrition.
Several methods have been developed to reduce acute
surgical blood loss, including epinephrine tumescence,
thrombin-soaked pads, and tourniquet use. Although the
studies that examine epinephrine tumescence differ in their
methods and results, the injection of dilute epinephrine into
the subdermal space promotes vasoconstriction and reduces
blood loss during surgical management of a wound.71–74 For
example, in a prospective trial in children, epinephrine
tumescence alone reduced blood loss from 3.5–5% to 0.98%
of total blood volume/% of body excised and grafted.73
Epinephrine tumescence has no significant hemodynamic
consequences, nor does it alter wound healing.75–77 The addi­
tion of thrombin-soaked pads for extra hemostasis following
completion of the operative procedure has been studied in
the context of epinephrine tumescence and provides addi­
tional hemostasis by reducing unnecessary ooze from the
dressing site.33,78,79 Finally, the use of an extremity tourniquet
during excision and debridement can reduce surgical blood
is significantly reduced does it become clinically relevant,
leading to impaired end-organ perfusion and oxygenation.28
Defined hemoglobin concentrations and hematocrit levels
trigger the transfusion of packed red blood cells (pRBCs) in
order to restore perfusion. In patients who are not actively
bleeding, without coronary ischemia or without hemody­
namic compromise, the transfusion trigger is typically in the
range of 7–8 g/dL of hemoglobin or 21–24% hematocrit.
Traditionally, a hemoglobin trigger of 10 g/dL or a hemat­
ocrit of 30% has been used. However, both large-scale work
in the critical care literature29 and a smaller, retrospective
review of both adult30 and pediatric31 burn patients have
established the infectious, cost and survival benefit of a
lower, more restrictive transfusion trigger.
Burn patients are anemic because of both acute surgical
blood loss and the anemia of critical illness. Acute surgical
blood loss stems from repeated debridements of the burn
wound and wound coverage with autologous skin graft. For
grafting to be successful, the wound bed must be prepared
with well-vascularized tissue. Often, a clinically reliable
gauge of the viability of this tissue is bleeding during debri­
dement. As a result, much blood is lost during debridement,
despite the wound eschar being devoid of vascularized tissue.
Surgical blood loss has been estimated and measured in a
variety of ways,32–37 but can most simply and reliably be
reported based on surgical and anesthesia team estimates.38
In addition, owing to blood type and cross-matching
expenses, and overestimation of operative transfusion
needs,39 a preoperative estimate of 1.78 units of pRBCs per
1000 cm2 of burn wound excised is the best use of blood
bank resources.40
Although acute surgical blood loss is obvious and most
prominent during the treatment phase of burn injury, burn
patients also suffer a prolonged anemia of critical illness
during their recovery. The anemia of critical illness is the
inability of red blood cell production to meet red blood cell
demand and losses during a critical illness.41 Over 50% of
all transfusions during a burn patient’s hospital course may
be due to the anemia of critical illness.42 It has been equated
to an acute form of the anemia of chronic disease.43,44 The
etiology of the anemia of critical illness is multifactorial,
with blood loss from iatrogenic factors such as phlebotomy
and dressing changes,45,46 or erythropoiesis stunted by nutri­
tional deficiencies,47 and bone marrow dysfunction. Specifi­
cally, bone marrow dysfunction leading to dampened
erythropoiesis has been explored in autopsy studies and in
the mouse model of burn injury and in vitro. In an autopsy
study of patients who died from either myocardial infarc­
tion, sepsis or burns, the bone marrow of burn patients
contained significantly fewer erythroblasts than that in the
other groups.48 In the mouse model, both previous work
from Wallner and recent work in our laboratory have dem­
onstrated a shift in hematopoietic lineage commitment in
the bone marrow away from erythroid cell formation at the
expense of myeloid cell formation.49–51 Although Wallner’s
work helped to establish this phenomenon, hierarchical
models of hematopoiesis and the simple and reliable use of
flow cytometry to identify rare populations of cells (as
opposed to histologic and morphologic examination) have
allowed us to track the source of these changes from modi­
fications in HSCs with concomitant shifts in myeloid, eryth­
roid, and lymphoid progenitor groups, as mentioned earlier.

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23
280
innovative surgical and patient care techniques should help
to reduce overall transfusion rates further.
White blood cells
The primary effectors of host defense are the main popula­
tions of leukocytes, lymphocytes, NK cells, polymorphonu­
clear cells (PMN), and monocytes/macrophages. A balanced
activation of these cells is important for robust host defense.
Inappropriate activation of these leukocytes, especially the
PMN and macrophages, can lead to tissue destruction and
systemic inflammation, with dire consequences for the burn
patient. Overactivation of PMN and macrophages has been
implicated in the development of adult respiratory distress
syndrome (ARDS) and multiple organ failure.97–104
Early post-burn period
In the first 24–48 hours following burn, a leukocytosis, and
more specifically a granulocytosis, is generally observed that
is dependent on the size of the burn wound, with larger
burns giving rise to a greater degree of leukocytosis.105 The
initial increase in the white blood cell count (WBC) is attrib­
utable to three major factors: the acute plasma volume loss
due to the burn, demargination of mature neutrophils from
peripheral blood vessels, and the rapid release of bone
marrow reserves. Bone marrow myeloid progenitors from
post-burn day 1 mice have an altered phenotype compared
to controls, reflecting the more rapid maturation needed to
replenish reserves.106 Following this initial period of leuko­
cytosis burn patients frequently develop leukopenia, which
is related to trauma-induced failure of bone marrow hemat­
opoiesis.107 Leukopenia is also frequently seen in burn
patients whose wounds are treated with silver sulfadiazine,
a common topical antimicrobial agent.108 The severity of the
leukopenia that develops from drug toxicity is directly pro­
portional to the amount of agent that is applied to the
wound, and thus indirectly to the size of the burn wound
itself. The mechanism underlying this drug-induced leuko­
penia is yet to be elucidated, though direct bone marrow and
cellular toxicity may play a role. In general, leukopenia is
self-limiting and does not require discontinuation of silver
sulfadiazine treatment.
Leukopenia and granulocytopenia often persist in patients
when severe bacterial infection is superimposed on burn
injuries, especially those with Gram-negative sepsis.109–111 In
the early 1970s, Newsome and Eurenius demonstrated in
their rat model of thermal injury that the initial granulocy­
tosis was due to demargination of PMN from the blood
vessels and through accelerated release of bone marrow
stores.112 This granulocytosis, however, is transient, and is
followed by a robust bone marrow response to replenish
granulocyte stores.113,114 If the burn injury is complicated
by sepsis, granulocytopenia persists.115,116 Granulocytopenia
under these conditions appears to be due to bone marrow
failure.114,115,117,118 McEuen demonstrated a significant inhibi­
tion of granulocyte colony-forming units in the bone marrow
of burn septic rats.117 In addition, serum from septic burn-
injured animals retarded the granulocyte colony formation
when added to bone marrow cells from normal non-septic
animals.114 In septic animals and in burn patients with sepsis,
loss without compromising graft adherence.80–83 The combi­
nation of all three techniques (epinephrine tumescence,
tourniquets, and thrombin-soaked pads) can reduce intra­
operative transfusion from 3.3 to 0.1 units per operative
case, with 96% graft take33 and total units transfused from
15.7 to 7.9 units per patient.79
Recombinant human EPO helps to augment erythropoi­
esis in patients with chronic anemia (end-stage renal disease,
HIV with antiretroviral use, non-myeloid malignancies with
chemotherapy), reducing transfusion rates and improving
quality of life. To reduce transfusion rates and correct the
anemia of critical illness, multiple trials have explored rhEPO
use in the critically ill, including burn patients. Unfortu­
nately, both large clinical trials and meta-analyses of criti­
cally ill medical, surgical, and trauma patients show no
significant reduction in transfusion rates with rhEPO use.84,85
Two studies of rhEPO have been performed in burn patients
with no significant increase in hematocrit percentage or
decrease in transfusion rates.86,87 Critically ill patients may
possess a resistance to erythropoietin,88 which may be a func­
tion of antierythropoietin antibodies,89 or a relative reduc­
tion in erythropoietic response due to less EPO-responsive
erythroid precursors secondary to burn-induced dampened
erythropoiesis. Regardless of the cause, given the cost of
rhEPO and the lack of transfusion reduction, rhEPO is not
indicated for use in burn patients.
Ultimately, anemia is most easily corrected by the transfu­
sion of pRBCs. Burn patients, as a result of both acute blood
loss anemia and the anemia of critical illness, require a con­
siderable number of transfusions during their hospital
course. Transfusion rates increase with the size of the
burn.39,90,91 In a large study of transfusion trends in burn
patients, those with ≥ 20% TBSA required 13.7 ± 1.1 units,
whereas those with ≥50% TBSA required >30 units of
pRBCs.90 Although pRBC transfusion rapidly and reliably
corrects anemia, blood transfusion is associated with a con­
siderable number of consequences. The direct transmission
of hepatitis B, hepatitis C and HIV are well-known conse­
quences of transfusion, but their transmission rate has sig­
nificantly decreased with better screening methods.92,93 More
importantly, pRBC transfusion is associated with immuno­
modulation, including increased infectious morbidity,94
with a 13% increase in infections per unit of blood trans­
fused.90 Other significant consequences include transfusion-
related acute lung injury (TRALI), which is difficult to
diagnose in burn patients as simultaneous lung injury due
to resuscitation or inhalation injury may also contribute to
the diagnostic criteria for TRALI;95 and ABO incompatibility,
which can be rapidly fatal.96 As mentioned earlier, the imple­
mentation of restrictive transfusion strategies in which
pRBCs are transfused only for hemodynamic instability or
at lower, but still safe, hemoglobin concentrations, have
reduced overall transfusion rates while reducing infection
rates and providing cost and survival benefits.30,31
Anemia is common in burn patients, with greater transfu­
sion requirements for greater percent TBSA burned. Both
operative techniques (epinephrine tumescence, tourniquets
and thrombin-soaked pads) and transfusion restriction have
reduced overall transfusion rates. Other strategies for reduc­
ing transfusion rates, including rhEPO, have not proved
effective. More research into the molecular and cellular
mechanisms of burn-induced dampened erythropoiesis and

Hematologic and hematopoietic response to burn injury
281
assays reveal that despite the initial activation of T cells, they
were unable to respond to mitogenic and/or antigenic stimu­
lation. The addition of IL-2 fails to reverse T-cell anergy and
fails to relieve the suppression of IL-2R.150 In addition,
thermal injury triggers the apoptotic pathway in T cells.151,152
The exact mechanisms that initiate T-lymphocyte apoptosis
are still unclear. However, Fas ligand-, TNFα-, and IL-2-
mediated pathways have been implicated in T-lymphocyte
cell death.153,154 Lastly, macrophage activation products such
as PGE2 and transforming growth factor-β (TGFβ) can also
contribute to T-cell suppression.
B lymphocytes also undergo functional changes with a
profound reduction in immunoglobulin levels following
thermal injury. All classes of immunoglobulin are reduced,
but IgG levels display the greatest reduction, with concentra­
tions reaching as low as 300–400% mg/dL.155–158 This drop
in immunoglobulin is rapid and early, and is attributed to
plasma leakage, increased protein turnover, and decreased
IgG synthesis by the B cells. The initial deficit in immu­
noglobulins is slowly replenished to near normal levels
within 2 weeks.143 Major histocompatibility complex (MHC)
glycoproteins are reduced after thermal injury. Non-specific
B-cell activation by burn toxins and antigen-dependent
mechanisms, activation by phagocytosis of non-specific
antigen, may inhibit their ability to form antigen–MHC
complexes.159 Additionally, the display of self-antigens by
the B lymphocytes could contribute to antigen-dependent
cell death in T lymphocytes and T-cell anergy.141,143 Previous
work has shown that CD23 expression on activated B cells
is abrogated in response to thermal injury.160 IL-7 levels rise
during the first week after burn and could account for the
decreased proliferative capacity of mature B lymphocytes.
Taken together, these data indicate that the functional altera­
tions in B cells induced by thermal injury could further
exacerbate the immune suppression in these high-risk
patients.
As a whole, these changes in immune function are clini­
cally significant, as burn patients have an increased suscep­
tibility to nosocomial infections that increases the risk of
septic complications, multiorgan failure and mortality.
Unfortunately, there are no therapeutic modalities that can
reverse this immune dysfunction. As a result, the mainstay
of treatment remains the same as for any surgical or critically
ill patient: sterile technique, appropriate antibiotic use and
source control.
Megakaryocytes and disorders
of coagulation
The megakaryocytic lineage stems from MEPs, which are
derived from CMPs. Megakaryocytopoiesis leads, ultimately,
to the formation of platelets. Once megakaryocyte progeni­
tors proliferate and differentiate, mature megakaryocytes
produce platelets from cytoplasmic fragmentation.161 Cyto­
plasmic fragmentation results in the formation of proplate­
lets through regulation by the transcription factor NF-E2 that
occurs in the bloodstream. Approximately 1 × 1011 platelets
are produced daily.161 Platelets function to maintain hemo­
stasis through thrombus formation at sites of injury. Platelet
dysfunction occurs due to diminished platelet supply
(thrombocytopenia), inability to adhere to damaged tissue
the observed granulocytopenia is probably not due to lack
of available colony-stimulating factor.
Myeloid cells
In addition to alterations in the kinetics of production and
maturation, PMNs exhibit qualitative functional changes
after burn injury in both animals and humans.119–122 Some
of the documented functional changes include depressed
chemotaxis, phagocytosis, and intracellular killing.123–130 For
example, isolated neutrophils of burn patients were shown
to be defective in intracellular killing of Pseudomonas aerugi­
nosa, and the impairment in phagocytosis and intracellular
killing are further exacerbated with sepsis.131,132 These altera­
tions in the production and function of PMN provide a
framework for understanding the contributing factors in the
depressed immune status of severely burned patients.
Monocyte/macrophage function is also altered with severe
burns, but unlike PMNs, where neutropenia is common, in
severe burns and sepsis monocyte counts tend to increase
in both animals and humans.50,109,133 Studies demonstrate
marked monocytosis, with a dramatic increase (3–5-fold)
associated with sepsis.133,134 The importance of the burn-
induced monocytosis is emphasized by the observation that
attenuation of monocytosis as well as blunted macrophage
activation results in improved survival.135 Miller-Grazziano
and Faist demonstrated that after trauma, including burns,
monocytes/macrophages could be broken down into subsets
that were either hyper- or hyporeactive.136,137 These cells may
develop their phenotypic differences as a result of altered
monocytopoiesis within the bone marrow itself, or as a
result of local cytokine environments in the peripheral
tissues. Ogle et al. have demonstrated that bone marrow-
derived macrophages from thermally injured animals
produce increased amounts of TNFα, IL-1, and PGE2 com­
pared to macrophages from non-injured animals, suggesting
that thermal injury can stimulate the development of func­
tionally different monocytes within the bone marrow.138,139
Lymphoid cells
Patients with severe burns often suffer from suppressed cell-
mediated immunity owing to impairments in T-cell func­
tion.140,141 Impairment in cell-mediated immunity has been
implied by observations of delay in skin allograft rejection,
suppression of the graft-versus-host response, and skin
hypersensitivity reactions in burn patients.142–144 The various
alterations that have been reported include an overall sup­
pression of circulating T lymphocytes, decreased mitogenesis
in response to mitogens, reduced response to antigenic stim­
ulation or activation, and redistribution of T lymphocytes in
peripheral blood and tissue compartments.141,145–147 T lym­
phocytes are divided into T-helper (Th) and T-suppressor
populations based on expression of lymphokine profiles,
cell surface receptors, and ability to affect the function of NK
cells, T-cytotoxic, and B lymphocytes. In recent years strong
evidence has emerged to support the hypothesis that burn
injury-induced immunosuppression is partly mediated by a
shift in lymphocyte subpopulations from Th to T-suppressor
subtypes.140,142,143 Part of the initial response to a significant
burn is the activation of Th cells as assayed by IL-2R, HLA-2R,
and transferrin receptor markers.148,149 In vitro functional

Total Burn Care
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282
aware of the possibility of spurious platelet counts in the
presence of intravascular hemolysis.
Typically, changes in coagulation are transient and resolve
with resuscitation and resolution of the acute-phase response
to injury.168 In some cases significant alterations in the con­
centrations of coagulation proteins following thermal injury
may persist due to the severity of the burn, sepsis, or the
continued inflammatory state during a critical illness. Nor­
mally, the interplay among antithrombotic, prothrombotic
cellular interactions, and fibrinolytic processes within the
vasculature intricately controls the homeostatic regulation of
coagulation. Under steady-state physiologic conditions, the
fluidity of the blood is maintained by morphological integ­
rity of erythrocytes and the endothelial cells lining the blood
vessels.173 Normal levels of prothrombotic and antithrom­
botic factors, which are well regulated and remain for the
most part in their quiescent state, also help maintain
the homeostatic balance. In burn patients, however, both
the thrombotic and the fibrinolytic pathways are triggered in
direct proportion to the extent of the injury.166,174,175 During
the early resuscitation phase of a burn injury there is a
general reduction in the levels of coagulation proteins.166
Dilutional effects of volume administration during this
period and the loss of plasma proteins to the interstitium
could partially explain the decrease in plasma concentra­
tions of many coagulation proteins. Clinically significant
coagulopathic complications are uncommon. For example,
clinically significant DIC occurs in only 0.09% of burn
patients.176 However, the development of a coagulopathy,
especially DIC, is associated with a poor outcome.177,178
Unexpected spontaneous aggregation of platelets in the early
period following a burn injury may be due to hyperfibrino­
genemia and the interaction between fibrinogen and plate­
lets179 and can lead to the accumulation of thrombi in the
microcirculation, and may contribute to the development of
end-organ failure and death.167,170,180 Elevated levels of fibrin­
ogen are often present immediately following burn injury
owing to the shift in hepatic protein synthesis to acute-phase
proteins, including complement, interleukins, etc. in addi­
tion to fibrinogen.
Owing to the increase in these proteins and their conse­
quences, a significant number of studies have looked at dif­
ferent treatments aimed at offsetting this hypercoagulable
state or replacing depleted elements of the natural antico­
agulant proteins. The use of drotrecogin-α/human recom­
binant protein C181 and antithrombin infusions175,182,183 has
been studied and reported to be safe and beneficial. Anti­
thrombin III (ATIII) is a serine protease inhibitor that
regulates hemostasis and has been shown to have
anti-inflammatory properties.184 ATIII is depleted after
burn injuries, as both coagulation and fibrinolysis are
activated simultaneously.183 Administration of exogenous
antithrombin III to burn patients has been shown to be
beneficial in reversing thrombogenicity and reducing mor­
tality, and animal models have suggested a role for this agent
in attenuating pulmonary inflammation.174,175,183,184 Still, the
indication for their use has not been established in the burn
population.
Thrombus formation may also be due to decreases in the
anticoagulant proteins antithrombin, protein C, and protein
S.166 When anticoagulant proteins, including antithrombin,
do not return to normal levels, patients may have a longer
and form clots, or when thrombi are produced unnecessar­
ily. Dysregulated coagulation occurs through altered platelet
maturation and function, changes in the proteins of the
coagulation cascade, and imbalances in the deposition and
dissolution of peripheral clots. Because platelets and coagu­
lation disorders are interrelated, pathologic processes associ­
ated with both will be discussed in this section.
Platelets
Thrombocytopenia requiring platelet transfusion is rare in
burn patients. Often, platelet counts and function are stable
unless there is an infectious or septic event. In that case, burn
patients should be managed similarly to any critically ill
patient with sepsis. In patients with ongoing and hemody­
namically significant oozing from wound and donor sites in
addition to coagulopathy, the administration of platelets
and recombinant factor VIIa has been shown, in two case
reports, to significantly improve hemostasis.162,163
The transfusion of platelets is not without complications.
Platelets are transfused in an ABO-compatible fashion and
immediate transfusion reactions are rare. However, platelets
are stored at room temperature, allowing for higher rates of
bacterial contamination than other blood products. Bacterial
contamination of platelets occurs in 1 : 1000–1 : 3000 units,
with one-sixth of these episodes resulting in a septic event.164
In a study of blood bank use by a burn unit, 15% of all
admitted patients received platelets in some combination
with either pRBCs or FFP.39 So, although platelet transfusion
is not common in burn patients, it is necessary to limit its
use, given the significant infectious consequences.
Disorders of coagulation
Disorders of coagulation often occur early after the burn
injury. Burn patients may suffer thrombocytopenia,
disseminated intravascular coagulation (DIC), or other
coagulopathies.165–167 A marked reduction in circulating
platelet levels during the acute phase of burn resuscitation
is primarily due to the consumption of platelets during the
formation of systemic microthrombi.168,169 Although local
microthrombus formation at the site of injury helps main­
tain the integrity of the microvasculature surrounding the
burn wound, generalized systemic microthrombus forma­
tion leads to reduced end-organ perfusion and finally mul­
tiple organ failure.168,170 In addition, dilutional effects of
extensive fluid resuscitation may also contribute to a reduc­
tion in platelet counts. After the initial resuscitation, the
thrombocytopenia that is observed during the first week after
the thermal injury is believed to be due to the diminished
half-lives of platelets in circulation.169 The thrombocyto­
penic phase is followed during the 2–3 weeks after the initial
injury by a period of increased platelet production or bone
marrow megakaryocytopoiesis that results in either a return
to normal levels or to overt thrombocytosis.171 However, in
some burn patients thrombocytopenia persists and is often
considered a poor prognostic indicator.172 Among patients
with critical burn injuries who develop intravascular hemo­
lysis, an apparent thrombocytosis may be observed which
could be due to inadvertent counting of fragmented red cells
and red cell microvesicles as platelets in an automated
counter.171 Therefore, in severe burns the clinician should be

Hematologic and hematopoietic response to burn injury
283
hospital stay and worse mortality.185 During recovery from
the burn injury, coagulopathies are less related to the burn
injury and more likely due to critical care issues, including
sepsis. In fact, there is rapid recovery of coagulation factors
in the postoperative period of burn wound management,
making frequent excision and grafting safe from a hemo­
static standpoint.186
Fibrinolytic pathways are activated in burn injuries owing
to the increased levels of tissue plasminogen activator
protein.166 Consumption of antithrombotic proteins by acti­
vation of fibrinolytic activities predisposes burn patients to
thrombosis. Contributing to the thrombotic state in severely
injured burn patients are the release of tissue phospholipids
and tissue factor, activation of complement cascade, tissue
ischemia, and the presence of sepsis.166,168,172,187 As a result,
patients are at increased risk for developing disseminated
intravascular coagulation (DIC). DIC is characterized by acti­
vation of coagulation, intravascular fibrin formation and
vascular thrombosis, resulting in organ hypoperfusion and
failure. The consumption of coagulation and anticoagula­
tion factors leads to small vessel thrombosis and simultan­
eous uncontrolled bleeding.170 Because of the high morbidity
and mortality associated with episodes of DIC, a high index
of suspicion needs to be maintained in this patient popula­
tion when sepsis complicates the clinical course. Signs of
impending DIC may include refractory shock out of propor­
tion to apparent blood loss, bleeding from venepuncture
and catheter sites, and urinary and gastrointestinal bleeding.
Standard laboratory values in patients with suspected DIC
include prolonged prothrombin time (PT) and activated
partial thromboplastin time (APTT), increased levels of
fibrinogen degradation products, decreased levels of anti­
thrombin III, and decreased platelet counts and fibrinogen
levels. Vigilance must be maintained for other thrombo­
embolic complications in this population, such as deep
vein thrombosis and pulmonary embolism. The treatment
modalities recommended for patients who develop DIC are
primarily supportive and geared toward maintaining hemo­
static parameters with replacement therapy. In addition,
patients receiving broad-spectrum antibiotic therapy or
showing signs of hepatic failure should be carefully moni­
tored for vitamin K-dependent coagulopathy. This must be
corrected with vitamin K replacement, along with the neces­
sary coagulation factor component therapy. Future efforts in
the treatment of coagulopathies will focus on re-establishing
the balance of coagulation and fibrinolysis.170
Growth factors and transcription factors
As described above, the hematopoietic hierarchy and lineage
commitment patterns are a complex but well-preserved pro­
cesses. The maintenance of stem and progenitor populations
and the expansion of terminally differentiated cells are under
the control of the growth factors and cytokines present in
the bone marrow. Shifts in the concentration of growth
factors and cytokines due to illness and injury allow hemat­
opoietic lineage commitment patterns to change, resulting
in increases or decreases in terminally differentiated cell
populations (Table 23.1). Control of cell fate is most likely
due to growth factor- and cytokine-induced transcription
factors, as expression and blocking of these transcription
Table 23.1  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 DC 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
factors control lineage commitment in the stem and pro­
genitor cell populations.
Stem and progenitor cell growth factors
Hematopoietic stem cell maintenance and expansion are
controlled by growth factors/cytokines both unique to these
cells and also having roles in other hematopoietic and

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284
studies had small sample sizes, used unreliable urine bio­
assays, and could not overwhelmingly support an appropri­
ate EPO response.204,205 Later comparison of serum bioassays
and radioimmunoassays showed no correlation between the
two methods, and their results suggested significant differ­
ences between the sensitivities of these tests.206,207 More
recent, larger studies using serum radioimmunoassays dem­
onstrate an increase in EPO in response to decreased hemo­
globin concentrations but an inconsistent erythropoietic
response to this EPO increase.91,208
Whereas only erythroid-committed cells in the bone
marrow possess the EPO receptor, a related EPO receptor
and a response to EPO have been identified in non-
hematopoietic tissues, including neurons, glial cells, retina,
heart, skeletal muscle, kidney, ovary, uterus, testis and
endothelial cells.202,209–211 As a result, the ability of EPO to
reduce apoptosis and prevent damage to these tissues has
been explored. In particular, rhEPO can reduce apoptosis
after cerebral ischemia,212 protect the myocardium and
promote remodeling following myocardial ischemia, allow­
ing for restoration of cardiac function.213,214 and protect
against renal injury from ischemia, improving renal func­
tion.215 Despite these findings and the expected erythropoi­
etic response to rhEPO, its use in burn patients has not been
substantiated.
Myeloid growth factors
G-CSF
Granulocyte colony-stimulating factor (G-CSF) is the primary
growth factor responsible for the proliferation and differen­
tiation of bone marrow granulocyte progenitors into mature
granulocytes.216,217 G-CSF is produced by monocytes, fibrob­
lasts and endothelial cells which were stimulated to produce
G-CSF in response to inflammatory cytokines (TNFα, IL-6,
IL-1).202 Apart from stimulating the bone marrow produc­
tion of neutrophils, in the periphery, G-CSF augments the
bactericidal activity of neutrophils by priming the oxidative
burst, increases neutrophil half-life by preventing apoptosis,
and downregulates the overall inflammatory response by
reducing the cytokine production of monocytes and macro­
phages.218 An animal model of burn and burn sepsis
demonstrated the beneficial effects of G-CSF on killing of
translocated bacteria,219 regulating the proinflammatory
response to injury,220 improvement in neutrophil chemo­
taxis,221 and improved survival in combination with anti­
biotic therapy.131,222
At baseline, there are very low levels of G-CSF present in
the blood. However, following an inflammatory or infec­
tious process, G-CSF levels increase greatly. Following a burn
injury, G-CSF levels in the blood are initially increased and
then gradually decline to baseline 3–4 weeks later.53,223,224
The initial increase in G-CSF may prime the neutrophilic
component of the immune response for future bacterial
insult. However, the immune dysfunction seen following a
burn injury or burn sepsis may be related to hyporesponsive­
ness of bone marrow progenitors and peripheral neutrophils
to G-CSF.225
Administration of recombinant G-CSF to burn-septic
animals prior to the initiation of septic insult has been
shown to improve the survival rate of burn-septic mice.221,222,226
non-hematopoietic processes. For example, stem cell factor/
steel factor, produced by fibroblasts and endothelial cells,188
is a growth factor essential for hematopoietic stem cell self-
renewal and differentiation by activation of the c-kit (CD117)
receptor.189 Mutations or deletions of stem cell factor or the
c-kit receptor in embryogenesis can lead to in utero death
from impaired hematopoiesis.190,191 Additionally, stem cell
factor plays a role in melanocyte development,192 sperma­
togenesis193 and gut motility.189,194 Other growth factors that
play a dual role are thrombopoietin, which is essential to
megakaryocyte development and granulocyte–macrophage
colony-stimulating factor, and IL-3 which contributes to
both myeloid and erythroid cell proliferation. IL-6, which is
significantly increased immediately following burn and in a
variety of inflammatory states, is a proinflammatory cytokine
that also plays a role in the expansion of hematopoietic
stem cells.
Over 30 growth factors may play a role in stem and pro­
genitor cell maintenance and expansion.195 Of these, Flt-3
ligand (Fms-like tyrosine kinase-3/ flk-2 (fetal liver kinase
2)) plays an important role in stem and progenitor cell
expansion. Flt-3 ligand activates the Flt-3 tyrosine kinase
receptor/CD135. In the hematopoietic stem cell compart­
ment, Flt-3 is highly expressed on MPPs and typically absent
on LT-HSCs and ST-HSCs. Theoretically, elevated levels of
Flt-3 ligand should contribute to MPP expansion in response
to inflammation or infection. However, Flt-3 ligand levels
have not been shown to increase following burn injury.196
Further study into Flt-3 ligand levels during physiologic
stress may demonstrate a fundamental role in hematopoietic
expansion and response to injury. Like other growth factors,
Flt-3 ligand also influences myeloid differentiation197 and
early lymphoid development,198 and enhances NK and den­
dritic cell functions.199
Erythroid growth factors
The erythroid cell line is maintained and can be stimulated
for increased proliferation by erythropoietin (EPO). EPO
stimulates only cells already committed to the erythroid
lineage and does not induce other lineage-committed pro­
genitors or terminally differentiated cells to form erythroid
cells.200 The increase in erythroid cell formation is due
mainly to the prevention of apoptosis, improved erythroid
cell survival, decreased cell-cycle inhibition, and the promo­
tion of cell line expansion.201 EPO is produced in an induc­
ible fashion by the kidney and constitutively by the liver202
in a steady-state fashion, but its production can be signifi­
cantly increased in response to anemia or hypoxemia.201,202
Juxtatubular interstitial cells in the kidney sense oxygen
levels. Low oxygen levels induce the hydroxylation of
hypoxia-inducible factor 1 (HIF-1α), the transcription factor
responsible for EPO production.202,203
Owing to the anemia associated with burns, EPO levels
should be increased during the treatment and recovery from
the burn injury. However, in contrast to the expected EPO
response to anemia, there is limited support for an appropri­
ate increase in EPO following burn. These contradictory
results may stem from differences in the assay used to
measure EPO (urine vs serum; bioassay vs radioimmu­
noassay) and outcome measures of EPO response (hemo­
globin, reticulocyte count, transfusion rates, etc.). Earlier

Hematologic and hematopoietic response to burn injury
285
did not provide a survival benefit.246 Although the inactiva­
tion of GM-CSF or GM-CSF receptor genes in mice did not
alter the number of granulocytes and monocytes, these
animals exhibited significant dysfunction of alveolar macro­
phages, resulting in accumulation of surfactant and pro­
teinaceous material. Furthermore, GM-CSF-deficient mice
are very susceptible to pulmonary group B streptococcal
infection.243 In burn patients, administration of GM-CSF
resulted in a 50% increase in mean neutrophil count.
However, in GM-CSF-treated patients enhanced oxidative
function of PMN abated over a 3-week period but remained
undiminished in untreated patients.247 In a multicenter
clinical trial, administration of GM-CSF in hydrogel to deep
second-degree burn wounds was shown both to be safe and
to accelerate wound healing.248 However, this trial has not
been confirmed by other similar studies. Despite its recog­
nized role in modulating innate immune cells and their
function, the role of GM-CSF in burn care remains
inconclusive.
Lymphoid growth factors
Several growth factors/cytokines contribute to the formation
of lymphoid cells, the most prominent and best studied
being IL-7. The IL-7 receptor is unique to lymphoid cells. As
a result, IL-7 is the cytokine/growth factor that influences the
expansion of this cell line. IL-7 receptor engagement is essen­
tial not only for lymphoid cell proliferation and survival but
also for hematopoietic stem cell differentiation into the lym­
phoid lineage. The IL-7 receptor enhances lymphoid cell
survival through maintenance of Bcl-2.249 Bone marrow
stromal cells and the thymus predominantly produce IL-7.
T cells are unique in that their maturation takes place in the
thymus, as opposed to the bone marrow, and they undergo
a process of positive and negative selection which is depend­
ent on both IL-7 activation and expression of Notch1, a
transcription factor.250 Alterations in IL-7 production, in
addition to that of other cytokines, can negatively affect
survival after inhalation injury.251 Additional growth factors/
cytokines that contribute to lymphopoiesis include IL-2,
IL-15, and IL-23.
Megakaryocyte growth factors
Production of megakaryocytes and platelets is regulated by
thrombopoietin. Similar to erythropoietin, thrombopoietin
enhances megakaryocyte progenitor proliferation by ampli­
fying cell-cycle regulators and preventing apoptosis,202 and is
the only growth factor necessary for proliferation of meg­
akaryocytes and their progenitors.252 Unlike erythropoietin,
thrombopoietin has a synergistic role with other growth
factors and cytokines in the maintenance and proliferation
of HSCs,253 and can be used in their expansion.254 Throm­
bopoietin stimulates platelet release from the bone marrow
and in the periphery; thrombopoietin can upregulate plate­
let function and aggregation.255 Thrombopoietin is produced
in the liver, kidney, skeletal muscle and stromal cells of the
bone marrow.202,256 Thrombopoietin production may be
increased in response to increased IL-6 production.257 Given
the elevated IL-6 levels present following burn injury, IL-6-
induced thrombopoietin release may be responsible for
the thrombocytosis often seen immediately following burn
However, administration of G-CSF 24 hours after the onset
of septic insult had little effect on their survival.227,228 Despite
the potential benefit of exogenous G-CSF administration on
the inflammatory and infectious response during burn
injury, the use of recombinant human G-CSF (rhG-CSF; Fil­
gastrim) is not indicated in the treatment of burn patients.
RhG-CSF use is indicated for use in patients receiving myelo­
suppressive chemotherapy; with acute myeloid leukemia
receiving induction or consolidation therapy; recipients of
bone marrow transplantation undergoing peripheral blood
progenitor cell collection and therapy; and with severe
chronic neutropenia to stimulate neutrophil production
and egress from the bone marrow.229 Given the multitude of
changes in both progenitor and terminally differentiated cell
formation in the bone marrow, it is unlikely that the admin­
istration of one exogenous growth factor will significantly
affect the outcome of burn patients.
CSF-1
CSF-1 (M-CSF) is a pre-eminent growth factor for the dif­
ferentiation, proliferation and survival of monocytes and
macrophages.230 It also stimulates chemotaxis, cytokine and
superoxide production in macrophages.231,232 Hume et al.
first demonstrated that administration of CSF-1 to mice
resulted in monocytosis and an increase in peritoneal and
tissue macrophages.233 In response to burn injury, CSF-1-
responsive GM-CFU are increased in the bone marrow,
leading to enhanced monocytopoiesis.234 The underpinning
of this monocytopoiesis following burn injury has been
shown to be the result of increased expression of CSF-1
receptors in EMMP-20+ bone marrow compartment, which
comprises monoblasts and promonocytes.234 In addition,
burn injury and sepsis also change the inflammatory cytokine
phenotype of CFU-GM-derived macrophages in that they
result mainly in hyporesponsive macrophages.235,236 Similar
monocyte hyporesponsiveness has also been demonstrated
in trauma patients.137 These findings provide a plausible
mechanism and a role for CSF-1 and its cognate receptor
interactions in monocyte/macrophage biology after burn
injury.
GM-CSF
Granulocyte–monocyte colony-stimulating factor (GM-CSF)
regulates the proliferation and differentiation of hematopoi­
etic progenitor cells, as well as modulating the function of
mature leukocytes.237 GM-CSF has been shown to enhance
the antigen-presenting capacity of macrophages and den­
dritic cells, to increase complement-mediated phagocytosis,
and to augment bacterial killing by innate immune cells.238,239
Similarly, CSF-1 also stimulates chemotaxis of leuko­
cytes.240,241 GM-CSF is produced by a variety of cells, includ­
ing macrophages, B lymphocytes, pulmonary epithelial cells,
neutrophils, and stromal cells.242,243 In response to burn
injury bone marrow GM progenitors respond by producing
more GM-CFU colonies.234 Administration of GM-CSF prior
to burn injury and Escherichia coli sepsis enhanced bacterial
clearance and survival of the mice.244 Similarly, GM-CSF
improved the survival of neonatal rats when administered
prophylactically prior to Staphylococcus aureus infection.245
However, GM-CSF administration after the onset of infection

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286
GATA family
The GATA transcription factors are related zinc-finger DNA-
binding proteins. These transcription activators bind to the
canonical GATA sequence motif found in the cis-regulatory
regions of many hematopoietic genes. The proteins have
differential expression patterns and activate a unique set of
target genes. GATA-1, GATA-2, and GATA-3 proteins play
pivotal roles in hematopoiesis. GATA-1 is necessary for the
development of erythroid cells and megakaryocytes261 and
erythroid survival via Bcl-XL expression.262 Mice lacking
GATA-1 proteins display normal hematopoiesis, except for
the erythroid lineage.103 GATA-1 is repressed in cells develop­
ing throughout the myeloid and lymphoid lineages.263 In
fact, interrelated complex regulation between GATA-1 and
other transcription factors, including PU.1, may control
passage through the myeloid lineage. Increased expression
of GATA-1 has been shown to negatively modulate PU.1
expression and thus suppress myeloid commitment.264,265
Since burn injury is commonly associated with a down­
regulation of erythropoiesis despite adequate levels of
endogenous erythropoietin, studies specifically designed to
correlate the strength of GATA-1 expression in progenitor
cells to the status of erythropoiesis will provide novel and
mechanistic information on the pathophysiology of anemia
in burn injury. GATA-1 expression is assisted in its regulatory
functions with additional cofactors, including Friend of
GATA-1 (FOG-1), which helps GATA-1 localize to specific
areas of chromatin.266 GATA-1 may also help to control a
switch from fetal to adult hemoglobin production. GATA-2
expression is more important at the top of the hematopoietic
hierarchy as it is involved in proliferation and self-renewal
of early hematopoietic stem cells. Mice engineered with a
homozygous deletion of the GATA-2 gene display severe
hematopoietic defects. GATA-2 knockout mice survive to
embryonic day 10–11, harbor a small number of red blood
cells at that stage, undergo anemic crisis, and eventually
die.267 In vitro clonogenic assays revealed a drastic reduction
in the number of erythroid progenitors and a substantial loss
of mature erythroid precursors. Lastly, mice lacking GATA-3
fail to develop normal fetal liver hematopoiesis, lack all
hematopoietic lineages, except the megakaryocytic cells, and
succumb to embryonic hemorrhage.268
PU.1
PU.1 encodes a member of the ets family of DNA-binding
proteins. It was originally cloned as a sequence-specific
DNA-binding protein that was found to be homologous to
the spi-1 oncogene.269 PU.1 can act as a tumor suppressor
with alterations in its expression associated with acute
myeloid leukemia.270,271 PU.1 possesses transcriptional acti­
vation potential that requires other co-activators for full
potency.272 PU.1 is expressed early in the hematopoietic hier­
archy including HSCs. PU.1 expression has been tracked
using a GFP reporter strain and is interestingly expressed in
both CLPs and CMPs. Those CMPs which become GMPs
are PU.1hi while those that branch to the MEP lineage are
PU.1lo.273 The expression of PU.1 in both early lymphoid and
myeloid lineages reflects its role in regulating the expression
of receptors for IL-7 (lymphoid)274 and GM-CSF, G-CSF, and
M-CSF (myeloid).275 Monocytes and granulocytes highly
express PU.1, whereas only B cells of the lymphoid lineage
injury.258 Elevated levels of thrombopoietin may be present
following burn injury.259 In burn patients, elevated throm­
bopoietin levels have been found to enhance platelet
activation,which
may
contribute
to
microthrombus
formation.259
Transcription factors
Whereas 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 modulations in
the rate of gene transcription, which are accomplished
through the binding of DNA-binding proteins or transcrip­
tion factors to specific regions on a gene.260 Transcription
factors are nuclear proteins that act as control points in
the conversion of a gene to a functional protein.260 As many
key proteins are turned over rapidly to meet the changing
needs of the tissues, a complex system of cell signaling archi­
tecture, with the final common pathway of gene transcrip­
tion, must exist to produce bioactive proteins on demand.
To exquisitely regulate the rate of protein synthesis, genes
need to be quickly transcribed into RNA within the nucleus,
transported to the cytoplasm, and proteins synthesized from
RNA templates. Because cells respond to several signals
simultaneously, and many ligand–cell interactions stimulate
similar proximal signals, tight control of transcriptional ini­
tiation 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 prolifera­
tion and differentiation program of hematopoiesis is
achieved through switching on and off specific sets of genes
in response to cell signals. As thermal injury and sepsis are
accompanied by hematologic and hematopoietic changes
that determine the overall pathophysiological response of
burn patients, it is reasonable to assume that transcriptional
regulation of hematopoietic developmental genes plays a
significant role. Much of our current knowledge of hemat­
opoietic transcription factors has come from diverse fields
such as hematology, oncology, immunology, mammalian
virology, and signal transduction. Many concepts have been
found by studying the molecular controls of leukemias, in
vitro cell clonal assays, and various hematopoietic cell lines.
Gene knock-out technology has also aided in ascertaining
the functional roles of characterized genes in hematopoiesis.
The relationship between these transcription factors is
complex, as they are not independent of one another but
demonstrate antagonism. In fact, the inability of one trans­
cription factor to suppress another 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 following severe trauma
and burn injury. Given the importance of these transcription
factors to cell fate and the significant shifts in lineage com­
mitment patterns, knowledge of these transcription factors
and their current role in hematopoiesis may help in provid­
ing a foundation for future reference.

Hematologic and hematopoietic response to burn injury
287
showed that C/EBPa is present in monocytes, eosinophils,
and neutrophils.293 Moreover, human myeloid precursors
and immature myeloid cell line, 32 DC13, express high levels
of C/EBPa that decrease upon G-CSF-induced differentia­
tion.294 C/EBPa was shown to possess a transcriptional activa­
tion domain involved in the upregulation of mRNA from
certain neutrophil genes such as G-CSF-R, lactoferrin, and
collagenase. C/EBPa gene knockout mice are deficient in
neutrophils and eosinophils, but harbor functional
lymphocytes and monocytes.295 Fetal liver cells formed
M-CSF- and GM-CSF-responsive colonies, but G-CSF-induced
colonies were not obtained. Therefore, these studies deter­
mined that C/EBPa is essential for neutrophil differentiation
but not for monocytic differentiation. Conversely, during
neutrophil differentiation of myeloid cell line, 32 DC13, C/
EBPb levels increase. Recently, data from the C/EBPb-deficient
mice revealed that hematopoiesis proceeds normally,
but defects in macrophage activation and decreases in B
lymphocytes are observed.296,297 Additionally, C/EBPe gene
knockout mice exhibited abnormal neutrophilic function
and deficiencies in certain key enzymes.298 Otherwise, the
mice appeared to have intact hematopoietic tissues. The pre­
ceding studies demonstrate the important regulatory func­
tion of the C/EBPs transcription factors in myelopoiesis.
c-Myc
The c-myc proto-oncogene is part of the bHLHLZ (basic
helix–loop–helix leucine zipper) family of transcription
factors.299 c-Myc binds to canonical CANNTG DNA motifs
located in many proliferative or cell cycle-regulated genes.300
c-Myc has three transcriptional activation domains in the
amino terminus and a carboxy terminal with sequence-
specific basic region and helix–loop–helix leucine zipper
domains that mediate protein–protein interactions. c-Myc
is required for cellular proliferation and its downregulation
is essential for differentiation of many cell types.301 Max is
another bHLHLZ protein partner of c-Myc, and this het­
erodimeric complex is essential for cognate DNA binding
and transactivation of target genes.302 Another set of genes
that belong to c-myc family are MAD, Mxi-1, Mxi-3, and Mxi-
4. The most important ones in hematopoiesis are MAD and
Mxi-1.303 MAD and Mxi-1 proteins can heterodimerize with
Max to form heterodimers that, unlike Myc–Max, can repress
transcription at the same cognate DNA sites bound by
c-Myc–Max heterodimers. Hence, within a given cell there is
a dynamic equilibrium of c-Myc–Max and MAD–Max com­
plexes that compete for the same binding sites, and the
predominant complex determines whether proliferation or
differentiation ensues.304 During in vitro and in vivo hemat­
opoietic differentiation, MAD/Mxi-1 levels increase, whereas
c-myc expression is downregulated.305 Recently, it was
reported that MAD-null mice have defects in myelopoiesis,
as demonstrated by delayed cell cycle exit during granulo­
cytic differentiation.306 In summary, c-Myc/MAD’s roles in
regulating the onset of proliferation versus differentiation
are crucial for hematopoietic development.
MafB
MafB is a basic leucine zipper transcription factor that influ­
ences myeloid differentiation.307 Recent work on MafB
demonstrates not only the interaction among transcription
express low levels of PU.1. T cells do not express PU.1, sug­
gesting that PU.1 expression may contribute to B- and T-cell
differentiation.276 Two different PU.1 knockout mice reveal
the absence of monocytes, B cells, and greatly reduced neu­
trophil production.277,278 Moreover, these neutrophils are
unable to express some markers of fully differentiated neu­
trophils.278,279 Embryonic stem cells from PU.1-deficient
mice can differentiate into immature myeloid progenitors
in the presence of IL-3 and G-CSF cytokines. Nevertheless,
exogenous PU.1 expression in the PU.1-deficient hemat­
opoietic progenitors restores myeloid differentiation. While
GATA-1 may inhibit PU.1 expression, PU.1 expression
can block erythropoiesis by antagonizing GATA-1 DNA
binding.280 Unique to other transcription factors, PU.1 is
essential both early at the hematopoietic stem and progeni­
tor cell stage and also later during more specific differentia­
tion of myeloid and lymphoid cells.
c-Myb
c-Myb proto-oncogene belongs to the basic helix–turn–helix
(bHTH) family of DNA-binding proteins.281 c-Myb contains
an LZ motif that mediates homotypic and heterotypic
protein interactions.282 Multiple serine residues are located
within the amino-terminal and carboxy-terminal regions of
c-Myb that affect its DNA-binding activity and negative regu­
latory domain.283–285 Studies have shown that c-myb expres­
sion is restricted to myeloid, erythroid, and immature
lymphoid cells.286–288 Collaborative data from c-myb knock­
out mice reveal the absence of all hematopoietic lineages,
except within the megakaryocytic compartment. c-myb
knockout mice exhibited normal yolk sac hematopoiesis,
whereas liver hematopoiesis was greatly compromised, and
these mice die in utero at E14–15.289 Detailed analysis of
hematopoietic lineages revealed that functional granulocytes
and monocytes were present, but they harbored a 10–20-fold
reduction in mature cells compared to normal mice. It is
hypothesized that c-Myb functions to control quantitative
effects rather than differentiation per se during hemato­
poiesis. It was also noted that c-Myb levels decrease during
differentiation of hematopoietic progenitors and enforced
c-Myb expression promotes proliferation and blocks hemat­
opoietic differentiation. Hence, c-Myb plays a critical role in
controlling proliferation of immature hematopoietic pro­
genitors, and its physiological downregulation is required
for commitment towards lineage-specific differentiation.
C/EBPs
CCAAT/enhancer-binding proteins (C/EBPs) are transcrip­
tion factors that bind to core cis-regulatory sequence of
CCAAT found in many regulated genes. C/EBPa was the origi­
nal transcription factor, described as a basic leucine zipper
(bLZ) DNA-binding protein in hepatocytes and adipocytes.290
Interestingly, the CEBP family of transcription factors, includ­
ing CEBPa, have been shown to be elevated following thermal
injury.291 Although their expression is implicated in the acute-
phase response, the role of CEBPs in the regulation of hemat­
opoiesis during thermal injury and sepsis is yet to be
delineated. Other members of this family include C/EBPb, C/
EBPd, C/EBPe, and GADD153/CHOP proteins. These C/EBPs
are able to homodimerize and heterodimerize with each
other via the leucine zipper regions.292 Expression studies

Total Burn Care
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288
utero.268 These mice exhibited a failure in blood formation
and their yolk sac contained no detectable blood elements
and lacked in vitro clonogenic potential. These results were
further confirmed by the inability of the tal-1/SCL knockout
embryonic stem (ES) cells to develop into any hematopoietic
lineages in culture.
This section should illustrate the complex interplay
between transcription factors in the control of hematopoi­
esis. For example, GATA-1 and PU.1 are antagonists, with
GATA-1 expression essential for erythroid development and
repression needed for myeloid development, whereas PU.1
is needed for hematopoietic stem cell, early progenitor and
myeloid differentiation; it blocks GATA-1 binding, prevent­
ing competing erythroid signals. Most likely, currently
unknown transcription factors or cofactors will be identified
that will add to the already multifaceted character of
hematopoiesis.
Conclusion
Hematopoietic derangements following burn injury are not
as visibly prominent as the burn itself or as easily quantified
as the hemodynamic and physiologic alterations. However,
the pronounced effects of a burn injury on hematopoietic
processes greatly affects patient morbidity and survival via
immunomodulation and anemia. Evolving knowledge of
the cellular and molecular mechanisms responsible for
burn-induced anemia and immunomodulation, including
hematopoietic lineage commitment shifts, the bone marrow
response to inflammatory cytokines and catecholamines,
fluctuations in growth factor production, and the expression
and repression of transcription factors, may at some point
lead to therapeutic modalities to improve the care and sur­
vival of burn patients.
Further reading
Iwasaki H, Akashi K. Myeloid lineage commitment from the
hematopoietic stem cell. Immunity. Jun 2007;26(6):726-740.
Metcalf D. The hemopoietic regulators—an embarrassment of riches.
Bioessays. Dec 1992;14(12):799-805.
Morrison SJ, Wandycz AM, Hemmati HD, et al. Identification of a
lineage of multipotent hematopoietic progenitors. Development.
May 1997;124(10):1929-1939.
Palmieri TL, Caruso DM, Foster KN, et al. Effect of blood transfusion
on outcome after major burn injury: a multicenter study. Crit Care
Med. Jun 2006;34(6):1602-1607.
Shivdasani RA, Orkin SH. The transcriptional control of
hematopoiesis. Blood. May 15 1996;87(10):4025-4039.
Wallner SF, Warren GH. The haematopoietic response to burning: an
autopsy study. Burns Incl Therm Inj. Oct 1985;12(1):22-27.
factors but also with growth factors, as MafB deficiency
increases M-CSF responsiveness leading to PU.1 expression,
altering the repopulation and differentiation characteristics
of the myeloid lineage.308 MafB is specifically expressed in
the myeloid lineage of the hematopoietic system and is an
essential and specific determinant of myeloid progenitor dif­
ferentiation into monocytes and macrophages.307 In addi­
tion, MafB represses ets-1 transactivation to inhibit erythroid
differentiation.309 Monocyte and myeloid dendritic cell (DC)
differentiations represent alternate developmental programs
in hematopoiesis. Following a burn injury and trauma, the
bone marrow hematopoietic paradigm shifts towards mono­
cytopoiesis. However, there is resistance to driving the dif­
ferentiation of monocytes/macrophages to myeloid DC in
both trauma and burn injury.310,311 Because MafB and PU.1
expression plays an essential role in monocyte differentia­
tion, GATA-1 1 regulates DC development, burn-induced
skewed myeloid development may be the result of uncoor­
dinated expression of MafB, and PU.1 as well as GATA-1
expression.312,313
Altered
hematopiesis
and
associated
immune cell dysregulation are transient and self-correcting
as the burn wounds are closed and the patient has recovered.
Therefore, it is reasonable to assume that burn-induced
microenvironmental changes precipitate or play a major role
in orchestrating the differential expression of hematopoietic
transcription factors and thus reorganize hematopoietic
developmental paradigm. The net result is the reduced
erythropoiesis, and increased monocyte development with
a concomitant DC developmental arrest. Teasing out
and delineating the interplay of the microenvironment
with hematopoiesis holds one of the keys to better patient
management in critical care.
tal-1/SCL
The tal-1/SCL gene encodes a bHLH (basic helix–loop–helix)
protein that was originally identified at the chromosomal
breakpoint in a human acute T-cell leukemia.314 tal-1/SCL is
a master gene required for development of hematopoietic
stem cells that eventually differentiate into lineage-specific
blood cells.268 Previous studies have revealed that the early
hematopoietic stem cells (CD34+/c-kit+/Sca+ cells) express
the tal-1/SCL gene.268 T-cell leukemia, which consists of a
clonal cell line with the potential to differentiate into
myeloid and lymphoid lineages, was shown to express tal-1/
SCL protein.268 In addition, mature erythrocytes, megakaryo­
cytes, mast cells, and endothelial cells also express tal-1/SCL.
These data indicate that the tal-1/SCL gene may play a
required role in a later stage of maturation of committed
progenitors. Homozygous tal-1/SCL gene knockout mice
provided definitive evidence for its role in hematopoiesis.
The homozygous tal-1/SCL gene deletion was lethal in
Access the complete reference list online at

Hematologic and hematopoietic response to burn injury
288.e1
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11416-11420.

Introduction
The physiological importance of the adrenal gland pertains
to the release of epinephrine and glucocorticoids in response
to cognitive stress, recognized as the ‘fight or flight’ response.
Such responses involving the hypothalamopituitary–adrenal
axis begin with the hypothalamic release of corticotrophin-
releasing hormone (CRH), which mediates the release of
adrenocorticotrophic hormone (ACTH) from the pituitary,
which in turn stimulates the synthesis and release of cortisol
from the adrenal cortex. Hypothalamic stimulation also
initiates the release of epinephrine from the adrenal
medulla, and that of the neurotransmitter norepinephrine
from adrenal medulla and the adrenergic nerve terminals.
The action of these hormones and neurotransmitters is
traditionally thought to serve in a compensatory manner,
facilitating heightened mental awareness along with meta­
bolic and cardiovascular activity that supports rapid increases
in muscular work.
Thermal injury, like other forms of trauma, as well as infec­
tious challenge, is a non-cognitive stimulus but also results
in an elevated hormone/neurotransmitter milieu similar in
magnitude to that of the cognitive ‘fight or flight’ response.1,2
However, there are important characteristics of the injury
response that contrast with the fight or flight response. These
include prolonged hormone/neurotransmitter elevation,
the absence of increased muscle work limiting metabolic
demand, and the presence of massive tissue injury. Addi­
tional hormone/neurotransmitter responses may also be
evoked by surgical debridement of burn wounds and skin
grafting procedures. The second surge of stress hormones
complicates the severe metabolic derangements and com­
promised immune capacity, which is characteristic of the
burn course during the initial 7–10 days following injury.
Cognitive and non-cognitive events that increase corticos­
teroid and catecholamine levels represent a stress response
that may or may not involve pathology. Traumatic injury,
however, clearly initiates a stress response, with a magnitude
proportional to the severity of injury. Under these condi­
tions, hormone/neurotransmitter release seems to promote
survival. Although such a benefit may be difficult to see in
human injury, experimental animal models have provided
some insights. Animals that lack stress hormones or suffer
from impaired release or by pharmacological block often die
of an otherwise survivable event. Similarly, overwhelming
traumatic injury in man may result in stress hormone
release that is detrimental to survival. Whereas this may also
be difficult to document in burn patients, animal studies
have demonstrated that exogenous administration of large
amounts of stress hormones is detrimental.
Two historical perspectives are important to consider
regarding stress and the trauma of burn injury. First is
the concept described by Cuthbertson,3 where the initial
response to thermal injury is considered an ‘ebb’ phase
characterized by reduced metabolism and tissue perfusion.
Within days there is a transition to a ‘flow’ phase typified
by increased resting energy expenditure and hypermetabo­
lism, with supportive cardiovascular function. Changes in
endocrine hormone levels are important for these acute
catabolic alterations. The concepts of ‘stress’ and release of
‘stress hormones’ widely used today were clarified by the
classic work of Seyle.4 His notion of stress responses
include an initial ‘alarm reaction’ of fairly short duration
with high levels of stress hormones, followed by a pro­
longed ‘resistance phase’ during which there is compen­
sation to maintain homeostasis during continued stress.
Seyle’s final stage of ‘exhaustion’ is where compensation
cannot be maintained and death rapidly follows. The acute
initial period of high stress hormone release encompasses
both Cuthbertson’s ‘ebb’ phase and Seyle’s ‘alarm reaction,’
and the ‘flow phase’3 has similar features to the ‘resistance
phase.’4 These compensatory changes promote increased
energy expenditure and support cardiovascular function.
However, in patients with severe injury the same compen­
satory changes result in depletion of energy reserves, exten­
sive muscle wasting, and immune suppression, all of
which are hallmarks of post-burn sequelae. This compen­
satory pattern is described as a hypermetabolic state, with
patients displaying elevated resting metabolic rates for
several months following injury.5–7 The extent of the hyper­
metabolic response is dependent upon the extent and
depth of burn injury, septic complications, and surgical
interventions. Nonetheless, questions related to the magni­
tude of stress hormone responses and beneficial versus det­
rimental actions in the recovery from severe thermal injury
remain unanswered.
©2012 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2786-9.00024-2
Significance of the adrenal and
sympathetic response to burn injury
Kuzhali Muthu, Ravi Shankar, Richard L. Gamelli
CHAPTER 24 
Access the complete reference list online at

IN THIS CHAPTER
PowerPoint Presentation Online

Total Burn Care
24
290
ameliorate the extent or impact of the hormone response
(Table 24.1). In fact, the striking prolongation of sympa­
thetic activation extending up to 35 weeks after thermal
injury12 has been repeated by Herndon et al., using sophis­
ticated, precise techniques. They found a sustained elevation
in urinary epinephrine and norepinephrine levels, attesting
to the magnitude and duration of catecholamine surge in
pediatric burn patients.17,18 In light of the strong evidence
for sympathetic activation following thermal injury, the
compensatory or possible decompensatory consequences
are important to consider.
In response to thermal injury there are acute responses in
what Cuthbertson3 described as an ‘ebb’ phase and long-
term responses that support a ‘flow’ phase. Cardiovascular
During the last 50 years great advances have been made
in the care of burn patients and with various treatment
modalities attempting to exploit some of the concepts
described above. Examples include rapid fluid resuscitation
to stabilize cardiovascular function and reduce the stimulus
for continued sympathetic drive; nutritional support to
meet metabolic demands and to support homeostasis
during healing; elevated environmental temperatures and
occlusive dressings to lessen the metabolic demands, reduce
metabolic rate and cardiac output, and to optimize wound
healing. Aside from the regulation of metabolic and
cardiovascular function, neuroimmune interactions may be
important in mediating the marked alterations in
immune function that often follow severe injury. In this
chapter we have chosen to present the adrenomedullary–
neurotransmitter activation and actions as separate from
the adrenocortical activation and actions to clarify specific
responses, as we currently understand them. To this end we
will review the magnitude and time course of the stress
hormone/neurotransmitter responses to thermal injury as
well as how the action of these substances may be inte­
grated. How these responses may be beneficial or detrimen­
tal during the course of recovery will also be addressed.
Given the range of pharmacologic antagonists and agonists
available to the clinician, taking a mechanistic approach to
understanding adrenal hormones and neurotransmitter
involvement in the pathophysiology of burn injury is criti­
cal to further advance the successful treatment of these
patients.
PART I – SYMPATHETIC ACTIVATION
AND RELEASE OF CATECHOLAMINES
FOLLOWING BURN
Although clinical observations suggested the activation of
sympathetic nerves in response to thermal injury,8–10 direct
evidence for such activation was not fully appreciated until
the simultaneous publication of papers by American and
Swedish groups.11,12 These landmark studies described
marked elevations in 24-hour urinary levels of norepine­
phrine and epinephrine in burn patients. Despite consider­
able intra- and interindividual variations, the increases in
urinary norepinephrine and epinephrine were proportional
to the size of burn, were highest during first 3 days post burn,
and remained elevated for several weeks. Furthermore, these
studies also suggested that subsequent surgical interventions
and the onset of sepsis and septic shock such as hypotension
or serious infections caused catecholamine secretion to
increase again. Since these early reports of urinary catecho­
lamines as measured by bioassay techniques, many studies
have confirmed the initial sympathetic responses in burn
patients using fluorometric, HPLC/electrochemical or radio­
enzymatic techniques in plasma and urine samples.13–16
With improvements in critical care medicine and the man­
agement of burn patients during the last 40 years, one can
contemplate that prolonged sympathetic activity may not
occur during extended recovery. In contrast, elevations in
catecholamines may still occur in transient response to surgi­
cal procedures but cardiovascular, nutritional, and immune-
related interventions, as part of the treatment regimen, may
Table 24.1  Influence of catecholamines on cardiovascular,
metabolic, and immune response to thermal injury
Physiologic variable
Sympathetic mediated
change following
burn injury
Resting metabolic rate
Increase36
Increase37
Increase15
Increase (in vitro)272
Proteolysis
No change (urea production)38
No change (protein oxidation)36
Decrease47
Glucose production and
oxidation
Decrease secondary to increase in
lipid catabolism37,273
No change36
Glycogenolysis
Increase (indirect evidence via
cAMP)35
Gluconeogenesis
Increase (indirect evidence via
cAMP)35
Lipolysis
Increase38
Increase36
Increase37
Increase40
Cardiac output
Increase37
Increase38
Peripheral vascular resistance
Unknown
Heart rate
Increase47
Increase38
T-cell number and function
Unknown
B-cell number and function
Unknown
Neutrophil number and function
Decrease89
Monocyte number and function
Increase (indirect – clonogenic
potential)146
Increase (indirect – clonogenic
potential)159
Increase89
Citation of studies from the current literature suggesting that sympathetic
activation is involved in changing the above physiologic variables following
thermal injury.

Significance of the adrenal and sympathetic response to burn injury
291
release are not well defined. In fact, the significance of β2
adrenergic receptors in vasodilation has recently been dem­
onstrated using knockout mice,27 pointing to the importance
of epinephrine. The situation is complicated in the burn
patient by the increase in nerve-stimulated release of nore­
pinephrine, which has the potential to mediate vasoconstric­
tion. However, there is evidence that the local distribution
of adrenergic receptors mediating either vasodilation or
vasoconstriction will determine the effect of circulating
epinephrine and nerve-stimulated norepinephrine release
on peripheral vascular resistance.28 In addition, increased
tissue metabolism has been recognized to produce metabo­
lites that mediate increased blood flow by reducing vascular
resistance.29 With markedly increased metabolism in major
burns, these metabolites, along with catecholamines, nitric
oxide,30 and atrial natriuretic peptide,14 may contribute to
the observed decreased vascular resistance.
Typically, decreases in tissue perfusion leading to compro­
mised organ function only occur in patients with complica­
tions related to septic events or severe metabolic acidosis. In
burn patients there is often a modest decrease in mean arte­
rial blood pressure that is not indicative of hypoperfusion
and is left untreated. When decreases in peripheral vascular
resistance become dominant, with marked decreases in
mean arterial pressure, pressor agents may be required to
maintain adequate tissue perfusion, and norepinephrine is
the drug of choice, providing both vasoconstrictor and ino­
tropic effects. Clinical use of vasoconstrictor and inotropic
agents is essential to counter low tissue perfusion during the
periods of altered hemodynamic function often seen with
the onset of sepsis in burn patients.
In this regard Macarthur et al.31 suggest that the inactiva­
tion of catecholamines by superoxide anions contributes to
the observed hypotension of septic shock. Treatment with
superoxide dismutase not only abrogated endotoxin-induced
hypotension in anesthetized rats, but also elevated circulat­
ing levels of catecholamines. These findings suggest that
compensatory sympathetic activation, which counteracts
hypotension during conditions of sepsis, may be blunted
by inactivation of catecholamines by superoxides in the
extracellular milieu. More recently these studies have been
extended32 to a conscious rat model with the infusion of live
bacteria to simulate conditions of sepsis. Furthermore, in
this study a 100-fold increase in the activity of superoxide
dismutase mimetic agent was used to enhance plasma levels
of catecholamines, increase blood pressure and improve
survival. In their most recent work33 these investigators
demonstrated that nitric oxide (NO), widely recognized as
a mediator of hypotension during systemic inflammation, as
occurs in sepsis, reduces the biologic activity of norepine­
phrine. Furthermore, increasing NO levels in an isolated,
perfused, mesenteric circulation reduced vascular responses
to endogenously released norepinephrine without altering
nerve-stimulated release. These findings may provide some
insight into the clinical observations involving critically ill
trauma patients where exogenous norepinephrine admini­
stration is ineffective in correcting hypotension.
Following the initial insult of thermal injury the ‘ebb’
phase of recovery is characterized by a decrease in body
temperature and oxygen consumption and a progressive
elevation in lactate levels and hyperglycemia.34 The same
period of recovery involves intense sympathetic stimulation,
adjustments to thermal injury appear to be critical for sur­
vival following burn trauma, and with initial reductions in
cardiac output, sympathetic responses are rapidly brought
into play, as reviewed by Carleton.19 Initial sympathetic acti­
vation contributes to the dramatic increases in peripheral
vascular resistance that preserve mean arterial pressure but
typically limit perfusion to the kidney and splanchnic beds.
Although the mechanisms for the reduction in cardiac
output are not completely understood, they are in part
related to the sudden loss of vascular volume as a result of
fluid transudation of plasma from the wound and from non-
wound vascular sites.20,21 Movement of fluids from vascular
to interstitial spaces is compounded by the loss of plasma
proteins through the incompetent capillary beds that
normally act to retain ions by Donnan equilibrium.22
Such apparent hypovolemia would initially reduce blood
pressure and baroreceptor afferent nerve activity, with result­
ant increases in efferent sympathetic nerve activity. The
resultant increase in peripheral vasoconstriction and conse­
quent increase in peripheral vascular resistance are mediated
in part by nerve-stimulated release of norepinephrine, but
also to a significant degree by both angiotensin II (AII) and
arginine vasopressin (AVP).14,23 As AVP has been shown to
directly depress myocardial function in the isolated heart
and this depression can be reversed pharmacologically,
AVP may contribute to myocardial depression following
burn injury.24
Myocardial depression following thermal injury can be
manifest as decreased cardiac output due to decreases in
vascular volume, reductions in diastolic compliance, and
decreases in myocardial contractility. Various ‘myocardial
depressant factors’ have also long been described without
specific detailed identification of the actual substances. Such
deficits in contractility are compounded by the increases in
aortic pressure afterload that is the consequence of increased
peripheral vascular resistance and in total, contribute to
the observed reductions in cardiac output. Although dia­
stolic dysfunction has been demonstrated in burn patients,
evidence for decreases in contractility are largely based
on animal studies, with little evidence that this occurs in
patients. Consequent upon decreased ventricular perform­
ance and potential intrinsic myocardial dysfunction, sympa­
thetic drive would be important to maintain ventricular
function of the non-compromised muscle upon recovery
from thermal injury.
Cardiovascular disturbances might be predicted to be
the dominant signal initiating a generalized sympathetic
response, but the persistence of such sympathetic activation
after hemodynamic stabilization suggests that afferent stim­
ulation from other sources may initiate as well as maintain
this response. Hemodynamic stabilization in burn patients
typically requires 1–2 days after fluid resuscitation and is
followed by the ‘flow phase’ of recovery, characterized by
low peripheral vascular resistance, elevated cardiac output,
increased peripheral blood flow, and increased metabo­
lism.25,26 The marked decrease in peripheral vascular resist­
ance most likely drives this hyperdynamic phase by reducing
cardiac afterload, increasing cardiac preload, and thus
increasing cardiac output. There is abundant evidence that
mediators of neural, humoral, and metabolic origin are
involved in driving the decrease in vascular resistance fol­
lowing thermal injury, but their dominance and sequential

Total Burn Care
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292
An important and all too frequent complication of severe
thermal injury is infection, which frequently leads to sepsis,
septic shock, multiple organ failure, and death. The develop­
ment of septic complications can reduce predicted survi­
vability by up to 50%.52 As with burn, infection results in
marked sympathetic responses that are well characterized in
both experimental and clinical settings. Whereas experimen­
tal paradigms of sepsis have used plasma catecholamines,
nerve recordings and norepinephrine turnover to assess
sympathetic activation,53–58 human studies have primarily
focused on changes in plasma catecholamines.1 Similar to
thermal injury, sympathetic responses also appear to be pro­
portional to the degree of insult, based on experiments using
incremental doses of bacterial endotoxin.54 Furthermore,
animal models of septic peritonitis suggest that initial sym­
pathetic activation as measured by elevated levels of plasma
norepinephrine and norepinephrine turnover persist for
many hours.53,56 Burn patients are most susceptible to infec­
tion during the second week of their hospitalization, when
the sympathetic response as reflected by urinary and plasma
catecholamines has moderated but is still high.13,14 Although
the onset of bacterial infection and developing sepsis would
be expected to cause marked increases in plasma catecho­
lamines above that due to burn alone, longitudinal studies
charting the course of plasma catecholamines following
thermal injury leading into infection and progressing into
septic shock are not available.
Sympathetic influences on immune function
Over the last 20 years experimental evidence describing the
interactions between neural and immune cell systems has
expanded greatly. This has important implications in our
understanding of the pathobiology of thermal injury, as in
vivo sympathetic activation as well as compromised immune
function both occur following thermal injury. In addition to
endogenous release of catecholamines, burn patients are
often treated with adrenergic pressor agents; they may be on
a therapeutic regimen of β-adrenergic antagonist prior to
injury, or hypermetabolism may be controlled in pediatric
burn patients with β-adrenergic antagonists. Thus, adrener­
gic modulation following thermal injury may involve thera­
peutic as well as endogenous mediators and may have an
important impact on immune system function.
For the activation of sympathetic nerves to influence
immune responses, evidence of sympathetic innervation in
peripheral lymphoid organs is essential. Existing anatomical
evidence is based on immunohistochemical techniques to
visualize tyrosine hydroxylase, the rate-limiting step in the
biosynthesis of norepinephrine. These studies clearly indi­
cate a substantial innervation of all primary (thymus and
bone marrow) and secondary (spleen and lymph nodes)
lymphoid organs.59–63 Furthermore, they also show sympa­
thetic innervations in the immune cell compartment of the
spleen (the white pulp), the periarterial lymphoid sheath,
marginal zone and marginal sinus areas, as well as in the
splenic capsule and trabeculae.64–67 Sympathetic nerve termi­
nals have been described in direct apposition to T cells,
interdigitating dendritic cells and B cells.65 The proximity of
nerve terminals to immune cells may be critical in achieving
the necessary local concentrations of neurotransmitters at
suggesting the involvement of adrenergic mechanisms medi­
ated by adenylyl cyclase and cAMP in the mobilization of
liver glycogen to glucose.35 Hypermetabolism that follows
1–2 days later in the ‘flow’ phase can also be attributed to
adrenergic influences,15,36 but does not involve increased
glucose mobilization and utilization. Adrenergic blockade
only increased glucose production and clearance under these
hypermetabolic conditions.37 The experimental studies of
Wolfe and Durkot37 suggest that adrenergic drive following
burn facilitates lipolysis, influencing fatty acid oxidation.
These results are based on changes observed following
adrenergic blockade with propranolol and further clarify
that the observed increase in glucose production and clear­
ance under such conditions reflects a shift to carbohydrate
utilization in the absence of lipid mobilization. Examining
the importance of adrenergic drive on lipid metabolism in
burn was extended to human patients through the use of
stable isotopic studies as well as adrenergic antagonists.38–40
These results not only indicate that lipolysis following
thermal injury is mediated by β2 adrenergic receptors, but
suggest increased triglyceride–fatty acid cycling, with result­
ant heat production.
The initial description of the sustained hypermetabolic
response to thermal injury41 prompted studies to examine
the role of thyroid function and catecholamines in mediat­
ing this response. Although abnormal thyroid function was
not involved in the response,41,42 Wilmore developed experi­
mental paradigms suggesting the role of catecholamines in
mediating the hypermetabolic response to thermal injury.15
Evidence for the positive correlation of increased plasma
catecholamines and whole-body oxygen consumption fol­
lowing thermal injury,15 as well as the demonstration that
adrenergic blockade lowers the burn-induced increase in
metabolic rate and cardiac output to control levels in animal
models, directly support this contention.15,37 However, exper­
imental findings in rats suggested that the adrenal medulla
is essential for high rates of heat production following
thermal injury, but is not responsible for the primary drive
of the hypermetabolic response.43,44 Animals with hypotha­
lamic lesions did not increase metabolism following thermal
injury and were chronically hypothermic,45 not unlike exper­
iments where the adrenal medulla was removed prior to
thermal injury.43 These results are consistent with clinical
observations in burn patients in whom reductions in heat
loss were achieved with occlusive dressings, and elevated
environmental temperatures have reduced metabolic rate
and catecholamine secretion.46
Building on findings that catecholamines drive post-burn
hypermetabolism, Herndon et al.47,48 demonstrated that
paediatric 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,49 β-adrenergic blockade in pedi­
atric 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 provided for a more effica­
cious recovery in these children.50 Similarly, gluconeogenic
pathway was prevented with propranolol treatment in pedi­
atric patients by downregulation of a key catalytic enzyme
that generates fructose 6-phosphate.51

Significance of the adrenal and sympathetic response to burn injury
293
adrenergic inhibition of LPS-stimulated TNF-α production
has involved whole blood.83–88 In our recent documentation,
blocking β-adrenergic receptors soon after injury partially
reversed LPS-stimulated TNF-α potential of circulating
monocytes lost during the course of burn injury and sepsis.89
Apart from adrenergic inhibition of LPS-stimulated TNF-α
release in isolated macrophages,90–93 similar inhibition of
LPS-stimulated TNF-α production has also been demon­
strated in human mast cells,94 microglial cells,95 astrocytes,96
and cytotoxic T lymphocytes.97 In contrast to adrenergic
stimulation of TNF-α release, experiments with isolated
atria,98,99 myenteric plexus,100 and brain tissue101 have dem­
onstrated that TNF-α can negatively affect the release of
norepinephrine.
Adrenergic influences on the expression and release of
interleukin (IL)-6 have been suggested by a number of
studies demonstrating increases in plasma IL-6 in response
to direct or indirect stimulation.102–104 Adrenergic enhance­
ment of IL-6 responses to LPS has also been demonstrated
in vivo79,81 as well as ex vivo93 and in isolated cell systems.105,106
Catecholamines in combination with IL-1β stimulate IL-6
release from rat C6 glioma cells, and vasoactive intestinal
polypeptide (VIP) has been reported to synergize with nor­
epinephrine to induce IL-6 release in astrocytes.107,108 In addi­
tion, adrenergic agonists have been shown to mediate IL-6
release in brown adipocytes, pituicytes, hepatocytes, astro­
cytes, and thymic epithelial cells.107–113
In contrast, Nakamura et al.96 reported that catecho­
lamines reduced the IL-6 response to LPS, and van der Poll
et al.87 demonstrated that norepinephrine inhibits the LPS-
induced IL-6 response in whole blood. Other evidence for
adrenergic suppression of IL-6 responses has been suggested
by the work of Straub.114–116 Using isolated splenic tissue
preparation, electrically stimulated release of norepine­
phrine appeared to inhibit IL-6 production induced by LPS
or bacteria. These authors suggest that adrenergic inhibition
of IL-6 is reduced under conditions simulating infection,
where cytokine mediation of the inflammatory response is
compensatory in eradicating the bacterial load. It is apparent
from these studies that catecholamines can exert a negative
or a positive influence on IL-6. Given these different modula­
tory functions, the role(s) catecholamines play in the patho­
physiology of burn injury remain unexplored.
Although the exact mechanisms of the negative modula­
tion of proinflammatory cytokines by catecholamines are
poorly understood, it may be achieved through the ability
of catecholamines to induce the anti-inflammatory cytokine
IL-10.81,84,117,118 Whole animal studies involving assessment of
circulating levels of IL-1081 as well as studies of human whole
blood and mononuclear cells stimulated with LPS in the
presence of adrenergic agonists83,84,118 support this premise.
In addition, experimental neurotrauma results in increased
IL-10 consequent upon endogenous adrenergic stimulation
in the absence of LPS or other evidence of infectious
challenge.119 The only experimental evidence suggesting an
attenuation of IL-10 with adrenergic stimulation involved a
macrophage cell line (RAW 264.7).120
Evidence that elevations of IL-10 can be blocked with inhi­
bition of protein kinase A (PKA)118,121 is consistent with
adrenergic mediation of changes in TNF-α and IL-6, and
suggest that activation of PKA is important in effecting
these adrenergic modulations of cytokine release. More
the neuroimmune junctions to modulate immune func­
tions. In fact, the neuroimmune junction is estimated at
6 nm,68 compared to 20 nm in typical CNS junctions, indi­
cating that sufficient neurotransmitter concentration could
be released across these small junctions to affect resident
immune cells.
Anatomical evidence of sympathetic innervations of the
immune system is complemented by evidence for nerve-
stimulated release of norepinephrine in both spleen and
bone marrow.69 Whereas evidence in spleen has been recog­
nized for many years and has been assessed in a variety
of ways, norepinephrine release in bone marrow has only
been recently described, using norepinephrine turnover
techniques based on radiotracer methods involving in vivo
experimental paradigms.69 In contrast, exocytosis of nor­
epinephrine from lymph nodes has not been demonstrated.
To complete the criteria for the physiologic importance of
functional innervations, nerve-stimulated release of nor­
epinephrine within lymphoid organs must increase at the
appropriate time to influence the immune response in con­
junction with demonstration of norepinephrine-mediated
immune modulations.
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.70–72 Furthermore,
there is significant evidence that norepinephrine can modu­
late the function of CD4+T cells, which in turn can modulate
antibody production of B cells.73 In addition, norepine­
phrine can directly influence B-cell antibody production
depending on the time of exposure following activation.74
The physiologic importance of these in vitro findings is sup­
ported by a series of in vivo experiments involving severe
combined immunodeficient (scid) mice depleted of nor­
epinephrine prior to reconstitution with antigen-specific Th2
and B cells. These experiments demonstrate that norepine­
phrine is necessary for maintaining a normal level of anti­
body production in vivo.70 Furthermore, other recent whole
animal experiments, also involving scid mice, provide evi­
dence that the immune response itself stimulates the release
of norepinephrine from adrenergic nerve terminals in bone
marrow and spleen, which in turn can influence antibody
production by B cells.75 However, in a prospective intent-to-
treat study, β-blockade in 20 paediatric burn patients signifi­
cantly reduced serum TNFα and IL-1β.76 Although these
findings fall far short of direct application to immune cell
function following thermal injury, they suggest the potential
of sympathetic activation in mediating immune responses.
In addition to neural influences on T- and B-cell function,
there are direct effects on myeloid cell function, particularly
with respect to lipopolysaccharide (LPS)-stimulated cytokine
production. The most striking examples of neural influences
on macrophage function were demonstrated by the work of
Spengler et al.,77 who concluded that α-adrenergic stimula­
tion increases TNF-α release, whereas β-adrenergic stimula­
tion reduces such release in response to LPS. They provided
further evidence to suggest that extracellular stores of cat­
echolamines in macrophages are capable of modulating
TNF-α release. Furthermore, sympathetic inhibition of
LPS-induced TNF-α release has been suggested to occur in
whole animal preparations, although adrenergic actions on
macrophages were indirect.32,78–83 More direct evidence of

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The extensive sympathetic innervations of the gut and
associated structures has been recognized for many years,
with well-defined nerve terminals located primarily along
blood vessels but without evidence of neurotransmitter
release into the intestinal lumen. Furthermore, there is con­
siderable evidence that, once released from nerve terminals,
most norepinephrine is taken back into the same terminals
by reuptake mechanisms, metabolized into a non-active
form, or diffused through tissues to reach blood vessels to
become part of the circulation.133 Therefore, even though
intestinal bacterial growth has the potential to be enhanced
by the neurotransmitter norepinephrine, transport of the
norepinephrine into the intestinal lumen would seem
problematic. However, as massive catecholamine release is
such a consistent component of burn patients, especially
those with superimposed sepsis, the hypothesis that
bacterial growth can be enhanced by norepinephrine is
very appealing.
This concept is strengthened by studies demonstrating that
cecal bacterial growth increases dramatically following
massive in vivo release of norepinephrine, and that passage
of bacteria through the gut enhances their growth response
to norepinephrine. In the first case,126 mice were treated with
6-hydroxydopamine, a neurotoxin that displaces norepine­
phrine from adrenergic nerve terminals, causing a transient
but massive sympathetic reaction. At 24 hours post treat­
ment cecal bacterial growth was elevated 3–4 degrees of
magnitude compared to vehicle-treated controls, but bacte­
rial growth returned to control levels by 14 days. In the
second study131 an attenuated strain of Salmonella typhimu­
rium was administered to rhesus monkeys, whereupon iso­
lated fecal bacterial cultures from these animals displayed
increased in vitro growth responses to norepinephrine. To
elucidate whether this hypothesis has a role in the patho­
physiology of thermal injury with sepsis, future studies must
build on experimental paradigms of thermal injury to dem­
onstrate that endogenous norepinephrine enhances bac­
terial growth leading to sepsis.
Evidence for norepinephrine regulation
of myelopoiesis in experimental thermal
injury with sepsis
Patients with severe burn trauma often display significant
impairment in cell-mediated immunity involving defective
neutrophil chemotaxis, phagocytosis, and superoxide
production.134–137 Patients with sepsis and a systemic inflam­
matory response may also present with monocytosis and
neutropenia.138,139 Whereas neutropenia and defective neu­
trophil functions may compromise host defense, monocyto­
sis has the potential to fuel excessive cytokine production
through increased availability of circulating and tissue
monocyte/macrophages. For the past 10 years our laboratory
has been investigating bone marrow following thermal
injury with sepsis to understand the mechanisms that govern
leukocyte production, and how they might contribute to the
observed defects in leukocyte function. The potential for
sympathetic activation to modulate myelopoiesis following
thermal injury and sepsis is supported by previous studies
where adrenergic stimulation has been shown to participate
in the regulation and control of hematopoiesis.140,141
specifically, the recent work of Platzer et al.117 suggests that
catecholamines in monocytic cells directly stimulate the
IL-10 promoter/enhancer, and provide evidence that a cAMP
response element was the major target of the cAMP/PKA
pathway. In contrast, two independent studies from our
laboratory report evidence that, although adrenergic stimu­
lation increases IL-10 release from macrophages, release of
TNF-α and IL-6 is inhibited by direct adrenergic stimulation
not secondary to IL-10.122,123 These studies involved both
peritoneal-elicited and bone marrow progenitor-derived
macrophages under normal conditions as well as following
cecal ligation and puncture injury. Epinephrine attenuated
TNF-α but increased IL-10; however, addition of anti-IL-10
antibody did not prevent epinephrine’s ability to block
TNF-α reduction. Further experiments demonstrated the
action of epinephrine to inhibit LPS-stimulated release of
proinflammatory cytokines to be mediated by β2-adrenergic
receptors. The dominance of direct adrenergic inhibition of
LPS-mediated proinflammatory cytokines was maintained
during conditions of sepsis, although such conditions ele­
vated endogenous levels of IL-10.
Adrenergic stimulation of bacterial growth
Since the identification of mammalian hormone and neuro­
transmitter receptors in bacterial cells, there has been con­
siderable interest in defining a role for such signaling
molecules in bacterial cells. As a consequence, support has
emerged for the concept that release of norepinephrine
within intestinal tissue promotes the growth of bacteria in
the gut.124–126 Initial experiments demonstrated the growth-
promoting action of catecholamines in vitro using several
different bacterial species, and provided evidence that these
compounds were not acting as nutritional substrates. Since
adrenergic blocking agents did not block the growth-
stimulating effects of norepinephrine, adrenergic receptors
do not appear to be involved.127,128 Further observations
suggest that norepinephrine may act within 8 hours to
induce bacterial growth, during which time stimulation
of growth factors can promote bacterial growth.129,130
Norepinephrine-stimulated bacterial growth has also been
shown to produce Shiga-like enterotoxins from enterohem­
orrhagic strains of E. coli. Furthermore, norepinephrine pro­
motes the expression of K99+ pilus adhesin, a virulence factor
known to play a critical role in the attachment of these
bacteria to the intestinal wall, which initiates the infective
process.131,132 Although these studies use very high concentra­
tions of norepinephrine compared to the observed plasma
concentrations following thermal injury, bacteria in vivo may
be exposed to high norepinephrine concentrations if they
are in close proximity to the nerve terminal synapse. A related
concern is the lack of information regarding the actual nore­
pinephrine concentration in the culture media throughout
the incubation period. Whereas rapidly growing bacterial
cultures may generate an acid environment in which cate­
cholamines are quite stable, initial growth conditions con­
taining low bacterial counts and minimal nutrients may
promote rapid deterioration of norepinephrine. However,
high initial norepinephrine concentrations in culture may
counteract such unfavorable conditions but in turn would
provide misleading dose–response information.

Significance of the adrenal and sympathetic response to burn injury
295
protocol resulted in a significant survival benefit compared
to animals with intact norepinephrine content.
The influence of norepinephrine on bone marrow mono­
cyte progenitor differentiation following thermal injury with
sepsis was assessed by cell surface expression patterns of
ER-MP12 and ER-MP20. Whereas ER-MP12 antigen is
expressed in early monocyte progenitors and represents pre­
dominantly CFU-M, progressively more ER-MP20 antigen is
expressed from the CFU-M stage onwards but disappears in
mature monocytes.157 By following the distribution pattern
of the expression of these two antigens on bone marrow cells,
the phenotypic separation and identification of bone marrow
monocyte precursors have been demonstrated.158 Taken
together, results from ER-MP12 and ER-MP20 expression pat­
terns in burn-septic animals with intact and depleted nore­
pinephrine stores suggest that monocyte maturation
pathways may be greatly influenced by the presence of nore­
pinephrine, and that stimulation of such pathways may be
involved in the pathobiology of thermal injury with sepsis.
Cohen et al. have also examined very early progenitors not
committed to the myeloid lineage that express the CD117
antigen.159 They also isolated and examined cells expressing
ER-MP12 antigen, which are early myeloid-committed pro­
genitors that differentiate either into neutrophils or mono­
cytes. The monocytopoietic potential of both progenitor
types was enhanced above control values both following
thermal injury alone and with superimposed sepsis. However,
this enhancement was greatly reduced by depletion of nor­
epinephrine prior to the injury protocol. These findings
suggest that bone marrow myeloid progenitors, as well as
early progenitors that are not committed to the myeloid
lineage, can be stimulated by endogenous norepinephrine
release following thermal injury and sepsis to enhance
proliferation.
Another important aspect of Cohen et al.’s work159 is the
demonstration that progenitor-derived macrophages express
enhanced cytokine release following thermal injury and
sepsis. In this study, the authors elegantly isolated CD117+
and ERMP-12+ progenitor cells from the bone marrow at 72
hours after the thermal injury protocol and differentiated
them into macrophages ex vivo by supplementing with
GM-CSF- and M-CSF-rich medium. Subsequently, LPS-
stimulated cytokines were measured in the conditioned
media. Expression of both TNF-α and IL-6 was significantly
reduced in progenitor-derived macrophages from animals
with norepinephrine depletion prior to the injury protocol.
These results suggest that endogenous norepinephrine
released during conditions of burn and sepsis affect the
phenotype of differentiated macrophages. Collectively, the
work of Cohen et al. suggests that adrenergic stimulation
during experimental thermal injury and sepsis contributes
to enhanced numbers of macrophages as well as the expres­
sion of cytokines in bone marrow progenitor-derived
macrophages.
Bone marrow progenitor response
to β-adrenergic stimulus
In order for catecholamines to act on bone marrow progeni­
tors, such cells should express functional adrenergic recep­
tors. Recently, we have documented the expression of α1, α2,
Maestroni141 has not only provided evidence for the pres­
ence of adrenergic receptors on bone marrow immune cells,
but also that adrenergic agonists stimulate lymphopoiesis
while attenuating myelopoiesis under normal, non-injury
conditions. These findings are further strengthened by
animal experiments where adrenergic agents have been
shown to modulate both lympho- and myelopoiesis.142–145
Another important factor supporting the possible adrenergic
regulation of myelopoiesis following thermal injury is that
sympathetic activation can occur directly within the bone
marrow compartment, with nerve-stimulated release of
norepinephrine in close proximity to developing immune
cells. We have documented a significant increase in murine
bone marrow norepinephrine release in response to either
cold exposure or bacteria through the use of traditional
pulse-chase experiments.69 Furthermore, we have extended
these measurements to demonstrate increased bone marrow
norepinephrine release in response to thermal injury with
sepsis in our murine model.146
These findings suggest that sympathetic activation has
the capacity to drive events within the bone marrow, and
adrenergic-mediated expansion of leukocyte production
could conceivably contribute to perturbed inflammatory
responses with immune challenge following thermal injury
with sepsis. Experimental evidence suggesting that adrener­
gic stimulation inhibits myelopoiesis under normal condi­
tions141 but is shifted following injury to enhanced monocyte
development146 is a most interesting phenomenon. Whether
adrenergic stimulation within the bone marrow functions in
a compensatory or a decompensatory way toward the host
following thermal injury is also interesting to consider. Is
adrenergic stimulation involved in the immunosuppression
of patients with severe burns through functional alterations
in circulating and tissue leukocytes?147–153 These and other
important questions are likely to involve events that occur
within the bone marrow, as it serves as a major source
of new leukocytes both in the circulation and in tissues
following thermal injury with sepsis. Our laboratory is
beginning to confirm that perturbed bone marrow progeni­
tor development could lead to the production of hypore­
sponsive monocytes and dendritic cells following thermal
injury and sepsis.154
Alterations in bone marrow hematopoietic progenitor
cells has been the focus of our work and has involved the
murine model of thermal injury (15% TBSA) and sepsis via
Pseudomonas aeruginosa applied directly to the wound site to
establish sepsis. Following the demonstration of a shift in
bone marrow myeloid commitment toward monocytopoi­
esis and away from granulocytopoiesis in thermal injury and
sepsis,155,156 we began to focus on the potential significance
of the increased nerve-stimulated release of norepinephrine
within the bone marrow under these same experimental
conditions. We tested the premise that neural stimulation
was modulating myeloid lineage function by manipulating
the peripheral stores of norepinephrine prior to injury.
This was achieved by administering 6-hydroxydopamine
(6-OHDA) before subjecting the animals to thermal injury
and sepsis. Femoral bone marrow cells from mice with
reduced norepinephrine content demonstrated a significant
decrease in monocytopoietic potential compared to mice
with intact norepinephrine stores.146 In addition, reduction
of peripheral norepinephrine content prior to the injury

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that occur during cellular differentiation in the bone marrow
compartment.
Nonetheless, this premise is supported by the evidence
from our laboratory demonstrating a correlation between
the phenotypes of bone marrow monocyte progenitor-
derived macrophages and circulating monocytes following
burn and sepsis.154 In this study, the authors measured intra­
cellular or cell-associated cytokine expression by flow cytom­
etry, and not the secreted cytokines in the conditioned
medium by traditional methods. As a result, it comes to light
that the F4/80+Gr-1+ subset of macrophages produced LPS-
stimulated TNF-α and IL-6, and not the F4/80+Gr-1- subset.
Further, the results showed a twofold increase in the
F4/80+Gr-1+ subset in circulation at 48 hours post burn and
sepsis that started to decline at 72 hours and remained low
at 96 hours. Concurrently, bone marrow ER-MP20 progeni­
tors isolated at 48 hours exhibited robust macrophage
differentiation potential but a significant decline in the
percentage of the F4/80+Gr-1+ subset with a concomitant
decrease in TNF-α production. These results support the
argument that bone marrow progenitor-derived monocytes
will replace the transient hyperresponsive circulating mono­
cytes later in the course of the septic insult, providing a
plausible explanation for the immunosuppression that
follows a critical burn injury and sepsis.154 In a subsequent
study the same authors demonstrated that administering
β-blockade can restore the inflammatory potential of circu­
lating monocytes and granulocytes in experimental burn
sepsis.89 Taken together, burn and sepsis-induced sympa­
thetic response has greater influence on bone marrow cel­
lular events and warrants further investigation.
PART II – ADRENAL CORTICAL STEROIDS
FOLLOWING BURN TRAUMA
Release of glucocorticoids
Whereas the acute ‘ebb’ phase of recovery from thermal
injury is mainly dependent upon the re-establishment of
cardiovascular function following circulatory disruption, the
‘flow’ phase is considered to be dependent upon an adequate
metabolic response. These responses are mediated in part by
adrenal cortical steroids, of which cortisol is the dominant
glucocorticoid hormone (Table 24.2). Elevation of gluco­
corticoids occurs in response to most forms of trauma,165
including burn injury, with rapid increases in blood and
urine levels.8,166 During the first 2 weeks following burn
injury the increase in total plasma cortisol concentration is
proportional to the severity of the injury. Early studies
observed that glucocorticoid levels were excessively high in
severely burned patients and remained high in non-surviving
patients.167 In burn patients in whom recovery is likely,
plasma glucocorticoid levels are moderately elevated or in
the upper normal range, and can persist for up to 36 days168,169
and return to normal as healing progresses.166 In contrast,
patients with severe injury (90% TBSA) have markedly lower
levels of glucocorticoids, suggesting that they are unable to
mount an adequate response.169
Glucocorticoids circulate in the body bound to cortisol-
binding globulin (CBG) or transcortin, as an inactive
and β2 adrenergic receptors in murine hematopoietic stem
cells and progenitors. Muthu et al. used a combination of
flow cytometry and confocal imaging techniques to circum­
vent the requirement for large sample size in rare progenitor
populations, otherwise needed in traditional radio receptor
techniques.160 In fact, specific β-adrenergic receptors on bone
marrow progenitors enriched for ER-MP20 antigen were
characterized by Muthu et al. using conventional pharmaco­
logic binding techniques, and values of total receptors (BMAX)
and affinity (KD) were determined. Furthermore, the effect of
thermal injury and sepsis on these receptors was determined
at 72 hours post injury.161 Thermal injury and sepsis resulted
in significant reductions in cell surface β-adrenergic recep­
tors (BMAX) but binding affinity was increased (decreased KD
values). This paradoxical change was resolved by agonist
stimulation of intracellular cAMP, which showed that agonist
coupling was increased in burn sepsis. Increased cAMP pro­
duction under conditions of decreased receptor number but
increased affinity suggests the dominant effect of changes
in affinity in the bone marrow monocyte progenitor
cells. Although these findings do not provide evidence that
β-adrenergic–cAMP coupling alters the phenotype of these
progenitors in vivo, additional in vitro experiments demon­
strated that adrenergic stimulation during differentiation of
ER-MP20 progenitors significantly alters the phenotype
of mature macrophages, increasing cell surface CD14
expressions. These changes in phenotype expression with
adrenergic stimulation could be reversed with the
selective β2-adrenergic blocker.161
In an independent study, the same authors observed a
time- and dose-dependent β-adrenergic augmentation of
membrane CD14 via cAMP-dependent PKA signaling mech­
anisms in mature bone marrow and peritoneal macro­
phages.162 Interestingly, β-adrenergic stimulation of bone
marrow macrophages for >8 hours increased E. coli uptake
through enhanced CD14 expression via PKA, whereas <1
hour incubation reduced the bone marrow macrophage
phagocytic response by some other mechanism, suggestive
of a disparity in adrenergic regulation of phagocytosis.162,163
One potential explanation for the increase in E. coli phago­
cytosis is that by changing the expression of CD14 on mac­
rophage cell surface, β-adrenergic agonists might favorably
change the stoichiometry of CD14/TLR4-MD2 complex
formation leading, to increased bacterial binding to this
complex and eventual phagocytosis.164 In the context where
CD14 is associated with high mortality in Gram-negative
sepsis, the in vitro phagocytosis measurements made with
live E. coli cultures elevate the need for such clinically rele­
vant experimental models.
Although the murine animal model reflects important
clinical features of thermal injury with infection, there may
be important limitations. Whereas the murine animal model
involves immediate infection following thermal injury, burn
patients typically develop septic complications in the second
week of their hospitalization. This does not, however, change
the interpretation of these experimental findings that
increased sympathetic activation in the bone marrow may
result in both increased myelopoietic potential and altered
cellular phenotype following thermal injury with sepsis. This
frame of reference suggests that immune responses following
injury should be considered in the context of the potential
action of sympathetic neurotransmitters on cellular events

Significance of the adrenal and sympathetic response to burn injury
297
Additional explanations for the increased levels of corticos­
teroids in burn patients may be due to the direct inhibitory
effect of corticosteroids on the biosynthesis of CBG.175–177
Furthermore, IL-6 elevation associated with massive burns
has also been implicated in reducing CBG synthesis.178
The hypothalamopituitary–adrenal axis displays a biphasic
pattern during the course of critical illness. In the initial
phase, excessive cortisol levels are associated with elevated
levels of ACTH. In the second phase (3–5 days later) ACTH
levels decline while cortisol remains elevated.2,179 There is
some evidence to suggest that cortisol elevation with
decreased ACTH may be driven by endothelin or atrial
naturetic peptide/hormone (ANP/H). Vermes et al.179 dem­
onstrated that both plasma endothelin and ANP levels were
significantly elevated for 8 days following hospitalization
in severely ill patients with sepsis or trauma. In addition,
infusion of ANP in humans has been shown to block
CRH-stimulated secretion of ACTH and cortisol,180 while
endothelin-1 and endothelin-3 enhance secretion of
steroid hormones from the adrenal cortex.181 Furthermore,
endothelin-3 has been reported to elevate ACTH and
corticosterone levels in rats,182 whereas endothelin-1 results
in elevated ACTH in humans.183 Based on this information,
Vermes et al.179 suggest that endothelin may be responsible
for stimulating steroid secretion, whereas ANP’s action
on the hypothalamopituitary axis may suppress ACTH
secretion, thereby explaining the paradoxical increase in
cortisol with concomitant low ACTH levels in severely
stressed patients.
Release of C19 steroids
Dehydroepiandrosterone sulfate (DHEAS), a weak andro­
gen, is the major secretory product of the human adrenal
cortex. Despite the increase in cortisol secretion by the
adrenals in burn patients, there is a distinct decrease in
serum DHEAS levels184 owing to a reduction in synthesis
and secretion, rather than enhanced metabolism or excre­
tion.185 Whereas serum DHEAS levels decrease gradually,
testosterone and androstenedione levels decrease abruptly.
In some burn patients subnormal testosterone levels persist
for 3–18 months post burn, whereas cortisol levels return
to normal earlier.185 The decrease in testosterone secretion
may be due to a direct effect of excessive cortisol levels on
the testis.186,187
It appears that synthesis of C19 steroids by the adrenals and
testes is compromised as a result of enhanced production of
the C21 steroids, such as cortisol. Aldosterone levels are also
subnormal despite elevated plasma renin activity. This sug­
gests a shift in pregnenolone metabolism away from miner­
alocorticoid and adrenal androgen pathways towards the
glucocorticoid pathway.184 The low level of DHEAS may also
contribute to the immune suppression in burn patients, and
will be discussed later.
Influence on metabolic pathways
High energy expenditure and hyperglycemia are hallmarks
of thermal injury. The heavy demand for energy is due to
the increase in essential functions, such as the synthesis of
complex. Only 1–10% of total plasma cortisol circulates
unbound and is responsible for the biological activity of
glucocorticoids. Burn injury results in a shift in the equilib­
rium between unbound and total cortisol towards an eleva­
tion in the unbound fraction.169 Serum CBG and CBG-binding
capacity are low in burn injury, severe infection, and septic
shock.169–171 In burn patients, CBG levels have been shown
to decrease markedly, with the lowest values occurring 48
hours after injury.172 Even a minor burn such as 3% TBSA
results in a reduction of serum CBG levels by 30%,173 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 concentration
was observed to increase progressively with burn size, with
the highest levels in the 60–99% TBSA burn groups.174
Table 24.2  Influence of glucocorticoids on metabolic and
immune response to thermal injury
Physiologic variable
Glucocorticoid-mediated
change following
burn injury
Resting energy expenditure
Increased5–7
Oxygen consumption
Increased274,275
Primary fuel
Lipids, glucose224
Proteolysis
Increased in skeletal
muscle198,199,201,202,276
Acute phase protein synthesis
Increased178,277,278
Nitrogen excretion
Increased275
Glycogenolysis
Increased via effect on
glucagon194,196
Gluconeogenesis
Increased190,191,277
Lipolysis
Increased225
Ketone body formation
Normal227
Triglyceride level
Increased227,277
Thymic changes
Involution245
  T-cell population
Decreased244,279
  T-cell proliferation
Inhibited246,247,278
  B-cell population
Not conclusive from current data
Neutrophil population
Increased249,279,280
  chemotaxis
Suppressed249
  demargination
Increased249,252
  bactericidal activity
Suppressed253
Monocyte population
Increased transiently with
corticosteroids but decreased in
burn patients139,280,281
  chemotaxis
Suppressed250
  bactericidal activity
Suppressed250,282
Bone formation
Decreased233
Citation of studies from the current literature suggesting that glucocorticoid
release is involved in changing the above physiologic variables following thermal
injury.

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the liver, where, unlike in other tissues, cortisol stimulates
protein synthesis. The increased hepatic protein synthesis in
response to cortisol can drive the new synthesis of gluconeo­
genic enzymes and acute-phase proteins in response to
injury.
The specific mechanisms involved in burn-mediated alter­
ations in protein metabolism are not known. However, some
information could be gleaned from studies on other states
of excessive catabolism. In conditions such as metabolic
acidosis, adrenalectomy halts muscle proteolysis and does
not increase expression of components of the ubiquitin–
proteasome pathway.201,202 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
degradation in myocytes can be abolished by the glucocor­
ticoid inhibitor RU486.203 Ding and coworkers204 suggest
that partial inhibition of the ubiquitin–proteasome pathway
may be beneficial in enhanced catabolic states. Taken
together, these data suggest that interaction of glucocorti­
coids and the ATP requiring ubiquitin–proteosome system
may play an important role in burn-induced proteolysis.204–209
Another aspect of protein catabolism following burn is
the generation of gluconeogenic amino acids. In fact,
plasma levels of alanine are increased following burn.210
Nitrogen produced as a result of transaminating alanine to
the gluconeogenic intermediate pyruvate is converted into
glutamine and then to urea for excretion by the liver.
Glutamine is one of the major participants in the transloca­
tion of amino acids from peripheral tissues to the liver for
nitrogen excretion. Expression of glutamine synthase, the
enzyme responsible for synthesis of this amino acid, is
increased to compensate for the glutamine depletion in
peripheral tissues. Following burn injury, glutamine syn­
thase mRNA is increased first in the lung and later in
muscle.211 This is further supported by the observation that
adrenalectomy partially reduces burn-induced glutamine
synthase mRNA211 in a tissue-specific manner, with no such
effect in the kidney or liver. There is evidence to suggest that
glucocorticoids may augment glutamine synthesis in lung
and muscle tissues.212 Mobilization of protein from periph­
eral tissues is also indicated by the increase in phenyla­
lanine in the blood of burn patients.210 Phenylalanine is the
only amino acid that is not degraded by peripheral tissue,
and hence 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 is completely
healed,5–7,213,214 as reduction in protein catabolism and
enhancement of lean body mass were only seen 9–12
months after the initial injury.213 Therefore, treatments
towards growth deficiency must be prolonged longer than
wound healing.
Other more indirect effects of glucocorticoids on glucose
levels in burn include modulation of insulin-like growth
factor-1 (IGF-1), an important mediator of growth hormone
(GH) action.215,216 Marked depression of all components of
the IGF-1 complex is seen following burn.217–221 Elevated
glucocorticoid levels in burn patients may contribute to the
suppression of the acid labile subunit (ALS) of the IGF-1
complex. Treatment of rats with dexamethasone results in
low levels of serum ALS as well as liver ALS mRNA.222,223
proteins required for wound healing, the synthesis of acute-
phase proteins, and inflammatory mediators. In addition,
severe burns exert a burden on the metabolism to generate
heat, which in part compensates for the loss through the
wound site. Part of the elevation in resting energy expendi­
ture in burn patients is due to the increase in substrate
cycling. This occurs when enzymes catalyzing opposing reac­
tions of the same pathway are active simultaneously. For
example, in the conversion of glucose to glucose-6-
phosphate and back to glucose, the demand for energy is
increased in order to resynthesize ATP used in this and
similar reactions. In burn patients the rate of glucose produc­
tion and glycolysis, as well as of lipolysis and re-esterification
of triglycerides, is elevated.39 This cycling of substrates gener­
ates heat due to the hydrolysis of high-energy phosphate
bonds in ATP, thereby contributing to thermogenesis as well
as increased energy requirements in burn patients. Keeping
burn patients thermally comfortable lowers the metabolic
rate and can therefore reduce the demand for energy.188
Increased glucocorticoid levels during severe burns can
orchestrate multiple metabolic pathways to meet this energy
demand. In order to understand how glucocorticoids may
influence major metabolic pathways to facilitate the hyper­
metabolic state, we will review the effects of glucocorticoids
on glucose, protein, and fatty acid metabolism as they
pertain to thermal injury.
Glucocortiocoids and glucose metabolism
Glucocorticoids can contribute to hyperglycemia, which per­
sists for several days, by enhancing endogenous production
of glucose in the liver.6,189–191 Following burn, elevated
glucose levels are sustained through gluconeogenesis and
impaired glucose utilization. The increased plasma lactate
produced by peripheral tissues following burn, as docu­
mented by Wolfe et al.,192 is an essential substrate for
gluconeogenesis by the liver. Burn injury causes intrinsic
alterations in the liver, which increases the conversion of
pyruvate to oxaloacetate at the expense of non-tricarboxylic
acid cycle sources.193 Mobilization of glucose from glycogen
and skeletal muscle amino acids for gluconeogenesis
requires glucagon secretion,194,195 which is stimulated
by glucocorticoids.194–196 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.6
Glucocorticoids and protein metabolism
Protein catabolism is a part of the hypermetabolic state of
burn, resulting in negative nitrogen balance. Cuthbertson’s197
landmark studies were the first to suggest the important
concept that nitrogen loss is a whole-body response rather
than a local burn-wound response. The increase in proteoly­
sis seen in burn injury is at least partly mediated by
glucocorticoids. In humans198 and in animal models,199
administration of glucocorticoids enhances muscle proteoly­
sis. Further, burn injury-induced muscle proteolysis can be
inhibited by a glucocorticoid receptor antagonist.200 Amino
acids mobilized from peripheral tissues are transported to

Significance of the adrenal and sympathetic response to burn injury
299
through a number of routes. Patients can be infected through
the wound site and by translocation of gut bacteria.238
Surgery and other life-supporting procedures, such as venti­
lation, are also fertile sources of infection. The glucocorti­
coid response to thermal injury appears to play an important
role in immune dysfunction, with impairment of both spe­
cific and non-specific defenses. Corticosteroids reduce lym­
phocyte, eosinophil, and basophil numbers; alter lymphocyte
subpopulations; depress immunoglobulin production by B
cells; and suppress neutrophil and monocyte/macrophage
activity.
Acute thymic involution239,240 and a reduction of the total
T-cell population occur soon after burn injury.239–242 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.243
In humans, the depression of T lymphocytes is reflected by
reduction of both CD4+ and CD8+ cell numbers.241 In an
animal model239 CD4+CD8− cells are reported to be more
sensitive to the effects of thermal injury than CD4−CD8+
cells. CD4+CD8− cell numbers remain constantly depressed
during a 2-week period following burn injury.
Thymic changes following exogenous administration of
glucocorticoids are similar to those seen in burn244,245 in
that exogenous hypercortisolism in non-injury states, or
that following burn injury, is associated with decreasing
CD4+CD8+ and increasing CD4+CD8− thymocytes.240 The
reduction in CD4+CD8+ cell numbers during the first 24
hours after burn is due to glucocorticoid-mediated apopto­
sis, as burn injury-induced thymocyte apoptosis is sup­
pressed by adrenalectomy or the administration of a
glucocorticoid antagonist.240 Other factors contributing to
lymphocyte dysfunction and immunosuppression resulting
from elevated corticosteroid levels may include direct inhi­
bition of T-cell proliferation, IL-2 production,246,247 and the
ability to alter lymphocyte membrane fluidity.248
Apart from these effects on lymphocytes, glucocorticoids
also enhance susceptibility to infections by altering mono­
cyte and neutrophil functions at several stages. Movement
of circulating inflammatory cells to the site of infection
is suppressed by the ability of glucocorticoids to reduce
the cellular response to chemotactic stimuli,249–251 diminish
neutrophil adherence252 and induce a shift from marginal to
circulating cells.249 Glucocorticoids also suppress the bac­
tericidal activity of monocytes250 and neutrophils,253 perhaps
through impairment of lysosomal function.254
Although severe burns are associated with alterations in
B-cell production and function, there is considerable incon­
sistency in the literature.255–260 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.261 Others have found an increase in
circulating B cells early after burn injury.257 Interestingly,
administration of methylprednisolone to normal volunteers
for 2–4 weeks also reduces serum immunoglobulin levels.262
Aside from glucocorticoids, adrenal androgens such as
dehydroepiandrosterone sulfate (DHEAS) also have a pro­
found influence on the immune response ,and a role for
DHEAS as a potent modulator of the immune response is
now well established.263–266 DHEAS, which has immuno­
suppressive properties on Th1 cells, are low during severe
illness.184 In vitro treatment of human T cells with DHEAS
Besides amino acids released from peripheral tissue,224 free
fatty acids are released from adipose tissue by cortisol225 to
be used as an alternate source of fuel during times of crisis.
In burned children and adults increased lipolysis is reflected
in the elevated plasma levels of palmitic and oleic acids.40,226,227
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.228,229 In children, the reduction in
bone mineral density persists for at least 5 years after severe
burn injury (>40% TBSA) and results in permanent retarda­
tion of linear growth.230,231 The reasons for loss of bone
mineral density include increased production of endog­
enous glucocorticoids, the inflammatory response, immobi­
lization, aluminium loading, and production of cytokines
such as IL-1 and IL-6 that facilitate bone resorption.232
Glucocorticoids have potent effects on bone formation
and resorption, resulting in loss of bone mass. Weinstein and
coworkers233 investigated the long-term (equivalent to 3–4
human years) effects of glucocorticoids on bone metabolism
in an animal model and reported a reduction in osteoclas­
togenesis 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 administration as well
as in patients with glucocorticoid-induced osteoporosis.233
This depletion in the bone cell population limits the number
of cells that can synthesize matrix proteins. In addition,
glucocorticoids directly downregulate expression of type I
collagen and upregulate expression of collagenase-3 in
chondrocytes.234 On the other hand, IGF-1 enhances expres­
sion of type I collagen and suppresses the expression of
collagenase-3.235 Thus, the massive increase in glucocorti­
coids and the corresponding decrease in IGF-1 in burn injury
has the ability to profoundly alter bone and cartilage
formation.
The mechanisms by which glucocorticoids mediate bone
resorption are not clear. Glucocorticoids may mediate bone
resorption by its dual capacity to initially inhibit osteoclast
synthesis but later to stimulate osteoclast synthesis coupled
with an increase in bone resorption.236 Yet another mecha­
nism by which cortisol may influence bone resorption is by
suppression of IGF-1 or GH-induced chondrocyte prolifera­
tion.237 The anti-proliferative effect of glucocorticoids may
be mediated through downregulation of the GH receptor
and binding affinity, as well as suppression of the local pro­
duction of IGF-1 by these cells. These effects illustrate prob­
able mechanisms by which glucocorticoids may impair the
growth stimulatory effects of GH.
Glucocorticoids on immune suppression
Severely burned patients are susceptible to opportunistic
infections, and sepsis is a major cause of death associated
with burn. Immune suppression occurs soon after burn
injury, perhaps to prevent over-responsiveness. However, this
leaves the patient extremely vulnerable to bacterial infection

Total Burn Care
24
300
signaling pathways, their role as modulators of gene expres­
sion is still being explored. On the other hand, although
much is known about the modulation of gene expression by
glucocorticoids, very little is known about their modulation
of gene expression following severe thermal injury or other
forms of trauma. Future studies hold great promise of pro­
viding important new information in these areas as to how
these bioactive compounds may influence responses to
thermal injury, and how such information can lead to the
development of new treatment modalities.
Further reading
Atiyeh BS, Gunn SW, Dibo SA. Metabolic implications of severe burn
injuries and their management: a systematic review of the
literature. World J Surg. 2008;32(8):1857-1869.
Cuthbertson D. Post-shock metabolic response. Lancet. 1942;1:
433-436.
Goodall M, Stone C, Haynes BW. Urinary output of adrenaline and
noradrenaline in severe thernal burns. Ann Surg. 1957;145(4):
479-487.
Norbury WB, Herndon DN, Branski LK, et al. Urinary cortisol and
catecholamine excretion after burn injury in children. J Clin
Endocrinol Metab. Apr 2008;93(4):1270-1275.
Seyle H. A syndrome produced by diverse nocuous agents. Nature.
1936;138:32-33.
Tang Y, Shankar R, Gamboa M, et al. Norepinephrine modulates
myelopoiesis after experimental thermal injury with sepsis. Ann
Surg. Feb 2001;233(2):266-275.
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.
increases IL-2 production (which is required for clonal
expansion) and IL-2 mRNA synthesis.266 It is interesting to
note that 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 untreated cells.
Yet another factor that profoundly influences immune
status and adrenal steroid secretion in burn patients is the
neurotransmitter dopamine. Dopamine is often used in the
treatment of critically ill patients because of its vasopressor,
renal vasodilator and cardiac inotropic properties. However,
several studies indicate that dopamine treatment may under­
mine 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 concentration.267,268 In
vitro, prolactin has a synergistic effect on ACTH-induced
DHEAS secretion by human adrenal cells.269 Thus it is pos­
sible that the dopamine-induced suppression of prolactin is
responsible for lowering DHEAS levels and hence suppres­
sion of the T-cell proliferative response. The in vitro prolif­
erative response of T cells from patients on dopamine
therapy is diminished,267 and cells treated with DHEAS
mediate a more potent T-cell cytotoxic effect.266 Dopamine
levels are elevated under conditions of severe physical stress
and chronic illness.270,271 This may be partly responsible for
the anergic state of the immune system during severe stress.
This review affirms that catecholamines and adrenal
steroid hormones are integral parts of the physiologic
response to thermal injury that are thought to support
recovery through compensatory cardiovascular, metabolic,
and immunologic changes. Although adrenergic mechanisms
are important for their ability to influence intracellular
 
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300.e1
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230. Klein GL, Herndon DN, Langman CB, et al. Long-term
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238. Herndon DN, Zeigler ST. Bacterial translocation after thermal
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241. Maldonado MD, Venturoli A, Franco A, et al. Specific changes in
peripheral blood lymphocyte phenotype from burn patients.
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247. Taniguchi T. Regulation of cytokine gene expression. Annu Rev
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248. Tolentino MV, Sarasua MM, Hill OA, et al. Peripheral
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249. Dale DC, Fauci AS, Wolff SM. Alternate-day prednisone.
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252. MacGregor RR, Spagnuolo PJ, Lentnek AL. Inhibition of
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253. Mandell GL, Rubin W, Hook EW. The effect of an NADH
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254. Hibbs JB Jr. Heterocytolysis by macrophages activated by
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257. Kagan RJ, Bratescu A, Jonasson O, et al. The relationship
between the percentage of circulating B cells, corticosteroid
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258. Kawakami M, Meyer AA, deSerres S, et al. Effects of acute
ethanol ingestion and burn injury on serum immunoglobulin.
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261. Kawakami M, deSerres S, Meyer AA. Immunoglobulin synthesis
by cultured lymphocytes from spleen and mesenteric lymph
nodes after thermal injury. J Burn Care Rehabil. 1991;12(5):
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262. Butler WT, Rossen RD. Effects of corticosteroids on immunity in
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dehydroepiandrosterone to burned mice preserves normal
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264. Blauer KL, Poth M, Rogers WM, et al. Dehydroepiandrosterone
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265. Daynes RA, Meikle AW, Araneo BA. Locally active steroid
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in the increase of oxidative phosphorylation coupling in rat-liver
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wound on local and systemic responses to injury. Ann Surg.
1977;186(4):444-458.
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276. Batstone GF, Levick PL, Spurr E, et al. Changes in acute phase
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277. Batstone GF, Alberti KGMM, Hinks L, et al. Metabolic studies in
subects following thermal injury. Burns. 1976;2(4):207-225.
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279. Calvano SE, Albert JD, Legaspi A, et al. Comparison of
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509-520.
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281. Wallner S, Vautrin R, Murphy J, et al. The haematopoietic
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282. Rinehart JJ, Sagone AL, Balcerzak SP, et al. Effects of
corticosteroid therapy on human monocyte function. N Engl J
Med. 1975;292(5):236-241.

The hepatic response to
thermal injury
Marc G. Jeschke, Celeste C. Finnerty
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 in the control of 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. These authors, and others, have elucidated
the function of the liver following a severe burn injury, and
these studies have demonstrated that both the integrity of
liver and the preservation of liver function are essential for
survival. The expression of hepatic cytokines and acute phase
proteins, which strongly correlates with post-burn survival,
further supports this contention.
More than 2 million Americans each year experience a
thermal injury – one of the most severe examples of a trau­
matic injury.1 Worldwide, the World Health Organization
(WHO) attributes >330 000 deaths each year to thermal inju­
ries and their sequelae.2 In the USA alone, more than 440 000
children are treated for burn injuries annually.3 Severe burn
injuries – the third most common cause of death for Ameri­
can children – account for up to 1100 pediatric deaths each
year,4,5 accounting for a significant number of hospital
admissions.6,7 The effects induced by these injuries are not
limited to the injured area alone. A severe burn injury has a
devastating effect on the injured patient by affecting almost
every organ system, resulting in heightened morbidity and
mortality.8 Amplified availability of glucose leads to increased
protein catabolism and lipolysis, initiating the post-burn
hypermetabolic stress response.7–9 Systemic inflammation,
including pathophy­siologic regulation of cytokines, hor­
mones, and acute phase proteins, drives the hypermetabolic
stress response.10–12 Prolongation or amplification of the
hypermetabolic, inflammatory, or acute phase responses
may result in dysregulation of counter-regulatory stress hor­
mones (catecholamines, cortisol, glucagon), thereby exacer­
bating post-burn hyper­catabolism, multi-organ failure, and
death.11–13
For more than 20 years, focused research efforts on improv­
ing post-burn resuscitation, hypermetabolism, infection,
ventilation, resuscitation, and wound healing have led to
reduced morbidity and mortality.7 Further advances in clini­
cal care, however, are needed to reduce morbidity and mor­
tality even further. Through a series of studies, we have built
a foundation that supports the hypothesis that the liver is
a central player in the response to burn.14–17 Through the
modulation of immune, inflammatory, metabolic, and acute
phase response signal transduction pathways, the liver con­
tributes greatly to survival and recovery following a severe
burn injury.13 Because of the dearth of information delineat­
ing the liver’s role after a thermal injury, we have spent the
past 15 years engaging in studies to shed light on this topic.
This chapter discusses liver function under normal condi­
tions and following a severe insult such as a burn injury.
Anatomy, function, and physiology of the liver
Anatomy
In an average-sized adult, the liver weighs approximately
1500 g, making up almost 2% of total body weight. When
the liver is injured, such as following a severe burn injury,
its size can increase as needed to meet the additional
demands. The lobar anatomy is used to divide the liver in
the American system, using the intrahepatic location of the
branches of the hepatic artery, portal vein and bile ducts. In
this method, the left lobe is divided into medial and lateral
sections, while the right lobe is divided into anterior and
posterior sections. Soupault and Couinaud’s segmental
system is used by the French to divide the liver into VIII seg­
ments. The hepatic artery and the portal vein are the two
sources of the liver’s blood supply. One-quarter of the hepatic
blood flow occurs via the hepatic artery, which provides
oxygenated blood. Three-quarters of the blood flow through
the liver is accounted for by the portal vein, which drains the
splanchnic circulation.18
Physiology
A broad spectrum of biological functions is orchestrated by
the liver. The fine interrelated physiologic-anatomic units
of the liver direct these necessary processes: regulation of
energy availability; nutrient management (including storage,
©2012 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2786-9.00025-4
CHAPTER 25 
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25
302
Portal venous flow into the liver is largely regulated by
extrahepatic factors, including the flow rate from the intes­
tines and spleen, food, bile salts, secretin, cholecystokinin,
pentagastrin, epinephrine, vasoactive intestinal peptide, and
glucagon. With blood making up 25–30% of the liver
volume, the liver acts as a reservoir that can be tapped in
time of physiologic need. More than 300 mL can be released
into systemic circulation without adversely affecting liver
function during acute blood loss. The liver can also store
great amounts of blood – up to 1000 mL of blood can be
taken up during right-sided heart failure without adversely
affecting liver function.18–20
Biliary system
Although bile secretion occurs independently of liver blood
flow, this is not the case when a patient is in shock. Bile is
either formed at the hepatocyte’s canalicular membrane or
by the bile ductules and ducts. Hepatocytes secrete the
majority (four-fifths or approximately 1500 mL) of the total
daily production of bile, while the bile duct epithelial cells
secrete the remaining fifth. Phospholipids, proteins, conju­
gated bile acids, and cholesterol are the principal organic
compounds in bile. Bile is modified by epithelial cells as it
passes through the biliary ductules or ducts. Cholangiocytes,
the highest cells lining the biliary ductules, seem to be
hybrids of hepatocytes and ductular cells due to common
functions and architecture. Bile secretion is stimulated by
secretin, and the bile is secreted into the gallbladder where
it is concentrated and stored under fasting conditions.
Concentration of bile within the gallbladder is stimulated
principally by cholecystokinin, with absorption of up to
90% of the water occurring within a 4-hour period. Bile is
forced into the intestines following gallbladder contraction
induced by cholinergic stimulation and subsequent relaxa­
tion of the sphincter of Oddi. The majority of the bile salt
is absorbed into the enterohepatic circulation. Bile acids are
then extracted by the liver and transported back to the canal­
icular membrane for re-secretion into the biliary system.
Complete circulation of the total bile pool occurs 6–10
times/day in addition to 2–3 times per meal. Of the total
2–5 g pool, each day 0.2–0.6 g are lost in the stool; however,
this is rapidly replaced by the synthesis of new bile acids.20
When heme breaks down, bilirubin is produced and elimi­
nated in the bile. Accumulation of bilirubin in the tissue
or blood may occur with extrahepatic biliary obstruction
or hepatocellular disease. The conjugation of bilirubin to
albumin protects tissue from bilirubin’s toxicity until it is
removed from the circulation by the liver via a carrier trans­
port system. Bilirubin and glucuronide are conjugated within
the hepatocyte, and then secreted into the bile. When this
complex binds covalently with albumin, delta bilirubin is
formed. Bacterial reduction of bilirubin in the intestine
yields mesobilirubin and stercobilirubin, together known as
urobilirubin, which are then excreted in the stool. Oxidation
of urobilinogen to urobilin gives the stool its normal brown
color.18–21
Mononuclear phagocyte system (MPS)
The mononuclear phagocyte system (MPS), formerly known
as the reticuloendothelial system (RES), is a component of
distribution, and disposal); substrate synthesis, transforma­
tion, and metabolism; and metabolism and removal or
toxins and pollutants.18,19
1. The circulatory system. In order to build the pool of
metabolites for energy and other functions, the liver
extracts nourishment from the blood supply that
extracts absorbed nutrients from the intestinal tract.
2. The biliary system. Bilirubin, cholesterol, detoxified
drugs, and other liver-secreted substances are
eliminated through the biliary system.
3. The mononuclear phagocyte system (MPS) (formerly
known as the reticuloendothelial system, RES). A part of
the immune system that detects antigens and disposes
of senescent cells. Within the liver, Kupffer, endothelial,
and phagocytic cells make up 60% of the MPS.
4. The hepatocytes. The metabolic demands of the entire
body are met by the body. These cells synthesize,
secrete, and store metabolites, and perform catabolic
and anabolic functions. The generation of energy by
converting adenosine triphosphate (ATP) to adenosine
diphosphate (ADP) fuels local and systemic functions.
5. The liver as the source of hormones. The liver is the site
of the synthesis and secretion of a variety of hormones
including insulin-like growth factor-I (IGF-I), IGF
binding proteins (IGFBPs), and hepatocyte growth
factor (HGF). In addition to synthesizing and secreting
necessary hormones, the liver acts as both a paracrine
and an endocrine tissue, thereby amplifying the hepatic
role in the hormonal axes.
Circulatory system
The majority of metabolic processes are regulated in one way
or another by the liver. To fuel these functions, the liver
expends 20% of the body’s total energy supply while con­
suming up to 25% of total utilized oxygen. These utilizations
are not as high as one might expect due to an unfettered
blood supply and the unique architecture within the liver.
Estimations of the mean total hepatic blood flow range from
100 to 130 mL/kg per min. The majority (three-quarters) of
the total hepatic blood flow is via the portal vein, while the
remaining quarter is from the hepatic artery. When portal
flow is reduced, a reciprocal increase in hepatic arterial blood
flow follows; however, the reverse does not occur.13,18 Plasma
membrane-bound hepatocellular organelles enable specific
functions while concurrently interacting with the extracel­
lular matrix, facilitating exchange of metabolites between
the blood compartment and the hepatocytes.18,19 At the same
time, the liver manufactures proteins, substrates, enzymes,
and other substances for local use as well as for use by distal
organs and tissues. Metabolic signals direct the liver to
produce substrates needed to meet the energy requirements
in other tissues. For example, the liver produces acetoacetate
for utilization by brain, muscle, and the kidneys; however,
this substrate is not used by the liver. Agonists, hormones,
and substrates regulate the hepatic energy-related functions.
As the liver receives blood via the arterial and portal circula­
tion, nutrients are processed while toxins are metabolized,
and then these are stored for later use, transformed for
immediate use, or distributed to their final destination via
lymphatic, vascular, or biliary circulations.

The hepatic response to thermal injury
303
only apparent when coupled with extensive hepatic disease.
Hyperglycemia, however, results from deficiencies in glyco­
genesis and commonly occurs alongside severe liver disease.
Under ordinary conditions, lactate is produced in the muscles
as a result of anaerobic glycolysis. The lactate is then shuttled
to the liver where it is converted back into glucose, which is
then sent back to the peripheral tissues. The constant shut­
tling of lactate and glucose is known as the Cori cycle. The
brain must be continually supplied with glucose as it does
not participate in the Cori cycle. Under starvation condi­
tions, glucose is supplied to the brain at the expense of
muscle proteins. Glucose metabolism is often deranged in
liver disease. Patients with cirrhosis of the liver frequently
experience a reduction in the portal-systemic shunting,
decreasing the hepatocyte exposure to portal blood. The
clinical presentation of this occurrence is an abnormal result
following an oral glucose tolerance test. As the severity of
the liver disease progresses, so does the extent of the dysfunc­
tion. In patients with fulminating hepatic failure, massive
loss of hepatic mass and hepatocyte function occurs, leading
to hypoglycemia as gluconeogenesis ceases.21
Lipid metabolism
Absorption of fat from the gut, lipolysis-induced liberation
of fat from adipocytes, and synthesis of fatty acids from
amino acids and carbohydrates are the three main sources
of free fatty acids (FFA) used by the liver. Triglycerides (TG)
are then formed following the etherification of FFA with
glycerol. TG export is a direct function of the availability of
very low density lipoproteins (VLDL). Lipids accumulate in
the liver in the presence of excess FFA; this results from an
imbalance in the TG to VLDL ratio and is commonly a
sequela of pregnancy, obesity, diabetes, corticosteroid use, or
total parenteral nutrition. When inadequate amounts of
protein are ingested or absorbed, the liver undergoes fatty
alterations as the TG accumulate due to limited protein avail­
ability for lipoprotein synthesis.21,25
In addition to TG and FFA, cholesterol and phospholipid
synthesis occurs in the liver, and lipid metabolism can be
indirectly determined by measuring cholesterol production.
The liver is the primary site of cholesterol synthesis, esterifi­
cation, and excretion. There is a decrease in total cholesterol
as well as in the percentage of esterified cholesterol when
parenchymal damage is present. Elevations in cholesterol
can result from biliary obstruction, biliary cirrhosis, or as a
result of toxic reactions to phenothiazine drugs.20,21
Protein metabolism
The liver synthesizes and secretes 17 of the major plasma
proteins in addition to the majority of urea produced in the
body. Measurement of serum proteins produced by the liver
can serve as an index of hepatic function. The liver is the sole
producer of serum albumin and α-globulin. The most abun­
dant serum protein is albumin, and its creation accounts for
approximately 15% of total hepatic protein synthesis. As a
result, serum albumin levels can be used as a marker of liver
function, liver disease, or side-effects following therapeutic
administration. However, albumin has a half-life of 21 days;
therefore, albumin can only be used to monitor reductions
in hepatic protein synthesis if the condition has continued
the immune system and is made up of phagocytic cells,
mainly monocytes and macrophages residing in the reticular
connective tissue – such as the Kupffer cells in the liver. The
Kupffer cells participate in the immune response by detect­
ing foreign antigens and mobilizing the subsequent immune
response. These cells further participate in immune function
by removing and digesting senescent cells residing in the
liver tissue.
Metabolic system
Acute phase response
In order to limit tissue damage and to initiate repair proc­
esses, the acute phase response (APR) is triggered following
activating events such as a severe burn or trauma.13,22 Pro-
inflammatory cytokines are released locally by fibroblasts,
endothelial cells, and activated phagocytic cells, which then
leads to systemic dispersion of the APR.13,22 The systemic
phase of the APR induces a body-wide response encompass­
ing the participation of many organs. The hypothalamus
acts to raise body temperature, leading to fever. Steroid
hormones are released by the pituitary–adrenal axis. Acute
phase proteins are synthesized and secreted by the liver.
Further promulgation of the hemopoietic responses is initi­
ated in the bone marrow. Finally, the MPS involves the
immune system in the APR, as the lymphocytes are activated
to detect foreign antigens.13,22 The interaction between the
injury site and the liver, however, is a critical step in the
initiation of the APR, as the liver is the primary site of acute
phase protein production and modulation of the systemic
inflammatory response. The APR is characterized by increased
production of positive acute phase proteins such as C-
reactive protein, α2-macroglobulin, and haptoglobin, with
decreased expression of negative acute phase proteins,
including albumin, transthyretin, transferrin, and retinol-
binding protein.
Carbohydrate metabolism
Another major function of the liver is to provide a readily
available source of energy – glucose – to the adrenal medulla,
red blood cells, and the central nervous system. Postprandial
intestinal carbohydrate digestion delivers 80% glucose and
20% galactose and fructose to the liver, where galactose and
fructose are rapidly converted into glucose. Hepatocytes
absorb the glucose and convert it directly into glycogen for
storage. Up to 65 g of glycogen per kg of liver mass can be
stored in this manner, while excess glucose is converted to
fat. Although skeletal muscle also produces glycogen, it is
only for use locally by this tissue. The glycogen produced by
the liver is unique, in that it is available for use by other
tissues when needed. Under fasting or starvation conditions,
glycogen conversion is the primary source of glucose for the
first 48 hours. After that, liver glycogen stores have been
depleted, and proteins and fat are instead mobilized to meet
the metabolic demands. The main substrate mobilized in the
muscle is alanine, which then is converted into glucose by
the liver.23,24
Adequate glucose synthesis is ensured by hepatic glycog­
enolysis, glycogenesis, and the conversion of galactose into
glucose. As a result, hypoglycemia is a rarity and is usually

Total Burn Care
25
304
damaged, the hepatocellular dysfunction is so extensive that
prothrombin is not produced at all. Clinical measurements
of prothrombin and prothrombin time can be used to deter­
mine whether the synthesis of prothrombin has been
impaired. Hepatic disease is also associated with reductions
in factors V, VII, IX, and fibrinogen.20,21
Hormonal system
The liver is the site of hormonal synthesis, secretion, or
interaction. Production and secretion into the bloodstream
of angiotensinogen occurs within the liver. As noted
above, Vitamin D is synthesized when cholecalciferol is
hydroxylated by the enzyme 25-hydroxylase to become
25-hydroxycholecalciferol. Growth factors that are impor­
tant for growth and development such as insulin-like growth
factor-I (IGF-I) and the IGF binding proteins (IGFBPs) are
made and secreted by the liver. Growth hormone (GH), the
primary stimulus for the production of IGF-I, is produced by
the pituitary gland but acts mainly on the hepatic cells
(GH). Finally, synthesis of hepatocyte growth factor (HGF),
a major hepatic regenerative growth factor, occurs in the
liver.27
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 post-burn finding (Fig. 25.1). These
changes can be reversed; however, the significance of these
alterations depends on the cause and the extent of the fat
accumulation.28 Autopsies of deceased pediatric burn victims
have revealed that fatty infiltration of the liver is associated
with increased bacterial translocation, liver failure, and
for at least 3 weeks. Furthermore, one has to be cautious to
interpret albumin levels, as albumin synthesis can be affected
by nutrition, hormones, and inflammatory mediators.16,26
In addition to albumin, hepatic cells also produce fibrino­
gen, prothrombin, and other blood clotting factors. Despite
the numerous proteins being produced by the liver, total
protein cannot be used to reflect the extent or severity of liver
disease. Although albumin concentrations accurately corre­
late with liver disease, only hepatic cells produce albumin,
so decreases in albumin production trigger a compensatory
increase in globin concentrations.21
Vitamin metabolism
Vitamin uptake, storage, and mobilization are additional
important functions of the liver. The absorption of fat-
soluble vitamins (A,E,D, and K) is dependent on bile salts.
At 2–6 hours following oral administration, these vitamins
can be found in the thoracic duct. Because Vitamin A is
stored exclusively in the liver, excess ingestion may be associ­
ated with significant hepatic injury. Ito cells (fat-storing
cells) are thought to play a role in Vitamin A storage as well.
The initial Vitamin D activation step, conversion of Vitamin
D3 to 25-hydroxycholecalciferol, occurs in the liver. Coagula­
tion factors II, VII, IX, and X are dependent on Vitamin K,
which is essential for the γ-carboxylation, and activation, of
these factors (see below).20,21 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.
Coagulation
Many of the blood coagulation factors are produced in the
liver. When liver disease is present, these factors may be
altered or rendered defective. There is a decrease in Vitamin
K resorption and a subsequent reduction in prothrombin
synthesis in the jaundiced liver. When the liver is severely
Figure 25.1  (a) Massive hepatomegaly (upper)
and hepatic fatty infiltration (lower) of a burn
victim at autopsy. (b) Liver size increased
throughout acute hospitalization by over 200% in
242 surviving burn patients. (With permission from
Jeschke MG. The hepatic response to thermal injury: is the
liver important for postburn outcomes? Mol Med.
2009;15:337-351.)
Time postburn
* Significant difference
burn vs. normal, p<0.05.
*
*
*
*
Week 1
Normal Range
D/C
Week 3
Week 2
Liver size
% to Predicted
260
140
120
160
100
220
240
200
180
Aii
B
Ai

The hepatic response to thermal injury
305
release of the hepatic enzymes into the circulation. Following
a severe burn, elevations between 50% and 200% above age-
matched normals are recorded for serum AST, ALT, and ALKP
(Fig. 25.2). These serum markers peak early – AST and ALT
during the first post-burn day and ALKP during the second,16,26
indicating that burn-induced liver damage is a rapid phe­
nomenon. During the acute hospitalization period, there is
regeneration of the liver, which is apparent by the return of
these enzymes to baseline. Although these enzymes are ele­
vated as a direct result of the burn injury, additional physio­
logic processes may be amplifying their expression, including
the elevation of ALKP occurring during growth spurts or
alongside massive bone resorption. The careful evaluation of
hepatic enzyme levels is warranted, and we recommend the
comparison of multiple enzymes, as opposed to a single one,
to determine whether liver damage is resolving.
Increases in hepatocyte death, both by apoptosis and
necrosis, are associated with liver damage.15 Two distinctly
different pathways result in cell death – programmed cell
death (apoptosis) and necrosis.30 Cell shrinkage, uniform
fragmentation of DNA, and membrane blebbing character­
ize apoptotic cells, with the cell fragments being phagocy­
tized by neighboring 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 inflam­
matory cells, causing them to release free radicals and
endotoxemia.29 How these fatty changes in the liver are
induced by a burn injury is largely unknown; however, we
posit that hepatic apoptosis (described in detail below) plays
a major role in this development. Immediately following the
thermal injury, increased hepatic edema is associated with
damage to the liver. Jeschke et al.15 have shown that liver and
body weight significantly increase at 2-7 days post-burn, as
compared to non-burned liver/body weight. We also found
that in burned rats, total hepatic protein concentrations were
reduced significantly. These findings led to the notion that
increased edema, not increased protein levels or hepatocyte
numbers, underlies the increase in liver weight. This increase
in edema, however, may induce release of hepatic enzymes
into the circulation as a result of cellular damage or by alter­
ing membrane permeability. Aspartate aminotransferase
(AST) and alanine aminotransferase (ALT) are typically
detected only at low levels in plasma. Therefore, their detec­
tion at elevated levels in the circulation are reliable indica­
tions of hepatocyte injury. Because elevations of AST can
occur as a result of cardiac arrest or following muscle injury,
ALT is considered to be a more specific test for hepatocyte
injury. Severe hepatic damage can also be detected by eleva­
tions in serum glutamate dehydrogenase or alkaline phos­
phatase (ALKP). Elevations in ALKP provide insight into the
function of the extrahepatic biliary tract as well and are fre­
quently elevated in hepatobiliary disease. The liver damage
induced by thermal injury is a result of the combination
of edema formation, hypoperfusion, expression of pro-
inflammatory cytokines and other cell death signals, and the
Figure 25.2  Hepatic dysfunction of the rat burn model mimics the post-burn human disease state. (a) Serum aspartate amino transferase (AST) 24 and
48 h after thermal injury. (b) Serum alanine amino transferase (ALT) 24 and 48 h after thermal injury. (c) Serum albumin 24 and 48 h 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 (Control) and 24 h after (Burn) thermal injury. (f) Quantified TUNEL positive cells
24 and 48 h 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. (With permission from Jeschke MG. The hepatic response to thermal injury: is
the liver important for postburn outcomes? Mol Med. 2009;15:337-351.)
*
*
A
AST (U/L)
100
200
300
400
500
600
0
C
B
24
C
B
48
*
*
B
ALT (U/L)
20
40
60
80
100
120
140
160
180
200
Control
Burn
0
C
B
24
C
B
48
*
*
C
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
*
*
D
Caspase-3
(OD/OD actin)
0.1
0.2
0.3
0.4
0.0
C
B
24
C
B
48
*
*
F
Ei
Eii
TUNEL positive cells (%)
1
2
3
4
0
C
B
24
C
B
48

Total Burn Care
25
306
protein burden can be limited through the use of chemical
chaperones, this discovery may be of therapeutic significance
as a method to promote hepatocyte survival.47 Alternative
pharmacologic agents are being developed to block pro-
apoptotic ER stress signaling pathways, and, looking ahead,
these alternatives may prove beneficial in the clinic by
improving organ function and patient survival.48
Effects on the biliary system
Intrahepatic cholestasis frequently occurs following trauma
or sepsis without demonstrable extrahepatic obstruction.
Conditions such as drug toxicity, total parenteral nutrition,
and hypoxia are also associated with this phenomenon.49
The occurrence of intrahepatic cholestasis is associated with
impaired bile acid and organic anion transport in basolateral
and cunicular hepatocytes.50,51 Reduction of transporter RNA
and protein expression and the subsequent increase in bile
potentially indicate the molecular mechanism driving the
development of one of the major mani­festations of hepato­
cellular injury. In a clinical study, intrahepatic cholestasis
was reported in 26% of patients.28
pro-inflammatory cytokines, leading to additional tissue
breakdown. The morphological 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 liver necrosis, as determined by
pathological examination.28 The hepatic necrosis related to
burn-induced shock or sepsis was typically focal or zonal,
central or paracentral, and sometimes microfocal.
Apoptosis also occurs in the liver following a cutaneous
thermal injury (Fig. 25.2).15 The liver tries to maintain
homeostasis when hepatocyte apoptosis increases by a com­
pensatory increase in hepatocyte proliferation. Despite the
attempt to maintain homeostasis in overall hepatocyte
number, the liver is unable to immediately regain mass or
maintain protein concentration. A severe thermal injury also
can induce apoptosis of the epithelial cells in the small
bowel.31,32 Additionally, no increase is found in proliferation
of the epithelial cells in the small bowel, resulting in a
net loss of mucosal cells, and ultimately this is apparent
as reduction in mucosal mass.31,32 Cardiomyocytes are
similarly affected by burn injury,33,34 although despite apop­
tosis of the cells, there is no compensatory increase in
cardiocyte proliferation, leading to cardiac impairment and
dysfunction.33,34
The molecular mechanisms that initiate and propagate
hepatocyte apoptosis following a cutaneous burn are not
known, although recent work associates hypoperfusion and
ischemia-reperfusion with the induction of programmed cell
death.35–38 Blood flow to the bowel is decreased by approxi­
mately 60% for up to 4 hours following a thermal injury.31
Hepatic blood flow is likely decreased as well, and this
may be one of the early events inducing programmed cell
death. Apoptotic signals, including IL-1 and tumor necrosis
factor (TNF)-α increase systemically during this same time
frame.30,39–42 Additional studies have revealed that these
elevations 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.14,43–45 Taken together, these events –
reduced splanchnic bloodflow and elevation of pro-inflam­
matory cytokines – are probably early events in the induction
of hepatocyte apoptotic signaling.
Identifying molecular mechanisms
In identifying the molecular mechanisms that mediate the
induction of hepatocyte apoptosis and dysfunction follow­
ing a severe burn (Fig. 25.3), recent work has shown that ER
stress is increased following a thermal injury and that
cell-wide alterations in calcium are apparent with specific
reductions in ER calcium that led to increases in cytosolic
calcium.46 Mitochondrial damage occurs as a result of
increased cytosolic calcium, leading to the release of cyto­
chrome c which then binds to the inositol triphosphate
receptor (IP3R), inducing further depletion of calcium stores
in the ER. ER stress and the unfolded protein response trigger
apoptosis by activating JNK and initiating the downstream
response. The serine on IRS-1 is then phosphorylated, block­
ing the tyrosine on the same protein from being activated by
phosphorylation. At the same time, the pro-survival PI3K/
Akt signaling pathway is blocked, amplifying the ER stress
response by further activating the IP3R. If the unfolded
Figure 25.3  Schematic of suggested pathways involved in the hepatic
response post-burn. Thermal injury leads to gross alterations in ER calcium
with increased cytosolic calcium concentration. Increased cytosolic calcium
induces mitochondrial damage, which releases cytochrome c. Cytochrome c
increases the existing ER stress/UPR but also binds to the IP3R, augmenting
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
pro-survival PI3K/Akt signaling, resulting in increased activation of the IP3R,
increasing ER stress/UPR. (With permission from Jeschke MG. The hepatic response to
thermal injury: is the liver important for postburn outcomes? Mol Med. 2009;15:337-351.)
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

The hepatic response to thermal injury
307
The precise temporal occurrence of the modulation of
these post-injury metabolic events has led to the classifica­
tion of two events: the ‘ebb phase’ and the ‘flow phase’.26,66
The first 12–14 hours following a severe burn injury is called
the ‘ebb phase’.66–68 Events characterizing this period include
decreased cardiac output, reduced oxygen consumption,
attenuated metabolic rate, and a hyperglycemic state with
impaired glucose tolerance. These metabolic processes slowly
increase to a plateau over the next 5-day period, termed the
‘flow phase’. This is when a hyperdynamic circulation devel­
ops and the hypermetabolic state is noted.66 During this
time, insulin release in response to glucose challenge is twice
that seen in non-burned volunteers.26,69 With concurrent
elevation in plasma glucose levels, insulin resistance charac­
teristically develops during this period as well.26,69 Although
these metabolic alterations were assumed to resolve as soon
as wound closure was complete and the patient was well
enough to be discharged, we have recently determined that
the hypermetabolic response induced by a severe burn injury
may last for 12 months or more.16,58,70,71
Under normal conditions, there is tight regulation of
glucose metabolism. In a non-injured state, blood glucose
concentrations increase following a meal, stimulating the
pancreatic β-cells to release insulin. Peripheral uptake of
glucose into adipose and skeletal muscle tissue is mediated
by insulin. Blood glucose homeostasis is maintained by the
concurrent suppression of hepatic gluconeogenesis.72,73
Because the metabolic alterations that accompany critical
illness have the potential to induce significant changes in
energy substrate metabolism, glucose availability must be
maintained. The release of the stress mediators (catecho­
lamines, etc.) acts in opposition to the anabolic actions of
insulin, by augmenting hepatic glucose production74 to
increase gluconeogenic substrates such as glycerol, alanine,
and lactate by increasing lipolysis of adipose tissue75
and proteolysis of skeletal muscle.72,73,76,77 The release of
hepatic glucose is not suppressed by hyperglycemia,23 and
the suppressive effect of insulin on hepatic glucose release
is attenuated, significantly contributing to post-trauma
Mononuclear phagocyte system (MPS)
The immune system is severely compromised following a
major thermal injury, resulting in heightened susceptibility
to infections and sepsis.52–54 The phagocytic functions of the
MPS are depressed post-burn,55,56 although the mechanism
by which this occurs is unknown. Investigations have
demonstrated that MPS dysfunction may be related to
hemolysis.55,56 The liver is also a significant source of the
inflammatory response and the APR, by increasing produc­
tion of acute phase proteins and proinflammatory cytokines,
thereby further impacting the immune response.15,16,22,43,57
Metabolic system
Glucose, protein, and lipid metabolism (Fig. 25.4)
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 development
of a hyperdynamic circulation, temperature elevation, and
increases in glycolysis, gluconeogenesis, glycogenolysis,
proteolysis, lipolysis, and futile substrate cycling.58–60 These
massive alterations in major physiologic processes occur fol­
lowing traumatic injury and critical illness as well, although
the duration, severity, and the magnitude of these responses
are far greater in severely burned patients.7 The hypermeta­
bolic response is believed to be initiated by huge elevations
in catecholamines, glucocorticoids, glucagon, and dopamine
via an unknown, yet probably highly complex, cascade of
events.7,8,26,61–63 Additional players in this response, however,
have been identified, including pro-inflammatory cytokines
(interleukin (IL)-1 and IL-6, TNF), platelet-activating factor,
endotoxin, neutrophil-adherence complexes, free radicals
(reactive oxygen species and nitric oxide), and factors
involved in the coagulation and complement cascades.64 Fol­
lowing activation of the biological processes, these media­
tors and the resulting by-products contribute to the increased
metabolic rate and altered glucose metabolism that occurs
following thermal injuries.65
Figure 25.4  Metabolic changes post-burn with
the liver playing an essential role. (With permission
from Jeschke MG. The hepatic response to thermal injury: is
the liver important for postburn outcomes? Mol Med.
2009;15:337-351.)
Lactate
Wound
6 carbon 3 carbon flow
Heat

± Insulin
++++ Catecholamines
++++ Glucagon
++++ Gucocorticoids

± Insulin
++++ Catecholamines
Glycogen
Protein
3-C
3-C
Heat
Glycogen
Protein
Urea
Fat
Fatty
acids
Triglycerides
Glucose
Anaerobic metabolism
Skeletal muscle
Liver