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Study of the Effect of Two Different Techniques of Early Burn Wound Excision on the Alteration of Interleukin-6
and Tumor Necrosis Factor-Alpha Levels in Severe Burns
A Thesis Submitted for Partial Fulfillment of M.D. degree in Plastic and Reconstructive Surgery
Doctor Mohamed Ahmed El Rouby
Consultant of Plastic & Reconstructive Surgery
Ain Shams University – Cairo – Egypt
+2 0101556023
+2 0126531265
http://www.elroubyegypt.com
http://tajmeel.ohost.de
محمذ أحمذ الروبي. د
مصر -القاهرة - مذرس جراحات التجميل واالصالح بجامعة عين شمس
Keywords
- Burn.
- Tangential excision.
- Down-to-fascia excision.
- Fascial excision.
- IL-6.
- TNF-α.
Index A
Index A
List of Figures C
List of Tables D
List of Charts E
List of Abbreviations F
Introduction 1
Aim of the work 4
Review of Literature 5
- Immune-Inflammatory Response to Burn 7 The Mediators of Inflammation 9 The Immune-Competent and Effector Cells 26 The Burn Toxin (Lipid Protein Complex) (LPC) 38 Paradoxes in Burn Immune Failure: The Activation-Induced
Cell Death Theory (AICD) (Apoptosis) 43
The Role of LPC in Paradoxes in Burn Immune Failure 44 The Role of Burn Wound Sepsis in the Post-burn Inflammatory
Response 49
The Pathogenesis of Multiple Organ Failure (MOF) Following
Severe Burns 52
- Evaluation of the Burn Wound Management Decisions 54 I- Estimation of burn wound depth 54 II- Surgical Burn Wound Management 59 A- Surgical Methods of Burn Wound Closure 62 B- Timing of Burn Wound Excision 63 C- Extent of Burn Wound Excision 64 D- Depth of Burn Wound Excision 65 E- Techniques of Burn Wound Excision and Closure 67 F- Coverage of Excised Burn Wound 70 III- Impact of burn wound excision on the Immune-
Inflammatory Response to Burn 71
Index B
Patients and Methods 75
- Study design 75
- Patient population 75
- Management Protocol 77
- Monitoring of the patients 83
- Statistical Methodology 87
Results 89
- Demography of Patients’ Population 89
- Analysis of Clinical Outcomes 91 Clinical outcomes of first group 91 Clinical outcomes of second group 93 Analysis of the clinical outcomes in both groups 95
- Analysis of Laboratory Investigations 98 Laboratory results of first group 98 Laboratory results of second group 103 Comparison between IL-6 assay levels of survivors in both
groups 108
Comparison between TNF-α assay levels of survivors in both
groups 109
Comparison between IL-6 assay levels of non-survivors in both
groups 110
Comparison between TNF-α assay levels of non-survivors in
both groups 111
Discussion 112
Summary and Conclusion 125
References 130
Arabic Summary
العربيالملخص أ
List of Figures C
No. Description Page
1 Complement activation pathways 12
2 The arachidonic acid cascade 16
3 Cytokines as communication links within the immune
system, and between the immune system and other
organs
19
4 Biological functions of TNF-α 22
5 case no. 7 in first group (tangential excision) 80
6 case no. 12 in second group (down-to-fascia excision) 82
List of Tables D
No. Description Page
1 The major inflammatory mediators 9
2 The major cytokines released following thermal injury 20
3 Paradoxes in Burn Immune Failure 44
4 Patient Population of first group 89
5 Patient Population of second group 90
6 Clinical outcomes of first group 92
7 Clinical outcomes of second group 94
8 IL-6 assay results in pg/ml of first group 99
9 TNF-α assay results in pg/ml of first group 100
10 IL-6 assay results in pg/ml of second group 104
11 TNF-α assay results in pg/ml of second group 105
List of Charts E
No. Description Page
1 Comparison between Average Hospital stay (AHS) of
survivors and non-survivors in both groups
96
2 Comparison between clinical outcomes of both groups 97
3 IL-6 assay levels of survivors and non-survivors of first
group at preoperative, 3rd
, 7th
and 14th
postoperative
(PO) days
101
4 TNF -α assay levels of survivors and non-survivors of
first group at preoperative, 3rd
, 7th and 14
th
postoperative (PO) days
102
5 IL-6 assay levels of survivors and non-survivors of
second group at preoperative, 3rd
, 7th
and 14th
postoperative (PO) days
106
6 TNF-α assay levels of survivors and non-survivors of
second group at preoperative, 3rd
, 7th
and 14th
postoperative (PO) days
107
7 IL-6 assay levels of survivors in both groups at
preoperative, 3rd
, 7th
and 14th
postoperative (PO) days
108
8 TNF-α assay levels of survivors in both groups at
preoperative, 3rd
, 7th
and 14th
postoperative (PO) days
109
9 IL-6 assay levels of non-survivors in both groups at
preoperative, 3rd
, 7th
and 14th
postoperative (PO) days
110
10 TNF-α assay levels of non-survivors in both groups at
preoperative, 3rd
, 7th
and 14th
postoperative (PO) days
111
List of Abbreviations F
5-HT 5-Hydroxytryptamine ( Serotonin)
ABG Arterial Blood Gases
AHS Average Hospital Stay
AICD The Activation-Induced Cell Death Theory
(Apoptosis)
AIDS Auto-Immunodeficiency Syndrome
Alb Serum albumin
anti-PGPS IgM Antibody of Bacterial Cell Wall Antigen-PGPS
APCs Antigen-Presenting Cells
b.p.m beat per minute
B - cells B-lymphocytes (The antibody-producing cells).
BDI Burn Depth Indicator
bFGF Basic Fibroblast Growth Factor
BSA Burned Surface Area
BUN Blood Urea Nitrogen
C1 Complement factor 1
C3a, C3bBbP Complement factor 3 (Activated, blocked)
C3dg Degraded product after activation of C3
C4, C4b, C4a Complement factor 4 (Activated, blocked)
C5a Activated Complement factor 5
CBC Complete Blood Count
CD-system Cluster Of Differentiation-System
CD-14 Lipopolysaccharide Receptor
CGRP Calcitonin Gene-Related Peptide
CPK Creatine Phosphokinase
C-RP C-Reactive Protein
DIC Disseminated Intravascular Coagulation
EASIA Immunoenzymometric Quantitative Assay of Human Serum Cytokines
EGF Epidermal Growth Factor
ET-1 Endothelin-1
Fn Fibronectin
GIT Gastro-intestinal tract
GM-CSF Granulocyte-Macrophage Colony Stimulating Factor
List of Abbreviations G
gram+ve Bacteria positive to stain
gram-ve Bacteria negative to stain
Hb Hemoglobin Concentration
Hct Hematocrite Value
HSR Ratio of Helper To Suppressor T-lymphocytes
IFN-α, β and γ Interferon α, β and γ
IGF-1 Insulin-Like Growth Factor-1
IgG Immunoglobulin G
IgM Immunoglobulin M
IL Interleukins
IL-1α, IL-1β Interleukin-1 α, β
IL-2 Interleukin-2
IL-2R IL-2 Receptor
IL-6 Interleukin-6
IL-8 Interleukin-8
LG Large Granular Lymphocytes
LPC Heat Induced Toxin Lipoprotein Complex
LPS Gram-ve Bacterial Endotoxin Lipopolysaccharide
LTB4, LTD4 Leukotrienes B4, D4
MBL Mannose-binding lectin
MILP Mitogen-Induced Lymphocyte Proliferation
MOD Multiple Organ Dysfunction
MOF Multiple Organ Failure
MRI Proton Magnetic Resonance Imaging
N. Non-Survivor
NK Natural Killer (type of T-lymphocytes)
OFRs Oxygen Free Radicals
ρ-values Probability value
PAF Platelet Activating Factor
PaO2 Oxygen pressure in arterial blood gases test
PBD Post-Burn Day
PBMC Peripheral Blood Mononuclear Cells
PDGF Platelet Derived Growth Factor
List of Abbreviations H
PGD2 Prostaglandins D2
PGE2 Prostaglandin E2
PGF2 Prostaglandin F2α
PGI2 Prostacyclin
PGPS Bacterial Cell Wall Antigen
PMNLs Polymorphonuclear Leukocytes
PT Prothrombin Time
PTT Partial Thromboplastin Time
S. Survivor
SaO2 Oxygen saturation in arterial blood gases test
SD Standard Deviation
SGOT Serum Glutamic Oxaloacetic Transaminase
SGPT Serum Glutamic Pyruvic Transaminase
SIRS Systemic Inflammatory Response Syndrome
SR Survival Rate
STF Subeschar Tissue Fluid
TBSA Total Body Surface Area Burned
TC T-Cytotoxic (type of T-lymphocytes)
T- cells T-lymphocytes (The Thymus-Dependent Lymphocytes)
TGFα, TGFβ1,
TGFβ2
Transforming Growth Factors α, β1 and β2
TH T-Helper (type of T-lymphocytes)
TLC Total Leucocytic Count
TM Thrombomodulin
TNF- α Tumor Necrosis Factor-Alpha
TS T-Suppressor (type of T-lymphocytes)
TSS Toxic Shock Syndrome
TSST-1 Toxic Shock Syndrome Toxin-1
TX A2 Thromboxane A2
Introduction 1
Although burn injuries are frequent in our society,
many surgeons feel uncomfortable in managing patients
with major thermal trauma.
The burn wound is the source of virtually all ill
effects, local and systemic, seen in a burned patient.
Burn eschar exerts a systemic immune response that
cascades through cytokine pathways leading to Systemic
Inflammatory Response Syndrome (SIRS), which may
progress to Multiple Organ Failure (MOF) (Monafo et
al., 1992).
In addition, eschar acts as a nidus for infection that
is aggravated by immune suppression state. This may
progress to sepsis or sepsis-induced SIRS (Monafo et al.,
1992).
Munster in 1996, suggested that high serum level of
tumor necrosis factor-alpha (TNF-α) and low serum
level of Interleukin-6 (IL-6) may be considered to be the
most important poor prognostic factors related to
Introduction 2
systemic inflammation and multiple organ failure
following thermal injury.
In addition, Yamamoto et al in 1996 stated that
patients who are subjected to early escharectomy
showed a significant increase in blood platelets, decrease
in fibronectin, white blood cells, albumin and total
proteins and no significant variations in C-reactive
protein level.
Therefore, surgical removal of the burn wound in
resuscitated patients especially when done early, results
in improvement in survival rates and morbidity (Hart et
al., 2003).
There are two main techniques for early burn
wound excision, namely tangential and down-to-fascia
excision (Herndon et al., 1999).
It is hypothesized that the accumulation and
reabsorption of subeschar tissue fluid (STF) may
increase the morbidity and mortality rates in severely
burned patients. Therefore, the unburned tissues at the
Introduction 3
margin and the depth of the burn may be affected and
may exaggerate the systemic inflammation (Chen et al.,
2000).
The study of the alteration of the immunological
profile in relation to timing and extend of early excision
has been established. However, the impact of technique
of early burn wound excision on the immunological
profile changes has not yet been studied.
Aim of The Work 4
The aim of this thesis is to compare the effect of
two different techniques of early burn wound excision
(tangential excision and down-to-fascia excision) on
alteration of interleukin-6 (IL-6) and tumor necrosis
factor-alpha (TNF-α) levels as indicators for the
immunological profile alterations.
This would enable the burn surgeons to decide the
proper technique and proper depth of early burn wound
excision that would decrease the systemic inflammatory
response in order to decrease hospital stay, decline the
morbidity and improve clinical outcome and survival
rate in extensively burned patients.
Review of Literature 5
The integument is the principle site of interaction with
the surrounding world. It serves as a protective barrier,
immunologic surveillance and thermoregulation. It consists
of two mutually dependent layers, the epidermis and dermis,
which rest on hypodermis, which is a fatty subcutaneous
layer, the panniculus adiposus (Van De Graff et al., 1986).
Epidermal thickness is variable in different anatomic
locations, sexes, and ages of man and ranges between 0.5 to
1.5 mm. This varying thickness primarily represents a
difference in dermal thickness, as epidermal thickness is
rather constant throughout life and from one anatomic
location to another. The thickest epidermis is found in the
palms and soles, while the thinnest epidermis is found on the
eyelids and in the post-auricular region. Male skin is thicker
than female skin in all anatomic locations. Children have
relatively thin skin, which progressively thickens until the
fourth or fifth decade of life when it begins to thin. This
thinning is also primarily a dermal change, with loss of
elastic fibers, epithelial appendages, and ground substance
(Moore et al., 1998).
Following a major burn injury a myriad of physiologic
Review of Literature 6
changes occur that together comprise the clinical scenario of
the burn patient (Herndon et al., 1999).
Fluid and electrolyte imbalance, which results in
systemic intravascular losses of water, sodium, albumin and
red blood cells and unless intravascular volume is rapidly
restored, shock develops. Metabolic disturbances are
evidenced by increased resting oxygen consumption
(hypermetabolism), an excessive nitrogen loss (catabolism),
and a pronounced weight loss (malnutrition). Bacterial
contamination of tissues is another complication of major
burns where patients are unable to mount an adequate
immunologic defense, increasing the risks for septic shock
(Lowry, 1993).
Later on, vital organs dysfunctions occur which
include, renal insufficiency can result from hypoperfusion or
from nephron obstruction with myoglobulin; pulmonary
dysfunction may be caused from initial respiratory tract
damage or from progressive respiratory insufficiency due to
pulmonary edema, adult respiratory distress syndrome or
bronchopneumonia and gastrointestinal complications which
include paralytic ileus and gastrointestinal ulcerations. Small
Review of Literature 7
bowel ischemia and stasis promote bacterial translocation as
a mechanism for endogenous infection (Beal et al., 1994).
Immune-Inflammatory Response to Burn
The burn wound is the source of virtually all ill effects,
local and systemic, seen in a burned patient. Locally, the
burn wound is characteristically made up of several
concentric three-dimensional zones of tissue damage due to
different heat transfer. The zone of coagulative necrosis,
where irreversible skin death occurs, is surrounded by an
intermediate zone of stasis and the zone of hyperaemia,
which is the outermost zone. Tissue damage in the zone of
hyperaemia and the zone of necrosis, which do not show an
inflammatory response, is primarily attributed to the direct
effect of heat on blood vessels and tissue respectively. In
contrast, in the zone of stasis, thermal injury triggers a
pronounced inflammatory reaction (Knabl et al., 1999).
Burn eschar – through heat induced toxin lipoprotein
complex (LPC) – exerts a systemic immune response leading
to Systemic Inflammatory Response Syndrome (SIRS),
Review of Literature 8
which may progress to Multiple Organ Dysfunction
Syndrome (MOD) or Multiple Organ Failure (MOF). In
addition, eschar acts as a nidus for infection that is
aggravated by immune suppression state. This may progress
to sepsis or sepsis-induced SIRS through lipopolysaccharides
(LPS) which present in microorganisms (Ikeda et al., 2000).
The systemic inflammation has a cellular component
(consisting of different kinds of immune competent and
effector cells including leukocytes, platelets, vascular
endothelial cells, mast cells, and fibroblasts), and a vascular
component (related to blood flow and microvascular
permeability). Both components of the inflammatory
response are governed by a wide variety of biologically
active products, collectively termed “Inflammatory
Mediators” forming networks and cascades which involved
in the process of wound healing and tissue repair. These
mediators are produced by the circulating immune-
inflammatory cells (e.g. the leukocytes), the plasma, and the
tissue (Table 1). The inflammatory mediators fall into groups
depending upon their origin and specific regulatory function
(Cioffi et al., 1993).
Review of Literature 9
Table 1: The major inflammatory mediators, (Arturson, 1996).
Mediator Origin(s) Action(s)
Bradykinin Kinin system
(kininogen)
Pain, Vasodilatation
Increased microvascular permeability
Smooth muscle contraction
Fibrinopeptides
Fibrin split products
Coagulation system Increased microvascular permeability
PMNL and macrophage chemotaxis
C3a Complement C3 Mast cell degranulation
Smooth muscle contraction
C5a Complement C5 Mast cell degranulation
PMNL activation
PMNL and macrophage chemotaxis
Smooth muscle contraction
Substance P Sensory nerve endings Vasodilatation
Increased microvascular permeability
Histamine Mast cells, Basophils Increased microvascular permeability
Smooth muscle contraction
Chemokinesis
5-Hydroxytryptamine
(5HT = serotonin)
Platelets , Mast cells Increased microvascular permeability
Smooth muscle contraction
Platelet activating factor
(PAF)
PMNL, Macrophages,
Basophils
Increased microvascular permeability
Smooth muscle contraction
PGE2 Cyclooxygenase pathway PMNL activation
PGF2 Cyclooxygenase pathway Vasodilatation
LTB4 Lipoxygenase pathway Vasoconstriction , PMNL chemotaxis
LTD4 Lipoxygenase pathway Increased microvascular permeability
Smooth muscle contraction
I- The Mediators of Inflammation:
1- Oxygen Free Radicals (OFRs):
The phagocytotic cells (polymorphonuclear leukocytes,
monocytes, and macrophages) are known to be a potent
source for oxygen free radicals (OFRs), which are produced
Review of Literature 10
in connection with their oxidative metabolism. OFRs are
very short lived and their existence and pathophysiological
role are extremely difficult to demonstrate (Haglund et al.,
1991). Although they have no direct effect, yet they can
markedly influence effector cell movement and
microvascular integrity in target organs through the
stimulation of lipid peroxidation, with subsequent production
of biologically active arachidonic acid metabolites (Lipid
peroxides) (Kumar et al., 1995).
2- The Kinin System:
The kinin system is activated in two different pathways,
thereby generating the inflammatory mediators, bradykinin
and lysyl bradykinin. Activated Hageman factor of the
clotting system acts on prekallikrein to generate kallikrein,
which in turn releases bradykinin from low molecular weight
kininogen. Activation of the plasmin system as well as
enzymes release from damaged tissue cells act on
prekallikrein to generate tissue Kallikrein, which releases
Lysyl bradykinin (Kallidin) from low molecular weight
kininogen.
Bradykinin is a very powerful vasoactive mediator,
Review of Literature 11
which causes venular dilatation and increased microvascular
permeability. Furthermore, it has an indirect effect on cell
movement and microvascular integrity through its ability to
activate phospholipase of the cell membrane, thus resulting
in stimulation of the arachidonic acid cascade (Arturson,
1996).
3- The Coagulation and Fibrinolytic (Plasmin) Systems:
The hypercoagulable state following thermal injury
results from activation of Hageman factor with subsequent
activation of the coagulation cascade and ends by fibrin
formation. This state is paralleled with increased activity of
the plasma proteolytic enzyme plasmin, which serves to
slowly degrade fibrin to fibrin degradation products. This
can explain the high incidence of disseminated intravascular
coagulation (DIC) in association with severe burns (Garcia-
Avello et al., 1998).
4- The Complement System Cascade (Opsonins):
The complement system is a group of around 20
different serum proteins whose overall action is the control
of inflammation. Complement activation following thermal
injury occurs through two independent pathways, the
Review of Literature 12
classical and alternative pathway (Figure 1) (Arturson,
1996).
Fig.1: Complement activation pathways (Kaneko et al., 2001)
The process of activation occurs in a cascade fashion
that is closely similar to the blood-clotting mechanism.
Review of Literature 13
Activation of either pathway ends up by a central common
event, which is the activation of complement factor 3 (C3).
The active fragments of C3 start to regulate the function of
the phagocytic leukocytes (macrophages and neutrophils) via
specific receptors on their surface (Kaneko et al., 2001).
There are three major biological activities of the
complement system, the chemotaxis (attraction of phagocytic
leukocytes towards their target), the opsonization (coating of
the target so that it can be easily recognized by the
phagocytic cells) and phagocytosis and lysis of target cells
(Ono et al., 1993).
Dibirdik et al. in 1995 conducted a clinical study to
evaluate the changes in serum complement levels following
thermal injury. They demonstrated an initial rise of serum
complement C3 level, followed by a sustained decrease
during the next two to three weeks. Their explanation of the
phenomenon was that, the initial rise was due to stimulation
of the complement cascade by thermal injury, and the
subsequent decrease in levels was secondary to the initial
increased consumption, thus resulting in depletion of the
various complement components.
Review of Literature 14
5- Neurotransmitters:
Lofgren and Lundberg in 1994 demonstrated that,
Substance P and Calcitonin gene-related peptide (CGRP)
were the neurotransmitters sharing in the inflammatory
process. They modulate the vascular element of
inflammation through alteration of vascular permeability
effects.
6- Vasoactive Amines:
They play an important role in the modulation of blood
flow at the site of inflammation through vasodilatation,
vasoconstriction, and increased microvascular permeability.
The most important components include serotonin (5-
hydroxytryptamine) and histamine, which originate from
mast cells, basophils and platelets. Vasoactive amines,
through their modulatory effect on microcirculation, are
believed to share in post burn oedema formation, both
locally at the site of injury and systemically in distant organs
(Sanchez, 2002).
7- Platelet Activating Factor (PAF):
It is produced by platelets, neutrophils (PMNL),
eosinophils, monocytes and vascular endothelial cells. It is
Review of Literature 15
considered to induce marked enhancement of microvascular
permeability following thermal injury, thus resulting in
oedema formation in local and systemic organ tissue. PAF
seems to act synergistically with vasoactive amines to
produce marked alteration of microcirculation within target
tissue (Schenfeld et al., 1990).
8- The Arachidonic Acid Cascade:
Arachidonic acid results from the action of the enzyme
phospholipase A2 on phospholipids of the cell membrane.
The stimuli to this process, which is termed lipid
peroxidation, include a variety of hormones, collagen,
thrombin, bradykinin, antigen-antibody complex, bacterial
peptides, and oxygen free radicals (OFRs). Arachidonic acid
is the main precursor for the biosynthesis of many
biologically active mediators, through different enzymatic
pathways involving Cyclooxygenase, 5-Lipoxygenase, and
15-Lipoxygenase enzymes.
The mediators derived from the effect of the enzymatic
cascade on arachidonic acid include thromboxane A2,
prostacyclin (PGI2), prostaglandins (PGD2, PGE2 and
PGF2), Lipoxins, and the leukotrienes (A4, C4, B4, D4 and
Review of Literature 16
PE4). These mediators play an important role in the
thermally induced inflammatory response, acting on both
components of inflammation (Figure 2). Those mainly acting
on the cellular component can promote adhesiveness,
chemotaxis of leukocytes (e.g. Lipoxins, Leukotriene B4),
platelet aggregation (Thromboxane A2), and antiaggregation
(PGI2).
Fig. 2: The arachidonic acid cascade (Arturson, 1996)
The mediators acting on the vascular component (e.g.
Prostaglandins, Leukotriene C4) are capable of modulating
the microcirculatory status through vasoconstriction,
vasodilatation, and increasing microvascular permeability.
Phospholipides Lipase
Arachidonic acid
6-lipoxygenaseCyclo-oxygenase
6-Keto PGF1
LTB4 LTC4
LTD4
LTE4
PGD2
PGE2
PGF2
TXB2
TXA2 PGI2
PGH2PGG2
PGI2
synthetase
TX synthetase
isomerasehydrolase
LTC4
synthetase
LTC4
Phospholipides Lipase
Arachidonic acid
6-lipoxygenaseCyclo-oxygenase
6-Keto PGF1
LTB4 LTC4
LTD4
LTE4
PGD2
PGE2
PGF2
TXB2
TXA2 PGI2
PGH2PGG2
PGI2
synthetase
TX synthetase
isomerasehydrolase
LTC4
synthetase
LTC4
Review of Literature 17
Some mediators exert a dual effect (both cellular and
vascular), such as thromboxane A2, PGI2, and Lipoxins.
Therefore, the increased lipid peroxidation might be partially
responsible for the indirect (ischaemia induced) local tissue
damage following thermal injury (Arturson, 1990).
9- Cytokine Cascade:
Cytokines are intercellular signal proteins or peptides
that modulate the inflammatory response following trauma.
They were previously termed lymphokines, as they were
thought to have the lymphocytes as their only source.
However, other cells including phagocytic cells (PMNL,
macrophages), platelets, fibroblasts, endothelial cells, and
even keratinocytes, were all found to share in the production
of such mediators. Cytokines act primarily on the cellular
component of inflammation from which they originate, and
serve to regulate the complex interaction between the
different leukocytes and other effector cells (Figure 3).
Cytokines fall into a number of groups, of which
“Interleukins” consist the largest group.
There is about 12 interleukins (IL-1 to IL-12), produced
by the leukocytes and other effector cells, but not all of them
Review of Literature 18
are of clinical significance following thermal injuries. The
other cytokines that play an important role in thermal injury
include the tumour necrosis factor-alpha (TNF-α), interferon
(IFN), neopterin, and granulocyte-macrophage colony
stimulating factor (GM-CSF) (Table 2). Cytokines are
known to exert their effect by binding to specific receptors
present on the surface of immunecompetent and other
effector cells (Lowry, 1993).
Interleukin-1 (IL-1) is produced mainly by
macrophages and acts to stimulate T-Lymphocytes and
neutrophils. It can also act on the hypothalamus to induce
fever, and liver cells to induce the production of acute phase
proteins (e.g. C-reactive protein) (Dinarello et al., 1993).
Interleukin-2 (IL-2) is produced by T-Lymphocytes and
acts chiefly on all types of T-cells where it is the most
powerful activator and growth factor. Besides T-cell, it can
also activate macrophages (Teodorczyk-Injeyan et al., 1992).
Interleukin-6 (IL-6) is produced by T and B cells,
macrophages, fibroblasts, and endothelial cells and acts on
many cells. In the liver, it stimulates the production of acute
Review of Literature 19
phase proteins. Furthermore, it induces B cells to
differentiate into antibody forming cells. Increasing levels
have been observed in severely burned patients, denoting
strong activation of cellular and humoral immune
mechanisms. IL-6 is also increased in burn blister fluid,
suggesting a possible correlation with wound healing
(Bellomo, 1992).
Fig. 3: Cytokines as communication links within the immune system, and
between the immune system and other organs (Arturson, 1996)
Review of Literature 20
Table 2: The major cytokines released following thermal injury
(Arturson, 1996). Cytokine Immune system Other cells Main targets Main functions
IL-1 IL-2
IL-6 IL-8
TNF
IFN
Macrophages LGLs, B cells T cells
T cells, B cells Monocytes
Macrophages Lymphocytes Mast cells
T cells, NK cells
Endothelial cells Fibroblasts
Fibroblasts
Epithelial cells Fibroblasts
T cells, B cells Macrophages Endothelial cells Tissue cells T cells
B cells Hepatocytes PMNLs Basophils
Macrophages Granulocytes Tissue cells
Leukocytes Tissue cells
Activation of lymphocytes and macrophages. Leucocyte/endothelial adhesion. Acute-phase proteins. Activation of lymphocytes and macrophages.
T-cell proliferation and differentiation. Induce acute-phase proteins. B-cell differentiation. Chemotaxis.
Activation of macrophages, granulocytes and cytotoxic cells. Leucocyte/endothelial adhesion. Stimulation of acute-phase proteins and angiogenesis.
Cachexia and pyrexia. Activation of macrophages. Leucocyte/endothelial adhesion.
Interleukin-8 (IL-8) is a proinflammatory cytokine with
a chemoattractant activity. It is produced by monocytes,
endothelial cells, keratinocytes, and neutrophils. IL-8
stimulates neutrophil IgG-mediated phagocytosis and
oxidative burst. Furthermore, patients with total body surface
area burn covering more than 40% have significantly higher
Review of Literature 21
concentrations of IL-8 in their plasma than patients with
small burns i.e. IL-8 is a major contributor of the systemic
inflammatory response that follows major burns (Schroder et
al., 1992).
Tumour necrosis factor-α (TNF-α) is produced by
activated macrophages and is considered, together with
interleukin-1, to be an alarm cytokine, that can stimulate T-
Lymphocytes. Besides the activation of T-Lymphocytes,
TNF-α regulates the production of other cytokines, and
stimulates neutrophils and monocytes, promoting their
endothelial adhesiveness, phagocytosis, oxidative burst, and
degranulation. In addition to its regulatory function on the
cellular component of the inflammatory response, it can
stimulate liver cells to produce acute phase proteins (e.g. C-
reactive protein), and the hypothalamus to induce fever
(Figure 4) (Tracey et al., 1993).
Interferon (IFN) can be divided into three groups: IFN-
α, β and γ. IFN-γ is the only interferon that is known to play
an important immunoregulatory function in thermal injury. It
is produced by lymphocytes. It is considered to be the most
important inducer of macrophage activation (Suzuki et al.,
Review of Literature 22
TNF
Leukocyte
Endothelial cell
Bone marrow
BrainHeart
Blood vessels
Local inflammation Systemic effects Septic shock
Low quantities
(plasma conc. <10-9 M)High quantities
(plasma conc. >10-7 M)
Moderatequantities
activationfever
Low
output
ThrombusLow
Resistance
Hypoglycemia
Acute phase
protein
Leucocytes
Liver
Liver
Adhesion
molecule
IL-1,
chemokines
TNF
Leukocyte
Endothelial cell
Bone marrow
BrainHeart
Blood vessels
Local inflammation Systemic effects Septic shock
Low quantities
(plasma conc. <10-9 M)High quantities
(plasma conc. >10-7 M)
Moderatequantities
activationfever
Low
output
ThrombusLow
Resistance
Hypoglycemia
Acute phase
protein
Leucocytes
Liver
Liver
Adhesion
molecule
IL-1,
chemokines
1982).
Fig. 4: Biological functions of TNF-α (Lowry, 1993).
Neopterin works in close correlation with IFN-γ, being
primarily released by macrophages upon stimulation by the
latter. Neopterin is considered to be a marked activator of
cellular mechanisms (Grabosch et al., 1992).
The granulocyte-macrophage colony-stimulating factor
(GM-CSF) is a cytokine that plays an important role in
cellular immune mechanisms. It stimulates the proliferation
and differentiation of granulocyte and macrophage
Review of Literature 23
progenitor cells in the bone marrow. GM-CSF is not only
effective on immature cells but can also stimulate various
functions of mature granulocytes (PMNL) and macrophages.
It is evident that GM-CSF enhances the oxidative
metabolism, phagocytosis, and cytotoxic capacity for both
granulocytes and macrophages (Kaufman et al., 1989).
Munster in 1996, suggested that high serum level of
TNF-α and low serum level of IL-6 may be considered to be
the most important poor prognostic factors related to
systemic inflammation and multiple organ failure following
thermal injury.
Deveci and colleagues in 2000 stated that high levels of
IL-6 decrease the levels of TNF-α. Therefore, it may be
postulated that IL-6 inhibits the severity of the inflammatory
response in the early period of thermal injury.
On contrary, there is evidence that cytokines are
paradoxically involved in wound healing and tissue repair
mechanisms. Ono et al. in 1995 demonstrated the presence
of numerous cytokines and growth factors in the burn blister
fluid. These included IL-1α, IL-1β, IL-6, IL-8, epidermal
Review of Literature 24
growth factor (EGF), basic fibroblast growth factor (bFGF),
platelet derived growth factor (PDGF), transforming growth
factors (TGFα, TGFβ1 and TGFβ2). Therefore, although
cytokines were primarily described as mediators of systemic
inflammation with its related morbidity, they could
simultaneously promote wound healing procedures.
10- Fibronectin (Fn):
Fibronectin is a glycoprotein secreted by many cells,
e.g. the hepatocytes. It exerts a wide range of biological
functions, which are primarily related to the cellular element
of the post-burn immune-inflammatory response. Its function
closely resembles that of the complement cascade, which
acts as an opsonic system, but for the polymorphonuclear
neutrophils leukocytes (PMNL). Besides enhancing the
phagocytic function of the monocyte-macrophage system,
fibronectin activates thrombocytes, and regulates the
activities of many other effector cells contributing in the
acute inflammatory response. In addition, Fn is known to
participate in the organization of thrombus formation,
through special sites binding fibrin on fibronectin, thus
enhancing the removal of soluble fibrin by macrophages.
Review of Literature 25
Furthermore, Fn can play a beneficial role in the acceleration
of wound healing, by promoting the phagocytosis of cellular
debris by macrophages (Mosher et al., 1981).
11- Acute Phase Proteins (Acute Phase Reactants):
The hepatocytes respond to trauma by liberating a
series of proteins into the circulation, collectively known as
the acute phase proteins. The rise in plasma level of such
proteins, does not only reflect the change in hepatic protein
synthesis in response to trauma, but also reflects their
integral role in the host-protective mechanisms and tissue
restoration procedures. The release of acute phase proteins
by liver cells in response to thermal injury is triggered by the
circulating cytokines, namely IL-1, IL-6 and TNF-α
(Dowton et al., 1988).
The acute phase proteins known to play a crucial role in
the post-burn inflammatory response include C-reactive
protein, α1-antitrypsin, α2-antichymotrypsin, α2-
macroglobulin, and haptoglobin. Liver proteins, which
exhibit a rise in the course of the acute phase response, are
termed positive acute phase proteins. Other proteins, derived
Review of Literature 26
from the liver, exhibit a marked drop in their plasma
concentration, and hence are referred to as negative acute-
phase proteins. These include albumin and transferrin
(Castell et al., 1990).
C-reactive protein is one of the sensitive indicators of
the status of the post-burn inflammatory response as it is
correlated well with the extent of the burn. Its exact
physiological role is not definitely understood (Latha et al.,
1997).
II- The Immune-Competent and Effector Cells:
1- Polymorphonuclear Neutrophil Leukocytes (PMNL):
PMNLs constitute over 90% of the circulating
polymorphonuclear cells. Their main function within the
immune-inflammatory response is phagocytosis. They
constitute one of the two major arms of phagocytosis, the
second being mediated by the monocytic-macrophage
system. Neutrophils are derived from the bone marrow. The
initial event that immediately follows stimulation is the
phenomenon of aggregation of leukocytes to each other
(Rolling). This is followed by adhesion of the leukocytes to
Review of Literature 27
the vascular endothelium in the target tissue (Adherence).
The phenomenon of rolling and adherence, which result in
segregation of leukocytes from the circulation, are followed
by extravasation, then migration of the effector cells towards
their target (Chemotaxis). Leukocytes eventually bind, and
then phagocytose their target cell. Phagocytosis is followed
by a process of lysis of the ingested microorganism
(Arturson, 1996).
The phenomena of rolling and adherence involve
specific receptor-ligand interactions modulated by three
families of cell surface proteins. These are the selectins
(which mediate the phase of rolling and aggregation), the
integrins (which mediate the phase of adhesion) and the
platelet-endothelial adhesion molecule 1 (which mediates
the phase of endothelial transmigration) (Muller et al., 1993).
The chemotaxis is modulated by chemotactic molecules
acting on leukocytes such as activated complement 5 (C5a),
leukotriene B4 (LTB4), and interleukin-8 (IL-8). The
phenomenon of opsonization (phagocytosis) is facilitated by
the opsonic proteins which include immunoglobulin G (IgG),
complement 3 (C3), fibronectin, and C-reactive protein
Review of Literature 28
(Solomkin et al., 1984).
The process of lysis is mediated through two main
pathways. The first pathway is the oxygen-dependent killing,
in which the leukocyte utilizes energy derived from
oxidative metabolism by myeloperoxidase enzyme with
production of Oxygen free radicals (OFRs), as metabolic
wastes. The second pathway of intracellular killing is known
as the oxygen-independent killing, under the direct effect of
the lysozymes manufactured by the leukocyte secretory
granules (Arturson, 1990).
The cytoplasm of PMNLs contains many secretory
granules with specific enzymatic protein contents. The most
important secretory granules are those responsible for the
production of myeloperoxidase enzyme, and the lysozymes.
Other secretory granules are responsible for the production
of various enzymes including collagenase, elastase, neutral
proteases, and lactoferrin. Lactoferrin can affect stem-cell
proliferation into mature neutrophils and regulate all types of
neutrophils activities. Proteolytic enzymes (e.g. collagenase
and elastase) are believed to exert a damaging effect in target
tissues, and hence can also share in the pathogenesis of
Review of Literature 29
functional organ failure (Arturson, 1996).
The initial early post-burn phase of strong activation of
PMNLs function is eventually followed by phase
characterized by marked impairment of their activities. This
serious dampening of neutrophil functions eventually
predisposes to the occurrence of infectious complications
(El-Falaky et al., 1985).
Thus, both OFRs and proteolytic enzymes are
considered to be of great pathological importance, as they
can mediate much of the tissue damage and organ
dysfunction attributed to systemic inflammation after major
thermal injuries (Cioffi et al., 1993).
Vindenes and Bjerknes in 1997 reported that, the
second stage where there occurs a marked failure of PMNLs‟
function might be attributed to abnormalities in the
contractile protein actin. Actin is a key component of the
neutrophil cytoskeleton. Continuous polymerization and
depolymerization of actin is responsible for generating the
force for several forms of motile responses, principally
locomotion, but also shape change, pseudopod formation,
Review of Literature 30
phagocytosis and secretion. Furthermore, a strong correlation
exists between the neutrophil microfilament apparatus and
the surface adhesion molecules, which mediate the
leukocyte-endothelial interaction. Thus surface molecules
serve as the link between the cytoskeleton and the
extracellular matrix. This link depends upon a similarity
between actin filaments, and the adhesion molecules on the
surface of leukocytes and endothelial cells.
2- The Monocytic-Macrophage System:
Monocytes are always circulating in the blood stream.
Upon stimulation, they enter into target tissues where they
undergo maturation into macrophages. Besides its major
function in phagocytosis, the monocytic-macrophage system
is known to work in intimate correlation with the T-
lymphocytes. This occurs through the production of
interleukin-1 and tumour necrosis factor (TNF), which act as
“alarm cytokines” by their triggering effect on T-
lymphocytes. Neopterin is another cytokine originating from
the monocytic-macrophage system, and can trigger many of
the cellular immune-inflammatory mechanisms (Arturson,
1996).
Review of Literature 31
Therefore, macrophages can modulate the
inflammatory response through two major pathways. The
first pathway is related to cytokine production (cytokine
cascade) and results in marked activation of many effector
cell lines, mainly the T-lymphocytes. The second pathway is
related to OFRs production, and results in activation of the
arachidonic acid cascade, which in turn plays an integral role
in both vascular and cellular elements of inflammation
(Sparkes, 1997).
Macrophages can also participate in tissue restoration
mechanisms by phagocytosis of cellular debris and
production of proteolytic enzymes (e.g. collagenase), thus
promoting the separation of necrotic tissue (e.g. eschar).
Furthermore, many of the cytokines produced by
macrophage activation can promote healing by stimulating
the proliferation of fibroblasts and keratinocytes (Leibovich,
1984).
3- The lymphoid System:
Lymphocytes express a large number of different
molecules (markers) on their surfaces. These molecules are
peptide (protein) in nature. Some of these molecules function
Review of Literature 32
as receptors for cytokines. The peptide nature of these
molecules (markers) enables their identification by specific
monoclonal antibodies, constituting the CD-system (cluster
of differentiation-system). Thus, one can easily know the
ratio between the different lymphocytes and the status of
activity of the various cytokine receptors (Arturson, 1996).
a- The B-lymphocytes: (The antibody-producing cells).
They differentiate into plasma cells, which produce
antibodies. Antibodies exert many functions including the
neutralization of toxins, and the enhancement of
phagocytosis by PMNLs. Furthermore it may play a role in
triggering the arachidonic acid cascade, which plays an
important immune-regulatory function (Roitt et al., 1993).
The B-lymphocytes are the first to recognize the
antigen, and then present it to the T-lymphocytes. Thus, they
act as antigen-presenting cells (APCs) for the T-
lymphocytes, which start to produce cytokines, those are
essential for antibody production by B-lymphocytes.
Therefore, it is clear that, although B-lymphocytes are
responsible for the initial event (antigen presentation), yet
their further participation in the immune-inflammatory
Review of Literature 33
response is through a cytokine-mediated (T-lymphocyte-
derived) triggering of proliferation and differentiation into
active plasma cells (Arturson, 1996).
Teodorczyk-Injeyan and coworkers in 1989
demonstrated an initial rise in plasma level of
immunoglobulin M (IgM) in the early post-burn phase,
denoting the triggering of an inflammatory response. A
parallel rise in interleukin-2 (IL-2) level in plasma was
observed. This indicated that, immunoglobulin production by
B-lymphocytes is a cytokine (IL-2 dependent) event.
b- T-lymphocytes: (The thymus-dependent lymphocytes).
The T-lymphocytes constitute the other major
component of the immune-regulatory lymphoid system.
They are stimulated by the antigen-presenting cells (APCs).
Being stimulated, T-lymphocytes proliferate and
differentiate into a wide variety of T-lymphocyte
subpopulations. These include the T-helper (TH), T-
suppressor (TS), T-cytotoxic (TC), natural killer (NK), and
large granular lymphocytes (LG) (Bach et al., 1979).
According to the CD-system, T-Helper cell (TH cell)
Review of Literature 34
equals CD4+ and T-suppressor/T-cytotoxic (TS/TC) ratio
equals CD8+. Similarly, the CD-system can identify
interleukin-2 (IL-2) receptors as CD25, activation inducer
molecules as CD69, and transferrin receptors as CD71.
Natural killer cells (NK) are recognized as CD16 and B-
lymphocytes as CD20 (Arturson, 1996).
Each T-lymphocyte subpopulation is concerned with a
specific immune-regulatory function within the
inflammatory response. The various components of the T-
lymphocyte system are complexly interrelated via the
cytokine network. Cytokines also help in integrating the T-
lymphocyte functions with other immune-competent cell
functions. Thus T-lymphocytes, through cytokines, can
affect the functions of other cells of the immune-
inflammatory system, including vascular endothelial cells,
fibroblasts, mast cells, and phagocytic cells (PMNLs and
macrophages) (Lowry, 1993).
Thermal injury results in enhancement of T-lymphocyte
functions, which is indicated by an increase in the ratio of
helper to suppressor cells (HSR). This initial stimulation of
the T-lymphocytes is followed by a phase of marked
Review of Literature 35
exhaustion of their functions. Suppression of T-lymphocyte
functions eventually creates a status of marked increase in
the susceptibility of extensively burned patients to infectious
complications (Rioja et al., 1993).
4- The Mast Cells:
Mast cells lies close to the blood vessels in all tissues.
They constitute an important cellular element of the
inflammatory response. Upon stimulation, they start to
liberate their granule content of mediators. The most
important of these is histamine with its potent effect on the
vascular element of inflammation. Other mediators include
arachidonic acid metabolites (lipid peroxidases) and
cytokines. Thus, mediators derived from mast cell
degranulation have three main physiological effects. They
are chemoattractants (TNF-α, IL-8, LTB4, PAF),
vasoactivators (Histamine, PAF, kininogenase), and
spasmogens (Histamine, PGD2, LTC4, LTD4). Therefore, it
is clear that mast cells, through their rich content of
mediators, can markedly influence effector cell movement,
blood flow, and microvascular integrity (permeability) in
target tissue (Gordon et al., 1990).
Review of Literature 36
5- Platelets:
Platelets are derived from megakaryocytes in the bone
marrow. They have receptors for coagulation factors,
enabling them to share actively in the process of blood
clotting. In addition, platelets are also involved in the
immune-inflammatory response, and is rich in secretory
granules which contribute in both inflammation and tissue
restoration, through many biologically active products.
Those concerned with inflammation include Thromboxane
A2 (vasoconstrictor and proaggregator), platelet factor IV
(chemotactic), platelet activating factor (PAF) (enhancement
of microvascular permeability). On the other hand, platelet-
derived cytokines that are known to mediate healing
mechanisms involve insulin-like growth factor 1 (IGF-1),
platelet derived growth factor (PDGF), epidermal growth
factor (EGF), and transforming growth factor β (TGF-β).
These mediators can promote the proliferation of both
fibroblasts and keratinocytes (McGrath, 1990).
6- Vascular Endothelium:
The endothelium of small vessels (arterioles, capillaries
and postcapillary venules) plays important regulatory
Review of Literature 37
functions throughout the course of inflammation. This occurs
through the production of biologically active mediators
affecting both vascular and cellular elements of
inflammation. The chief endothelium-derived mediators
include prostacyclin (PGI2) which is lipid peroxide with
vasodilator effect, and various cytokines (Arturson, 1996).
The vascular endothelial cells have surface receptors
(protein in nature), which play an important integral function
in the locomotion of phagocytic cells (PMNLs and
macrophages) (Bevilacqua et al., 1993).
In addition, vascular endothelial cells produce two
other biologically significant products. These are the
endothelin-1 (ET-1), and thrombomodulin (TM). ET-1 is
believed to be involved in the onset of disseminated
intravascular coagulation (DIC) when produced in excess by
vascular endothelial cells. TM is a membrane protein with
antithrombus activity and is also involved in DIC (Ishibashi
et al., 1991).
Nakae and colleagues in 1996 found a significant
increase in the plasma levels of ET-1, TM, and TNF-α in
Review of Literature 38
patients who developed MOF (multiple organ failure) and
died in comparison to those who survived. Their findings
strongly suggested that the three mediators are intimately
related and can reflect the severity of the inflammatory
response in systemic organs and subsequently the degree of
multiple organ dysfunctions.
III- The Burn Toxin (Lipid Protein Complex) (LPC):
Careful biochemical analysis of the eschar enabled the
isolation of a heat-induced toxic material. The isolated toxic
material from the burned skin proved to be a polymerized
aggregate of lipids and proteins of the cell membranes in the
burned skin. The burn toxin (LPC) is elaborated in the eschar
under the polymerization effect of heat, and then, is
continuously absorbed into the circulation at the eschar-
subeschar (viable-nonviable) interface. Thus, LPC can also
be isolated by careful biochemical assay of the sera of burn
victims. In the circulation, the eschar (LPC), by acting as an
antigen, results in triggering of a system inflammatory
response (Schoenenberger et al., 1971).
When a patch of skin is separated from an animal,
Review of Literature 39
burned, and then applied back to the area of the mouse from
where it has been removed, it became highly toxic, and
resulted in death of the mice from severe inflammation in
systemic organ and eventually multiple organ failure (MOF).
If a barrier is placed under the burned skin patch, mortality
does not develop. These findings strongly suggest the
absorption of toxic material from the burned skin (LPC),
with subsequent strong triggering of a systemic
inflammatory response (Schoenenberger et al., 1971).
Animal experiments showed that, a sterile homogenate
of burned skin, injected into the mouse peritoneal cavity,
killed the mice whereas sterile homogenates of unburned
normal skin were not toxic. These findings confirmed the
capacity of burned skin to initiate a sustained systemic
inflammatory response, by being a constant source for burn
toxin (LPC) (Schoenenberger et al., 1975).
Demling and Lalonde in 1990 showed that in more than
half of the patients dying from the systemic inflammatory
response with its deleterious effects on vital organ function,
bacteria are not demonstrated. Their suggestion was that, the
uncontaminated eschar, by being a constant source for
Review of Literature 40
(LPC), could strongly enhance the systemic inflammatory
response.
Following severe burns, the gut, due to altered
permeability may become a constant source of bacterial
toxins, including the gram-ve bacterial endotoxin
(lipopolysaccharide of cell membrane) (LPS), and the
gram+ve exotoxins (superantigens) (enterotoxins). The
translocating toxins may result in triggering of a systemic
inflammatory response and subsequent vital organ
dysfunction. Thus, in the absence of burn wound infection,
there is much controversy about the triggering antigen of the
systemic inflammatory response, whether it is the eschar-
derived LPC or the gut-derived LPS and enterotoxins (Yao
et al., 1995).
Yao and colleagues in 1995 showed a significant
lowering of plasma endotoxin level that was associated with
marked improvement of survival rate after selective
intestinal decontamination.
On the other hand, Likewise, Carsin et al. in 1997 failed
to show a significant correlation between plasma levels of
Review of Literature 41
IL-6, and TNF-α, being significant members of the cytokine
cascade, and high plasma levels of gut-derived
endotoxaemia. They concluded that the post-burn
inflammatory response is mainly LPC-dependent, and thus
can occur irrespective of gut-derived toxaemia.
The fact that the sterile burn eschar is a continuous
source for a specific burn toxin (LPC), which can trigger a
vigorous systemic inflammatory response with multiple
organ dysfunctions, provided enough evidence that the burn
eschar is a dangerous thing to preserve. Early excision of the
burn eschar and wound closure eventually eliminates the
pernicious burn toxin before gaining access into the
circulation at the interface between the eschar and subeschar
viable tissue. Thus, the improvement in survival rate
following extensive burns, by prompt excision and wound
closure, is primarily attributed to marked dampening of the
post-burn LPC-triggered systemic inflammatory response
and the related vital organ dysfunction (Allgower et al.,
1995).
Kistler et al. 1990, conducted an experimental study on
rats to evaluate the effect of cerium nitrate on the liberation
Review of Literature 42
of the burn toxin (LPC) from the eschar. Rats covered with
cerium-treated burned skin survived, in contrast to the
control group covered saline-soaked burned skin. They
concluded that cerium nitrate, by having a high binding
affinity for LPC, is able to fix to LPC within the eschar,
thereby preventing it from gaining access into the
circulation, and resulting in its denaturation and
neutralization. Thus, cerium nitrate exerts a simple chemical
excision of the eschar. Kistler et al. also suggested the
possibility of using cerium nitrate in human burns, to affect a
non-traumatic fixation of the burned skin-derived toxin
(LPC), thus avoiding blood loss, surgical trauma, and
removal of second degree burn skin, which all accompany
the practice of early surgical excision of the eschar.
Scheidegger and coworkers in 1992 and Lamaie and
colleagues in 1999, achieved dramatic improvement in
survival of burned patients by bathing them, at the time of
hospital admission, in cerium nitrate on a 30-minutes basis.
They suggested that such non-traumatic excision of the burn
eschar should be a reliable alternative to early surgical
excision practice.
Review of Literature 43
IV- Paradoxes in Burn Immune Failure: The Activation-
Induced Cell Death Theory (AICD) (Apoptosis) (Table 3):
When T-lymphocytes, taken from burned patients, are
stimulated in vitro, they show marked reduction in their main
product, interleukin-2. They also show a markedly deficient
expression of IL-2 receptor (IL-2R) on their surface. These
findings suggest a definite failure in T-cell function.
However, paradoxically, the serum of burn patients is found
to contain high levels of IL-2 and IL-2R. This clearly
indicates that immune cell activation event takes place in
vivo, in response to the burn, and that the in vitro results
represent the activity of cells, which became exhausted or
refractory. Therefore, it is evident that T-lymphocyte failure
is not an initial event, but follows a state of vigorous initial
activation in vivo (Teodorczyk-Injeyan et al., 1991).
In addition, In vitro culture of macrophages withdrawn
from burn patients show marked reduction in interleukin-1
production, despite a high level of the same cytokine in vivo.
Thus, macrophages exhibit failure, secondary to a strong in
vivo activation (Liu et al., 1994).
Review of Literature 44
Table 3: Paradoxes in Burn Immune Failure (Atiyeh et al., 2005).
Vindenes and coworkers in 1994 described the pattern
of behaviour of PMNLs following thermal injury in the form
of an initial systemic activation of all functions including the
expression of surface adhesion molecules, surface receptors
for opsonins (immunoglobulins and complement),
phagocytosis, oxidative burst and intracellular degradation of
ingested microorganisms. The following impairment of
PMNL functions included the whole pattern of previously
enhanced activities.
The Role of LPC in Paradoxes in Burn Immune Failure:
Schoenenberger et al. in 1975 concluded that LPC is a
significant mediator of weakened host defenses following a
* Immune paradox of burns
Tissue ischemia and destruction.
Loss of barrier functions.
Foreign body introduction.
Inoculation of microorganisms.
Helper-cell dysfunction.
Neutrophil dysfunction.
Complement depletion.
Abnormal opsonic activity.
Stress-associated hormones.
Immunosuppressive substances.
Increased PGE2 level.
Review of Literature 45
thermal insult.
Consistent with the previous finding, Echinard et al. in
1982 demonstrated that, immediate excision of the burn
eschar in Guinea pigs could significantly enhance the host
defense mechanisms. They stressed that the eschar-derived
LPC should be the main cause for the observed post-burn
status of immunesuppression. They also stated that, their
results are perhaps convincing in the way that prompt
excision of the burn eschar should similarly enhance host
defenses in human burns.
Heberer et al. in 1982 studied the behaviour of
peripheral blood phagocytotic cells, when incubated in vitro,
in the presence of LPC. They found that LPC initially
enhanced phagocytosis but further contact with the
granulocytes and monocytes proved an exhaustive effect on
their function. They concluded that the burned skin-derived
LPC has a dual effect on immune cells, an initial triggering
effect and a later exhaustive effect, leading to suppression of
all functions.
Munster and colleagues in 1986 suggested that gut-
Review of Literature 46
derived bacterial toxins, due to bacterial translocation might
play a role in the pathogenesis of the phase of post-burn
immunesuppression. They found that although the
circulating endotoxaemia was markedly reduced by
administration of polymixin B, yet it failed to show any
enhancement in T-lymphocyte function. Munster et al.
concluded that, although gut-derived toxaemia is a common
finding following thermal insult, yet it could not be
considered as the main trigger for the observed immune-
inflammatory response, nor for the subsequent
immunefailure. Instead, it is suggested that the burned skin-
derived LPC is the primary aeteological factor for both
aspects of the post-burn immune dysfunction, i.e. the initial
stimulation, and the later on suppression.
Sparkes in 1991 studied the behaviour of T-
lymphocytes when cultured in vitro, in the presence of LPC.
He found that LPC was able to stimulate IL-2 production in
resting competent cells, therefore acting as an antigen.
However, paradoxically (LPC) inhibited the cells that are
already IL-2-dependent. This latter ability of (LPC) to arrest
the growth of cells that are already IL-2-dependent is termed
Review of Literature 47
the activation induced cell death (AICD) (Apoptosis).
Consequently, the LPC can be considered as the chief
mediator of both the post-burn inflammatory response and
the following status of immune-failure with increased
susceptibility to infection.
Cioffi et al. in 1993 stated that, thermal injury, like any
other major trauma, triggers the release of corticosteroids
and catecholamines from the suprarenal glands. Such
endogenous hormones have a well-known immune-
suppressive effect. Therefore, they are suspected to be the
cause of post-burn immune failure. However, Cioffi and co-
workers concentrated upon the fact that the post-burn
immune failure is far more serious than in any other major
trauma (e.g. blunt trauma). Thus, it is suggested that post-
burn immune failure is a specific (LPC)-mediated
phenomenon, while endogenous hormones are believed to be
secondary non-specific contributors in immune cell
dysfunction.
Allgower et al. in 1995 studied the behaviour of
peripheral blood mononuclear cells (PBMC), i.e. T-
Review of Literature 48
lymphocytes, withdrawn from burn patients and cultured in
vitro. They compared the in vitro capacity of lymphocytes to
produce IL-2 and to express IL-2R in patients treated
conventionally, and patients treated by once bathing in
cerium nitrate. They found that, in the first group, the T-
lymphocyte function was markedly dampened in vitro. In
contrast, lymphocyte withdrawn from cerium nitrate-bathed
patients showed a sustained capacity to produce IL-2 and to
express IL-2R. The explanation was that, cerium nitrate by
fixing LPC can prevent much of its paradoxical suppressive
effect on T-lymphocyte function, thereby achieving an
increased tolerance to infection.
Sparkes in 1997 stated that the burn-induced, eschar-
derived toxin (LPC) lies behind all the observed post-burn
immune cell dysfunctions. Initially, the LPC, released into
the circulation at the viable-nonviable interface, acts as an
antigen, thus resulting in a systemic immune-inflammatory
response (SIR). This LPC-triggered systemic inflammation
includes various cascades (e.g. the cytokine cascade), and
takes place in all vital organs, hence the name internal
inflammation. The magnitude of the LPC-triggered SIR is
Review of Literature 49
directly proportionate to the total body surface area burned
(percentage of TBSA), and can eventually end up by vital
organ dysfunction and failure (MOF). Thus, the first issue is
that the pernicious LPC can directly kill the burn victim,
without the presence of bacteria. Measures like prompt
excision and bathing in cerium nitrate proved efficiency in
improving survival by eliminating the burn toxin, and thus
dampening the systemic inflammatory response.
V- The Role of Burn Wound Sepsis in the Post-burn
Inflammatory Response:
It is strongly evident, nowadays, that burn wound
infection, is not a primary contributor in burn
pathophysiology. Thus, even a non-contaminated burn
eschar can threaten a burn patient‟s life, by the continuous
leaching of the pernicious burn toxin into the circulation. It
is therefore not surprising to have records of 50 % mortality
from extensive burns without evidences of burn wound
infection. It is only when the initial LPC-mediated (SIR) is
not strong enough to deteriorate vital organ functions, that
burn wound infection comes to the scene. In such situation,
Review of Literature 50
bacterial toxins start to menace the immune-competent cells.
Due to the immune failure, paradoxically induced by LPC,
the bacterial toxin-mediated inflammatory response becomes
enhanced and sustained, thus resulting in vital organ
dysfunction. Therefore, it is clear that, the LPC, by inducing
immunesuppression, creates a status of persistent bacterial
toxin-mediated systemic inflammation (Demling et al.,
1990).
Bacterial toxins, which can menace the immune-
inflammatory system, fall into two major groups. They are
either derived from the cell membrane of gram-ve bacteria,
hence the name (endotoxins), or produced by gram+ve
organisms, hence the name (exotoxins). Endotoxins of gram
-ve bacteria are lipopolysaccharide in nature (LPS), while
the exotoxins of gram+ve species are alternatively termed
bacterial superantigens (enterotoxins). Both groups are
known to drive the infection-mediated post-burn systemic
inflammatory response (SIR). Thus they can induce vital
organ dysfunction and shock, i.e. an endotoxin or enterotoxic
shock syndrome, comparable to the burn toxic shock
mediated by the (LPC) (Allgower et al., 1995).
Review of Literature 51
Childs et al. 1999, studied the pattern of illness in
gram+ve sepsis of burn wound, in relation to the type of
exotoxin produced. They demonstrated that all types of
gram+ve exotoxins could trigger a systemic inflammatory
response, with subsequent development of toxic shock
syndrome (TSS). TSS is specific to a special strain of staph.
aureus producing a special exotoxin, which was termed the
toxic shock syndrome toxin-1 (TSST-1).
Tanaka and colleagues in 1995 conducted a
comparative clinical study to evaluate the hemodynamic
changes resulting from toxic shock syndrome toxin-1 staph
aureus sepsis, and the endotoxin-producing gram-ve rod
sepsis in patients with severe burns. They stated that, in spite
of the widely spread data concerning gram-ve rod sepsis, i.e.
the endotoxic shock syndrome, little information is known
about the severity of the toxic shock syndrome toxin-1
gram+ve coccal sepsis. The findings of the study reported
that toxic shock syndrome toxin-1 gram+ve coccal sepsis
induces hyperdynamic hypermetabolic responses that are
equal or even more profound than does the endotoxin-
producing gram-ve rod sepsis. The results of Tanaka and co-
Review of Literature 52
workers are considered to be the first clinical report that
TSST-1 sepsis may result in more profound responses than
does endotoxin sepsis. This may be explained based on a
stronger stimulation of the inflammatory cascades (e.g.
cytokine cascade), by the TSST-1 than by the endotoxin.
VI- The Pathogenesis of Multiple Organ Failure (MOF)
Following Severe Burns:
Cioffi and coworkers in 1993 stated that, following
thermal injury, there occurs a sustained triggering of a
systemic inflammatory response (SIR). The initial chief
stimulation is mediated by the burn-induced eschar-derived
toxin (LPC). Subsequent stimulation of immune-competent
cells is mediated by wound bacterial toxins, resulting from
an LPC-mediated immune failure. Both groups of bacterial
toxins, the gram-ve derived endotoxins (LPS), and the
gram+ve-derived exotoxins (Superantigens), have an equal
capacity to trigger systemic inflammation. Thus, systemic
inflammation is initially triggered by the LPC, then sustained
and enhanced by the LPS and bacterial superantigens. The
systemic inflammatory response (SIR) entails the activation
Review of Literature 53
of various cascades of mediators that coordinate the function
of immunecompetent cells. Eventually, the persistent
inflammation in systemic organs (e.g. heart, liver, kidney,
and GIT) results in dysfunction (MOD), then complete
failure of function (MOF) and death of the burn victim.
Arturson, 1996, stated that, although the pathogenesis
of MOF is primarily attributed to the burn toxin (LPC) and
wound bacterial toxins (LPS and superantigens); yet other
factors may also contribute to the systemic inflammatory
response. Surgical procedures and gut-derived toxins (due to
translocation) may add to the initial LPC-driven systemic
inflammatory response (SIR). Surgical trauma and gut-
derived sepsis may also result in leukocyte exhaustion, thus
enhancing the specific LPC-mediated immunesuppression. It
is thus concluded that surgical trauma and gut-derived toxins
are only contributors to immunestimulation and exhaustive
immune failure, while the chief mediator of both aspects of
immune-dysfunction is the burn toxin (LPC).
Review of Literature 54
Evaluation of Burn Wound and Management Decisions
The hydrophilic human skin possesses a high specific
heat and a low thermal conductivity. Therefore, skin
becomes overheated slowly, but also cools slowly. As a
result, thermal damage continues after the burning agent is
extinguished or removed (Carvajal et al., 1979).
In addition to the appearance (i.e. extent and depth) of
the wound, other factors can determine burn wound
management decisions. These factors include the type of
burn, the age of the patient, and the circumstances
surrounding the injury (Herndon, 2001).
For many years, deep burns were treated
conservatively. However, modern treatment strategies
involve early aggressive surgical removal of the deep burns.
Therefore, an accurate estimation of burn depth becomes
crucial (Herndon et al., 1986).
I- Estimation of burn wound depth:
The standard technique for determining burn depth has
long been clinical observation of the wound. Unfortunately,
the difference in burn depth between a deep dermal burn and
Review of Literature 55
a full-thickness burn may be only a matter of only a few
tenths of a millimeter. Further, a burn is a dynamic process;
therefore, what appears shallow on first day may appear deep
by third post-burn day. Finally, the kind of topical wound
care used can dramatically change the appearance of the burn
(Hlava et al., 1983).
Because of these limitations, and because of its
increased importance in planning definitive burn wound
care, interest has been stirred and technology has brought
numerous devices and techniques to determine burn depth
more precisely than clinical observation. These techniques
have been used based on the physiology of the skin and
alterations produced by burn. These techniques take
advantage of, the ability to detect dead cells or denatured
collagen (e.g. biopsy, ultrasound, vital dyes), altered blood
flow (e.g. fluorescein, laser Doppler, and thermograph), the
color of the wound (e.g. light reflectance), and physical
changes, such as edema (e.g. magnetic resonance imaging)
(Wachtel, 1989 and Herndon, 2001).
The burn depth indicator (BDI) should be 100%
accurate for shallow and full-thickness wounds for any of
Review of Literature 56
these techniques (Herndon, 2001).
Histological wound biopsy would seem to be the most
precise diagnostic tool. However, biopsies leave permanent
scars in partial-thickness wounds, they are expensive and
they require an experienced pathologist to tell live from
denatured collagen and cells. Further, there is no guarantee
that areas adjacent to the biopsy are the same depth (Jackson,
1953).
Ultrasound technique has a problem that collagen
denatures at 65°C while the epidermal cells, from which the
burn must heal, are destroyed at about 47°C. As a result
apparent depth is likely to be underestimated by ultrasound
technique (Brink et al., 1986).
Vital Dyes application directly to the burn wound
would be useful in detecting dead tissue and also in
determining the depth of excision. Davies and coworker in
1980, described important characteristics of such a dye. It
should stain only dead tissue, not be removable with wound
treatment, be nontoxic, provide a sharp demarcation between
living and dead tissue, penetrate all dead tissue, and be
Review of Literature 57
compatible with topical treatments usually used in burn care.
Methylene blue, which is metabolized to a colorless
compound by living cells, when mixed with silver
sulfadiazine and applied topically, a significant blue
discoloration appeared within 48 hours, which remained
after vigorous washing (Zawacki et al., 1970).
Fluorescein Fluorometry is another technique, where
fluorescein injected systemically. It is delivered through the
patient‟s circulation and fluoresces under ultraviolet light.
Partial-thickness burns uniformly will exhibit fluorescence
within few minutes, but full-thickness burns will show nil
(Grossman et al., 1984).
Laser Doppler Flowmetry technique depends on the
electrical signal of blood flow in normal versus burned areas
of skin. The laser Doppler has the advantage of being easy to
use and non-invasive (Park, 1998).
Thermography is based on the concept that the
diminished blood flow to deep dermal and full-thickness
burns makes them cooler. However it is highly dependent on
room and patient temperature, the patient‟s anxiety and
Review of Literature 58
stress level (Henane et al., 1981).
Light Reflectance (Spectroscope) could estimate the
depth as the skin is relatively transparent to short wavelength
infrared light, and reduced hemoglobin absorbs more of the
light than oxygenated hemoglobin (Anselmo et al., 1973).
Proton Magnetic Resonance Imaging (MRI) correlate
with tissue water content, where full-thickness burns result
in slower resorption of wound edema than partial-thickness
burns (Koruda et al., 1986).
Based on these widely differing techniques, it becomes
apparent that precise determination of burn depth awaits
further refinement of instrumentation, and clinical
assessment remains the not-so-golden standard (Herndon,
2001).
Age of the patient is another determining factor for
burn wound management decisions. There are many factors
which make burn mortality in the geriatric patient is higher
than the rest of the population with similar burns (Heimbach,
1987).
As man ages, the skin atrophies with thinning of the
Review of Literature 59
dermis and disappearance of skin appendages. The thin skin
makes the diagnosis of burn depth difficult and the grafts on
fat often do not survive (Deitch, 1985).
The current plan is to excise to fascia full-thickness
burns, which will not heal, from the periphery or by
contraction, and to graft them with meshed grafts taken at
0.008 inch from the back. Indeterminate burns are generally
to be treated conservatively, as outpatients if possible
(Herndon, 2001).
II- Surgical Burn Wound Management
During the past thirty years, the treatment of deep burns
by experienced burn surgeons has changed dramatically!
(Heimbach, 1987).
Previously, nearly all large, deep burns were treated
expectantly, eschar was permitted to slough spontaneously
and the wounds were left to granulate before they were skin
grafted. Split-thickness skin grafts were procured and
applied in many instances, not in sheets, but using a variety
of free-hand techniques. Small patches or „stamps‟ of graft,
Review of Literature 60
or even smaller „punch‟ grafts were applied to maximize
epithelial perimeter and, hopefully to minimize graft loss
from the heavily contaminated wounds. Weeks or,
frequently, months passed before wound closure could be
achieved with these methods.
Survival rates were very low especially if the burn
surface area exceeded more than 40% of the body surface
area. Perceptive surgeons were of course fully aware of the
many disadvantages associated with such passive, expectant
therapy (Haynes, 1987).
During two World Wars, the idea of the prompt
excision of all devitalized tissue was elicited. This axiom
clearly seemed applicable to burn treatment, but numerous
practical clinical constraints prevented its general application
(Haynes, 1987).
In more extensive burns, effective measures for
controlling wound microbial growth were lacking, dense
wound colonization almost occurred within the first few days
and commonly. This was the source of invasive infection of
normal tissue at the burn margins, systemic sepsis and death.
Review of Literature 61
There were few safe, effective antibiotics and the importance
of nutritional support was ill-appreciated (Gray et al., 1982).
Then, effective topical therapy was introduced. This
one advance, more than any other, re-awakened widespread
interests by the surgical community in burn care (Jackson,
1969).
Other important advances particularly in the area of
critical care medicine, effective mechanical ventilation,
potent and relatively safe antibiotics, precision power
dermatomes, mesh-expansion techniques of the grafts, and
interested personnel in burn management contributed to the
dramatic overall improvement in burn care (Herndon et al.,
1987).
Nowadays, aggressive, earlier and more frequent use of
definitive surgical therapy for deep burns has become the
norm in the western world. The question remain open,
however, as to the timing, extent and depth to which surgical
wound closure should be utilized in patients with burns so
extensive that survival is problematic (Hart et al., 2003).
Review of Literature 62
Surgical Methods of Burn Wound Closure
The excision of necrotic tissue and the covering of
excised areas give local advantages, by eliminating lactic-
acid-rich necrotic tissues. These tissues influence collagen
synthesis, by reducing the soluble mediators that act on the
microcirculation and the impermeability of the blood vessels,
increasing antibacterial defense from external contamination
(Gray et al., 1982).
General advantages are also obtained by removing toxic
materials with protease activity, reducing hydro-electrolytic,
protein and heat loss, decreasing the risk of sepsis and
shortening the length of hospital stay (Heimbach, 1987).
Excision therapy may also reduce protein catabolism,
immunosuppression, and evaporative water losses. In some
cases, early excision can improve cosmosis by reducing
hypertrophic scarring (Gray et al., 1982).
Therefore, the ultimate solution of burn management is
closure of the burn wound through surgical intervention. The
alternative burn-care philosophies differ in the timing,
extent, depth and technique of the surgical procedure
Review of Literature 63
(Herndon et al., 1986)
A- Timing of Burn Wound Excision
Timing of excision therapy is debatable. The patient
should undergo excision therapy when surgical risks do not
increase risk of mortality nor compromise anticipated
functional and cosmetic results. It may be immediate (within
first 24 hours post-burn), early (within 3rd -5th PBD) or late
(within 4th to 14th PBD) when the acute resuscitation period
is well over (Burke et al., 1976).
Experimentally, immediate complete excision of the
wound within 24 hours of injury prevented hypermetabolism
and immune suppression in the post-burn period but
theoretically, it may aggravate the hemodynamic instability
in the major burns. Clinically, in children with greater than
60% TBSA burns, immediate excision therapy resulted in
improved survival (Desai et al., 1990).
Many surgeons prefer early excision of the burn wound
within 3rd and 5th PBD of the injury as soon as hemodynamic
stability, physiological tolerance, reliable determination of
burn depth are ascertained and prior to bacterial colonization
Review of Literature 64
of the wound (Heimbach, 1987).
For most flame burns, excision therapy can be
completed within 48 hours of admission unless delayed by
serious inhalation injury, concomitant injuries, frailty from
extremes of age, or pre-existing medical conditions.
However, in scald burns, delay of excision for one week
reduces blood loss and areas of skin grafting (Rose et al.,
1996).
Partial-thickness flame burns that will spontaneously
heal within 14-21 days may be not excised and if treated
conservatively, deep partial-thickness burns produce poorer
scars, more complications and prolonged hospitalization.
Therefore, deep partial-thickness wounds are often treated
similar to full-thickness injuries by surgical excision as soon
as possible (Heimbach, 1987).
B- Extent of Burn Wound Excision
The extent of excision is determined by the stability of
the patient, the burn size, the speed of the surgical team, the
adequacy of anesthesia, the rate of blood loss and the
availability of skin graft or its substitute (Engrav et al.,
Review of Literature 65
1983).
Blood losses are minimized by use of tourniquets,
pressure, topical thrombin and topical or subcutaneous
epinephrine. However, overdoses of epinephrine producing
hypertension or paroxysmal tachycardia do occur with
injudicious topical use, especially in children. In burns less
than 40% TBSA, excision can be completed in a single
procedure (Rose et al., 1996).
However, the practice of early excision and grafting is
ideally performed for 10 to 15% of TBSA per session, giving
priority as always to the face and hands. All full-thickness
burns can be excised first, so that deep dermal and
indeterminate depth wounds are addressed later, preventing
excision of potentially viable tissue (Herndon, 2001).
C- Depth of Burn Wound Excision
For instance, the ideal depth of burn wound excision
has not yet been established (Hart et al., 2003). However,
theoretically, injured tissue following thermal trauma
presents a central area of necrosis surrounded by a stasis
zone in which cell metabolism is slowed down, creating
Review of Literature 66
favorable conditions for wound sepsis (Herndon et al.,
1986).
The bacterial colonization is responsible for the
deepening of the wounds by lysis of the surrounding healthy
tissue, the most feared and serious complication in the burn
patient (Cope et al., 1947).
Episodes of sepsis also lead to ischemic necrosis of
subcutaneous fat subsequent to poor peripheral perfusion and
microvascular stasis, that leads to late graft loss and these
ischemic areas become portals for invasive wound sepsis
(Herndon et al., 1984).
Deeper excisions is also indicated for life-threatening
invasive wound sepsis with fungi and yeast such as
aspergillus and candida and also for large areas with failed
graft take (Engrav et al., 1983).
It is hypothesized that the accumulation and
reabsorption of subeschar tissue fluid (STF) may increase the
morbidity and mortality rates in severely burned patients.
Therefore, the unburned tissues at the margin and the depth
of the burn may be affected and may exaggerate the systemic
Review of Literature 67
inflammation (Chen et al., 2000).
D- Techniques of Burn Wound Excision
The aim of surgical treatment is to transform the
avascular burn wound into a uniformly bleeding non-
contaminated surgical wound, at the same time avoiding the
process of eschar demarcation due to granulation tissue,
which is the cause of hypertrophic scars. The areas prepared
in this way must then be covered to obtain definitive healing
(Herndon et al., 1989).
a- Primary closure of excised burns or donor sites
Small deep burns on lax skin areas such as the buttock,
female breast or the limbs or torso in the elderly can on
occasion be excised and closed primarily, particularly if
cosmosis is not an issue. In the elderly also, donor sites
harvested from lax skin areas can at times be closed
primarily (Herndon et al., 1990).
b- Amputation
When a major portion of a limb, hand, or digit has been
destroyed, or its potential for functional recovery is judged to
Review of Literature 68
be nil, amputation may be appropriate or even life saving,
especially when doing so eliminates the deep burn and the
stump can be closed primarily (Brown et al., 1994).
c- Tangential excision
The „tangential‟ or so-called „laminar‟ method of
sequentially shaving the eschar from the wound surface until
a viable-tissue plane is reached was first described by
Janzekovic in 1970s. It is particularly suitable for the
excision of deep dermal or shallow, superficial full-thickness
burns. The procedure is usually performed using a hand-held
blade equipped with a calibrated depth guard (0.010-0.025
inches), such as the small Goulian knife or the larger, more
cumbersome Humby knife (Gray et al., 1982).
For broad, relatively flat burn deep burns, a power
dermatome such as the Brown, with its depth gauge set
appropriately, is convenient for rapidly performing
tangential excision, but it is not suitable for use on the hand,
foot or face (Heimbach, 1987).
In experienced hands, tangential excision is rapid and
permits salvage of viable reticular dermis, although
Review of Literature 69
hemorrhage may be considerable. On limbs, a tourniquet
probably helps to reduce blood loss, although it makes the
differentiation of viable from non-viable tissue more
difficult. An acceptable wound bed is identified by active
punctuate bleeding. By using this technique, a maximum of
viable tissue is preserved and optimal functional and
cosmetic results are achieved (Herndon et al., 1989).
d- Down to fascia excision (degloving or avulsion)
Fascial excision is recommended if the subcutaneous
fat is burned, and in selected large burns with more than 60%
TBSA full-thickness who have high risks for infection, blood
loss, or skin graft slough. Excision to this plane minimizes
bleeding and provides a reliable, clean, vascular bed. Linear
escharotomies placed 180° apart on a limb, and/or at the
wound margins otherwise, which is best limited at the level
of wrist or ankle (Herndon et al., 1989).
Fascial excision results in damage to lymphatics and
cutaneous nerves and loss of subcutaneous fat (Rode, 2001).
The excised fat never regenerates and can give a spindly
appearance to the areas excised while any increase in body
Review of Literature 70
fat is deposited in the remaining beds of adipose tissue.
Moon faces and thick necks can result (Heimbach, 1987).
E- Coverage of Excised Burn Wound
Preferably, coverage of excised burn wound is
performed with permanent skin autograft, but closure can
also be achieved with skin allograft, other biological
dressings or skin substitutes. Without immediate coverage,
desiccation or infection can increase tissue loss and negate
the benefits of early excision (Heimbach, 1987).
In burns less than 40% TBSA, wide availability of
donor sites permits wound coverage with autograft. In burns
more than 40% TBSA, when immediate permanent coverage
is not possible after surgical excision, the area may be
temporarily covered with cadaver skin, which may later be
replaced by skin autograft. Alternatively, even if less
satisfactory, amniotic membrane may be used for this
function (Herndon, 2001).
The outcome of burns treatment will be further
improved only when optimal operating times and clear
technical criteria (extent, depth and technique of excision)
Review of Literature 71
will have been established (Hart et al., 2003).
III- Impact of burn wound excision on the Immune-
Inflammatory Response to Burn
Studies have shown that cell mediated immunity is
suppressed markedly following thermal injury. Macrophages
and the activation of an inflammatory cascade that includes
interleukins IL-1, IL-6, tumor necrosis factor-alpha (TNF-α)
and PGE2 have been implicated as causative factors
(Schwacha et al., 2000).
Burn wound excision and grafting restores cellular
immunity. It normalized TNF-α production to sham levels,
independent of when post-burn the procedure was
conducted. In contrast, the elevated production of other
inflammatory mediators (IL-1β, IL-6, nitric oxide, PGE2)
post-burn was unaffected by burn wound excision and
grafting. Moreover, splenic T-lymphocyte proliferation is
also suppressed at 7th day post-burn and is not improved by
burn wound excision and grafting (Schwacha et al., 2000).
Therefore, the beneficial effects of burn wound
excision and grafting are likely to be related to the
Review of Literature 72
normalization of macrophage TNF-α production as well as
the maintenance of skin barrier function (Schwacha et al.,
2000).
In addition, burn injury inhibits viral-specific cytotoxic
T-lymphocyte activity. Early, complete wound excision
augments cytotoxic T-lymphocyte function. Improved
cytotoxic T-lymphocyte activity after burn may reduce the
risk of infection, providing an immunologic rationale for
expeditious wound excision (Hultman et al., 1997).
Yamamoto et al. in 1996 stated that all B-cell functions
are significantly suppressed by burn injury. Immediate
excision and grafting restores anti-PGPS IgM synthesis to
normal, while nonspecific B-cell functions are not changed
significantly. However, early excision and grafting fails to
improve significantly any B-cell functions. Immediate but
not early excision restores antibody synthesis to the bacterial
cell wall antigen (PGPS). Immediate excision may therefore
lead to a decrease in bacterial infection after burn injury.
Huang et al., 1999 stated that eschar excision en masse
at one operation is feasible and effective in preventing and
Review of Literature 73
treating early post-burn organ dysfunction and multiorgan
failure, mainly by alleviating systemic inflammatory
response syndrome and endothelial cell injury.
Recent reports have suggested that very early excision
(less than 24 hours post-burn) and primary closure of burn
wounds might circumvent the immunosuppression, which
follows severe thermal trauma. The trauma of excision and
grafting alone results in depression of cell-mediated
immunity. This deterioration is due to the systemic cytokine
response, which is predominantly that of IL-6. It is also
related to the release of TNF-α (Herndon, 2001).
The subeschar tissue fluid possesses the ability to
inhibit mitogen-induced lymphocyte proliferation (MILP);
this suppressive nature is stable, persisting for prolonged
periods. The gradual absorption of STF likely contributes to
the serologic evidence of cell-mediated immune suppression
documented in victims of severe thermal injury (Dyess et al.,
1991).
Therefore, removing dead tissue, down-to-fascia
excision may better than tangential excision because it
Review of Literature 74
removes large amounts of immunosuppressive subeschar
tissue fluid (Schwacha et al., 2000).
These data call into question the ability of very early
excision and grafting to alter the immunosuppression, which
follows severe thermal trauma (Carsin et al., 2002).
Therefore, aggressive, earlier and more frequent use of
definitive surgical therapy for deep burns has become the
standard management of severe burns. However, the
outcome of burns treatment will be further improved when
optimal operating times and clear technical criteria (extent,
depth) will have been established (Hart et al., 2003).
Patients and Methods 75
A- Study Design:
The study was concerned with the comparison between the
technique of early burn wound excision (tangential excision
and down-to-fascia excision) and the immunological profile
changes, using alteration of interleukin-6 (IL-6) and tumor
necrosis factor-alpha (TNF-α) levels as indicators.
B - Patient Population:
This prospective comparative study was conducted in the
Burn Unit of Ain Shams University Hospitals, in the period
from January 2004 until March 2006. The study included 30
acutely burned adult patients admitted to the Burn Unit. All
patients had a combination of superficial and deep dermal
burns. Patients were chosen irrespective to age or sex (15
females, 15 males). The ages ranged between 20 - 50 years,
(29.2 + 9.8 years). The burned surface area (BSA) ranged
between 21 and 70% according to the Lund and Browder chart,
(42.8 + 13.4 %). The deep areas, (i.e. deep dermal) were
ranging between 15 and 25% of TBSA, (21.9 + 2.9%). Out of
Patients and Methods 76
the 30 patients, 25 had flame burns (83 %), 4 had scalds (13 %)
and 1 had flash burns (3 %). The shortest hospital stay was 8
days, and the longest stay was 39 days, (20.9 + 10 days).
All patients were admitted within 8 hours from the injury.
Patients with preexisting medical diseases (e.g. renal or liver
impairment, diabetes mellitus, immunodeficiency syndrome as
AIDS, leukemia, lymphoma, lymphocytopenia) were excluded.
All patients received parental antibiotics (according to our burn
unit protocol, it was ciprofloxacin) in the first week.
Escharotomy was performed in the emergency room under
general anesthesia for circumferential deep burns of the upper
limb, lower limb, neck, and trunk. Careful haemostasis was
performed to minimize blood loss to exclude immune response
to stress and blood loss especially with tangential excision,
(Basill, 2004).
Patients and Methods 77
The 30 patients were divided into two groups according to
the technique of the excision:
First group (15 patients: 9 females and 6 males):
This group included the patients who were candidates for
tangential early burn wound excision and application of
allograft.
Second group (15 patients: 6 females and 9 males):
This group included the patients who were candidates for
down-to fascia early burn wound excision and application of
allograft.
C- Management Protocol:
All patients were weighed in the admission room, prior to
resuscitation and the following protocols were applied:
I- Resuscitation Protocol:
Resuscitation was performed using the Modified Parkland
formula (Baxter, 1974):
Total amount of fluid = 3ml / kg body weight / % BSA.
Patients and Methods 78
The success of resuscitation was assessed by monitoring the
pulse rate, blood pressure, urine output per hour, and central
venous pressure. Throughout resuscitation, alterations could be
made on the amount of fluids given, depending upon the
hemodynamic status of the burned patient. In the first 24 hours,
the only solution given was Ringer‟s Lactate. In the following
days, a combination of crystalloids and colloids was given,
depending upon the hemodynamic status of the patient. Blood
transfusion, fresh frozen plasma, and albumin, were given
according to the laboratory data.
II- Nutritional Protocol:
The caloric and protein requirements were calculated
according to the Curreri formula, 1974:
Total caloric requirements /day = 25 x weight in kg + 40 x % BSA.
Feeding was started within 24 hours from the time of
admission, if the intestinal sounds were audible. The
requirements were given either orally or by tube feedings.
Multivitamins and trace elements were also supplemented on
daily basis.
Patients and Methods 79
III- Post-resuscitation Management:
1- Wound management:
Burn wounds were cleansed on admission using aqueous
povidone iodine (10 %). Superficial and deep dermal burns
were dressed with tulle grass. The change of dressing was
performed on a daily or twice daily basis. In most cases, the
dressing was performed in the hydrotherapy room, preferably
under general anesthesia.
2- Surgical Procedures (early excision and grafting):
- Timing of excision:
Early excision and grafting was attempted once the
resuscitation has been accomplished, and the patient‟s general
condition has become stable. The burn wound excision was
started within first five PBDs and it was completed by the
eleventh PBD.
-Extent of excision:
Extent of excised area ranged between 5% and 16% of
TBSA per session, (9.8 + 2.6%). A tourniquet or subeschar
adrenaline 1/200,000 infiltration was applied and the
Patients and Methods 80
electrosurgical unit was utilized especially in down to fascia
excision, in order to minimize blood loss. In extensive burns,
provided that the general condition of the patient permitted,
multiple sessions of excision were performed.
- Techniques and depth of excision:
a- Tangential excision:
The tangential method - sequentially shaving the eschar
from the wound surface until a viable-tissue plane - was
applied for first patient group. An acceptable wound bed was
identified by active punctuate bleeding.
Fig. 5: case no. 7 in first group (a) preoperative, (b) bed after
tangential excision, (c) after application of meshed autograft
a c b
Patients and Methods 81
The procedure was usually performed using a hand-held
blade equipped with a calibrated depth guard (0.010-0.025
inches), such as skin graft knife. For broad, relatively flat burn
deep burns, a power Brown dermatome, with its depth gauge
set appropriately (≈ 0.15 inch), was convenient for rapidly
performing tangential excision.
b- Down to fascia excision:
Excision to this plane minimized blood loss and provided a
reliable, clean, vascular bed. Linear escharotomies were placed
180° apart on a limb, and/or at the wound margins otherwise,
which was limited at the level of wrist or ankle.
The procedure was usually performed using a scalpel or
electrocautery unit (cutting or coagulation settings).
Patients and Methods 82
- Coverage of Excised Burn Wound
The total areas excised were covered by allograft (homograft
or amniotic membranes) except case no.7 in first group and
cases no. 1, 9 and 15 in second group, where autografts were
used.
a b
c d
Fig. 6: case no. 12 in second group (a) preoperative, (b) bed
after down-to-fascia excision, (c) excised eschar, (d) after
application of amniotic membranes
Patients and Methods 83
D - Monitoring of the patients:
Organ dysfunction was based on the following set of
clinical and/or laboratory criteria:
a- Clinical Monitoring:
i- Systemic monitoring:
a) Central nervous system:
Alteration in the level of consciousness and
Changes in temperature (hyper or hypothermia). A
low-grade fever, i.e. up to 38oC was considered to
reflect a hypermetabolic status and it thus not
indicative of sepsis.
b) Cardiovascular system:
Severe arrhythmias, Heart rate > 160 b.p.m and
lasting for more than 48 hours or Decrease in blood
pressure needing pharmacological support.
c) Renal system:
Anuria, oliguria or renal replacement therapy,
d) Respiratory system:
Tachypnea, orthopnea and/or cyanosis.
Assisted ventilation for more than 5 days,
Patients and Methods 84
ii- Local (burn wound) monitoring:
Local signs suggestive of burn wound infection.
Progression of partial-thickness to full-thickness injury.
Change in wound color (focal areas of red, brown, or black
discoloration).
Green discoloration of the subcutaneous fat.
Discoloration and edema of wound margins.
b- Laboratory Monitoring:
All laboratory tests were assessed at one day before
operation and 3rd, 7th and 14th days after escharectomy. Some
of the tests were performed on a daily basis to ensure careful
monitoring.
i. Routine laboratory investigations:
1) Complete blood count (CBC)
Hemoglobin concentration (Hb) (male: 13.8 ~ 17.2 gm/dL,
female: 12.1 ~ 15.1 gm/dL).
Hematocrite value (Hct) (male: 40.7~50.3%, female:
36.1~44.3 %).
Total leucocytic count (TLC) (4000~10.000 cells/ mm3):
Patients and Methods 85
o Any change from the base line was considered to be
alarming of sepsis. A decrease in count was to be taken more
serious than leukocytosis in the evaluation of the severity of
sepsis
Platelet count (150,000 ~ 300,000 / mm3).
2) Coagulation profile
Prothrombin time (PT) (11 ~ 13.5 seconds) and the partial
thromboplastin time (PTT) (25 ~ 35 seconds).
o These tests were performed to monitor the possible
occurrence of disseminated intravascular coagulopathy.
3) Random blood sugar
4) Serum albumin (Alb) (3.5 ~ 5.5 gm/L).
o Persistently low levels of serum albumin in spite of adequate
replacement reflected a sepsis-mediated hypercatabolic state.
5) C-reactive protein (less than 0.6 mg/dL)
ii. Specific Laboratory investigations were done for detection
of organ dysfunction (Yang et al., 1992):
Pulmonary function tests: arterial blood gases (ABG).
o PaO2 < 50 mm Hg or SaO2 < 90%,
Renal function tests: Serum creatinine (0.6 ~ 1 mg/d) and/or
Blood urea nitrogen (BUN) (10 ~ 15 mg/100 ml).
Patients and Methods 86
Hepatic function tests: elevated SGOT (male: 8-46 u/L,
female: 4-35 u/L), SGPT (male: 7-46 u/L, female: 4-35 u/L).
Cardiac function tests: SGPT and creatine phosphokinase
(CPK) (30 ~ 200 U/L).
iii. Assay of serum levels of cytokines: This was done in Ain
Shams University Hospital Laboratories (Immunity Lab)
Interleukin-6 (IL-6) assay: was done by an
immunoenzymometric assay for the quantitative
measurement of human IL-6 in serum (EASIA)
(Biosource Europe S.A., Belgium). The detection limits
were 80 ~ 2024 pg/ml for IL-6 assay
Tumor necrosis factor- alpha (TNF-α) assay: was done
by an immunoenzymometric assay for the quantitative
measurement of human TNF-α in serum (EASIA)
(Biosource Europe S.A., Belgium). The detection limits
were 50 ~ 1800 pg/ml for TNF-α assay.
Patients and Methods 87
E - Statistical Methodology:
i. To compare the effect of technique of burn wound excision on
the clinical outcome, these tests were performed:
1. Survival rate (SR) for each group, (percentage).
2. Average hospital stay (AHS) for each group, (Mean+SD).
3. Comparison between SR of both groups, (Fisher’s exact
test).
4. Comparison between AHS of both groups, (Fisher’s exact
test).
ii. To compare the effect of technique of burn wound excision on
the immunological profile changes, these tests were performed:
According to Mann-Whitney test (independent samples),
probability indices (ρ-values) were calculated for preoperative,
3rd, 7th and 14th postoperative days‟ IL-6 assay and TNF- α
assay levels of each group.
(A ρ-value less than 0.05 was considered statistically
significant otherwise, it was insignificant).
a- For first group: The comparison between: (Mean+SD)
1) Serum IL-6 assay levels in survivors and non-survivors.
Patients and Methods 88
2) Serum TNF-α assay levels in survivors and non-survivors.
b- For second group: The comparison between: (Mean+SD)
1) Serum IL-6 assay levels in survivors and non-survivors.
2) Serum TNF-α assay levels in survivors and non-survivors.
c- For both groups: The comparison between: (Mean+SD)
1) Serum IL-6 assay levels in survivors of both groups.
2) Serum IL-6 assay levels in non-survivors of both groups.
3) Serum TNF-α assay levels in survivors of both groups.
4) Serum TNF-α assay levels in non-survivors of both groups.
Results 89
A- Demography of Patients’ Population
I- Patient Population of first group:
This group included 6 males and 9 females. Their ages ranged
between 50-20 years, (29.9 + 11 years). The total burned surface
area (BSA) ranged between 23-60% of total body surface area
(TBSA), (42 + 9%). The deep areas, (i.e. deep dermal) were
ranging between 15 and 25% of TBSA, (22 + 2%). Out of these
15 cases, 13 had flame burns (87 %) and 2 had scalds (13%).
Table (4): Patient Population of first group:
Patients Gender Age % BSA****
% Deep Burn Type of burn
1 F* 50 y
*** 50 % 25 Flame
2 M**
20 y 50 % 22 Flame
3 M 27 y 48 % 23 Flame
4 M 26 y 42 % 20 Flame
5 F 35 y 50 % 25 Flame
6 F 20 y 30 % 22 Flame
7 M 50 y 23 % 16 Scald
8 F 26 y 30 % 22 Scald
9 M 20 y 42 % 22 Flame
10 F 20 y 60 % 25 Flame
11 F 20 y 40 % 23 Flame
12 M 44 y 40 % 20 Flame
13 F 37 y 46 % 24 Flame
14 F 20 y 40 % 20 Flame
15 F 34 y 40 % 23 Flame * Female ** Male ***years **** Total Burned Surface Area
Results 90
II- Patient Population of second group:
This group included 9 males and 6 females. Their ages ranged
between 45-20 years, (28.5 + 7.3 years). The total burned surface
area (BSA) ranged between 21-70% of total body surface area
(TBSA), (44 + 16%). The deep dermal areas were ranging
between 15 and 25% of TBSA area, (21.7 + 3.5%). Out of these
15 cases, 12 had flame burns (80 %) 2 had scalds (13 %) and 1
had flash burns (7 %).
Table (5): Patient Population of second group:
Patients Gender Age % BSA****
% Deep Burn Type of burn
1 F*
30 y***
25 % 15 Scald
2 M**
30 y 35 % 22 Flame
3 M 44 y 40 % 25 Flame
4 M 20 y 35 % 24 Flame
5 F 29 y 45 % 25 Flame
6 M 30 y 65 % 22 Flame
7 M 45 y 30 % 16 Flame
8 M 27 y 64 % 23 Flame
9 F 22 y 70 % 24 Flame
10 M 26 y 55 % 25 Flame
11 M 23 y 30 % 23 Flash
12 M 21 y 70 % 24 Flame
13 F 25 y 21 % 16 Scald
14 F 25 y 30 % 19 Flame
15 F 30 y 45 % 23 Flame * Female ** Male ***years **** Total Burned Surface Area
Results 91
B- Analysis of Clinical Outcomes
I- Clinical outcomes of first group:
Hospital stay ranged between 20-39 days in survivors,
(31.8 + 7 days) and between 8-16 days in non-survivor,
(12.5 + 3 days). The average hospital stay (AHS) for all
cases was 24.1 + 11.4 days.
The mortalities were 6 of 15 (40%) (2 cases with single
organ failure and 4 cases with multiple organs failure)
(Table 6).
Timing of tangential excision was within first five post-
burn days. Extent of excised area ranged between 5% and
16% of TBSA per session, (9.8 + 2.6%). All the excised
areas were covered by allograft except in one case, where
autograft was used.
Results 92
Table (6): Clinical outcomes of first group:
Patient Time of
excision session
extent of excision
per session
Hospital
Stay
Organ
Dysfunction Outcome
1 2nd
PBD* 10% 8 days Multiple N
2 4th,7
th PBDs 10% , 12% 39 days - S
3 2nd
PBD 10% 12 days Single N
4 3rd
,6th PBDs 10%,10% 35 days - S
5 3rd,6
th,11
th PBDs 10%,10%,5% 38 days - S
6 4th,7
th PBDs 10%,12% 14 days Multiple N
7 5th PBD 16%
A 20 days - S
8 4th,6
th,11
th PBDs 10%,5%,7% 35 days - S
9 4th,7
th PBDs 10%, 12% 32 days - S
10 3rd, 7
th PBDs 10%,10%,5% 39 days - S
11 2nd
,6th PBDs 10%,13% 27 days - S
12 4th,6
th PBDs 10%,10% 22 days - S
13 3rd
PBD 10% 15 days Multiple N
14 2nd
PBD 5% 10 days Single N
15 3rd
PBD 14% 16 days Multiple N
* = Post-burn day
S = Survivor
N = Non-survivor
A = autograft
Results 93
II- Clinical outcomes of second group:
Hospital stay ranged between 17-39 days in survivors,
(26 + 8.1 days) and between 9-18 days in non-survivors,
(12.8 + 3.2 days). The average hospital stay (AHS) for all
cases was 17.2 + 8.2 days.
The mortalities were 10 of 15 (66.7 %) (3 cases with
single organ failure and 7 cases with multiple organs
failure) (Table 7).
Timing of down-to-fascia excision was within first five
post-burn days. Extent of excised area ranged between 5%
and 14% of TBSA per session, (9.3 + 2.7%). All the
excised areas were covered by allograft except in three
cases, where autograft was used.
Results 94
Table (7): Clinical outcomes of second group:
Patient Time of
excision session
extent of excision
per session
Hospital
Stay
Organ
Dysfunction Outcome
1 2nd
, 5th PBD
* 10%,5%
A 25 days - S
2 4th PBDs 8% 17 days Multiple N
3 2nd
PBD 10% 12 days Single N
4 3rd
PBDs 12% 11 days Multiple N
5 3rd
PBDs 11% 9 days Multiple N
6 4th PBDs 10% 14 days Multiple N
7 5th PBD 6% 14 days Single N
8 4th PBD 11% 14 days Single N
9 4th,6
th,11
th PBDs 7%
A, 10%,6% 18 days Multiple N
10 3rd
PBDs 12% 11 days Multiple N
11 2nd
,6th PBDs 10%,13% 27 days - S
12 4th,6
th PBDs 11%,6% 8 days Multiple N
13 3rd, 5
th PBD 10%,6% 17 days - S
14 2nd
,6th PBD 14%,5% 22 days - S
15 3rd
,5th PBD 9%
A, 14%
39 days - S
* = Post-burn day
S = Survivor
N = Non-survivor
A = autograft
Results 95
III- Analysis of the clinical outcomes in both groups:
The Average Hospital stay (AHS) of all cases of first group
was 24.1 + 11.4 days and it was 17.2 + 8.2 days for all cases of
second group.
By comparing the AHS, it was significantly higher in first
group than in second group (ρ-value = 0.0674).
The AHS for survivors in first group was 31.8 + 7 days and it
was 26 + 8.1 days in second group. Wherever, The AHS for non-
survivors in first group was 12.5 + 3 days and it was 12.8 + 3.2
days in second group.
The AHS for survivors of both groups were not significantly
different (ρ-value = 0.1845), as well as, the AHS for non-
survivors in both groups were not significantly different (ρ-value
= 0.8554). (Chart 1).
Results 96
Error bars represent SD
Survivors AHS Non-Survivors AHS
Group I 31.8 + 7 days 12.5 + 3 days
Group II 26 + 8.1 days 12.8 + 3.2 days
ρ-value 0.1845 0.8554
Chart (1): Comparison between Average Hospital stay (AHS) of
survivors and non-survivors in both groups.
The first group mortalities were 6 cases (2 cases with single
organ failure and 4 cases with multiple organs failure). The
second group mortalities were 10 cases (3 cases with single
organ failure and 7 cases with multiple organs failure).
26
31.8
12.812.5
0
5
10
15
20
25
30
35
40
Group I Group II
Days Survivors
Non-survivor
Results 97
The incidence of MOD in non-survivors in first group (66.7%)
was not statistically significant than that of second group (70%)
(ρ-value = 0.6761). (Chart 2).
By comparing the Survival Rates (SR) of both groups, the SR
of first group (60 %) was not statistically significant than the SR
of second group (33.3%) (ρ-value = 0.2714).
Survivors
(Non-Survivors)
Organ Dysfunction
Single Multiple
Group I (15 cases) 9 cases 2 cases 4 cases
Group II (15 cases) 5 cases 3 cases 7 cases
ρ-value = 0.2714 ρ-value = 0.6761
Chart (2): Comparison between clinical outcomes of both groups
32
7
4 5
9
0
3
6
9
12
15
Group I Group II
Nu
mb
er
of
cases Multiple OD (non-survivors)
Single OD (non-survivors)
Survivors
32
7
4 5
9
0
3
6
9
12
15
Group I Group II
Nu
mb
er
of
cases Multiple OD (non-survivors)
Single OD (non-survivors)
Survivors
32
7
44 5
999
0
3
6
9
12
15
Group I Group II
Nu
mb
er
of
cases Multiple OD (non-survivors)
Single OD (non-survivors)
Survivors
Multiple OD (non-survivors)
Single OD (non-survivors)
Survivors
Multiple OD (non-survivors)Multiple OD (non-survivors)
Single OD (non-survivors)Single OD (non-survivors)
SurvivorsSurvivors
Results 98
C- Analysis of Laboratory Investigations
I- Laboratory results of first group:
All laboratory tests were assessed at one day before operation
and 3rd
, 7th
and 14th
days after tangential escharectomy.
All patients had high levels of all blood elements in the
preoperative samples (with first five PBDs) (due to
haemoconcentration) that began to resolve after proper fluid
therapy. Total leucocytic count was elevated in all patients
without clinical manifestations of infection. No patient
experienced leucopenia. Thrombocytosis occurred in 4 patients
who had MOD.
Elevated liver transaminases were noticed in 5 patients (4
patients had MOD and 1 patient had single organ dysfunction).
C-reactive protein and creatine phosphokinase (CPK) values
were high in 4 patients who had MOD.
Albumin, fasting blood sugar, serum creatinine and blood
urea/nitrogen (BUN) levels were within the normal values
throughout the study.
Assessment of serum levels of cytokines interleukin-6 (IL-6)
and tumor necrosis factor-alpha (TNF-α) were done by EASIA
Results 99
(Biosource Europe S.A., Belgium). Detection limits were of
80~2024 pg/ml for IL-6 assay and 50~1800 pg/ml for TNF-α
assay.
IL-6 assay results are listed in table (8) and TNF-α assay
results are listed in table (9).
Table (8): IL-6 assay results in pg/ml of first group:
Patients Preoperative
Day 3
rd Postoperative
day 7
th Postoperative
day 14
th Postoperative
day
1** 700 650 2024 -
2* 200 500 2024 1000
3** 570 200 850 -
4* 500 2024 700 450
5* 600 1000 1500 1000
6** 500 450 1300 2024
7* 600 650 200 150
8* 400 2024 430 400
9* 600 1000 700 450
10* 800 600 510 200
11* 700 510 1000 300
12* 600 450 1000 100
13** 1000 2024 1700 2024
14** 1250 650 2024 -
15** 620 700 2024 -
* Survivor ** Non-survivor
Results 100
Table (9): TNF-α assay results in pg/ml of first group:
Patients Preoperative
Day 3
rd Postoperative
day 7
th Postoperative
day 14
th Postoperative
day
1** 490 400 1400 -
2* 300 450 700 200
3** 340 300 1600 -
4* 350 500 500 100
5* 480 550 700 200
6** 350 400 1200 1800
7* 360 500 300 150
8* 240 300 240 160
9* 480 400 320 220
10* 640 500 300 130
11* 420 400 400 100
12* 360 450 200 80
13** 700 900 1400 1200
14** 1000 1200 1800 -
15** 500 700 1800 - * Survivor ** Non-survivor
Results 101
0
400
800
1200
1600
2000
Preop. 3rd P.O. 7th P.O. 14th P.O.
IL- 6
as
sa
y (
pg
/ml)
Post-operative Days
Survivors
Non-survivors
0
400
800
1200
1600
2000
Preop. 3rd P.O. 7th P.O. 14th P.O.
IL- 6
as
sa
y (
pg
/ml)
-
Survivors
Non-survivors
0
400
800
1200
1600
2000
Preop. 3rd P.O. 7th P.O. 14th P.O.
IL- 6
as
sa
y (
pg
/ml)
Post-operative Days
Survivors
Non-survivors
0
400
800
1200
1600
2000
Preop. 3rd P.O. 7th P.O. 14th P.O.
IL- 6
as
sa
y (
pg
/ml)
-
Survivors
Non-survivors
Chart 3; illustrates serum IL-6 assay levels of survivors and
non-survivors of first group at preoperative, 3rd
, 7th
and 14th
postoperative days.
Analysis of data revealed significant higher levels of IL-6 assay
of non-survivors compared to survivors at 7th
(896 + 568 pg/ml
for survivors, 1654 + 486 pg/ml for non survivors) and 14th
(450
+ 336 pg/ml for survivors, 2024 + 0 pg/ml for non survivors)
postoperative days (ρ-value = 0.0360, 0.0004 respectively).
Error bars represent range Preop. day
(1)
3rd
PO day
(2)
7th
PO day
(3)
14th
PO day
(4)
Su
rviv
ors
Highest value 800 2024 2024 1000
Lowest value 200 450 200 100
Mean + SD 555+147 973+629 896+568 450+336
No
n-
su
rviv
ors
Highest value 1250 2024 2024 2024
Lowest value 500 200 850 2024
Mean + SD 773+291 779+637 1654+486 2024+0
(1) ρ-value = 0.2238 (2) ρ-value = 0.5287
(3) ρ-value = 0.0360 (4) ρ-value = 0.0004
Results 102
0
400
800
1200
1600
Preop. 3rd P.O. 7th P.O. 14th P.O.
Postoperative days
TN
F- a
lph
a a
ssa
y (
pg
/ml) Survivors
Non-survivors
0
400
800
1200
1600
Preop. 3rd P.O. 7th P.O. 14th P.O.
Postoperative days
TN
F- a
lph
a a
ssa
y (
pg
/ml) Survivors
Non-survivors
0
400
800
1200
1600
Preop. 3rd P.O. 7th P.O. 14th P.O.
Postoperative days
TN
F- a
lph
a a
ssa
y (
pg
/ml) Survivors
Non-survivors
0
400
800
1200
1600
Preop. 3rd P.O. 7th P.O. 14th P.O.
Postoperative days
TN
F- a
lph
a a
ssa
y (
pg
/ml) Survivors
Non-survivors
Chart (3): IL-6 assay levels of survivors and non-survivors of first
group at preoperative, 3rd
, 7th
and 14th postoperative (PO) days.
Chart 4; illustrates serum TNF-α assay levels of survivors and
non-survivors of first group at preoperative, 3rd, 7th and 14th
postoperative days. Analysis of data revealed significant higher
levels of TNF-α assay of non-survivors compared to survivors at 7th
(406 + 187 pg/ml for survivors, 1533+242pg/ml for non survivors)
and 14th (148+50pg/ml for survivors, 1500+424pg/ml for non
survivors) postoperative days (ρ-value = 0.0004, 0.0004
respectively).
Error bars represent range Preop.
day(1)
3
rd PO
day(2)
7
th PO
day(3)
14
th PO
day(4)
Su
rviv
ors
Highest value 640 550 700 220
Lowest value 240 300 200 80
Mean + SD 403+118 450+75 406+187 148+50
No
n-
su
rviv
ors
Highest value 1000 1200 1800 1800
Lowest value 340 300 1200 1200
Mean + SD 563+250 650+350 1533+242 1500+424
(1) ρ-value = 0.2238 (2) ρ-value = 0.6889
(3) ρ-value = 0.0004 (4) ρ-value = 0.0004
Results 103
Chart (4): TNF-α assay levels of survivors and non-survivors of first
group at preoperative, 3rd
, 7th
and 14th postoperative (PO) days.
II- Laboratory results of second group:
All laboratory tests were assessed at one day before operation
and 3rd
, 7th
and 14th
days after down-to-fascia burn wound
excision.
All patients had high levels of all blood elements in the
preoperative samples (with first five PBDs) (due to
haemoconcentration) that began to resolve after proper fluid
therapy. Total leucocytic count was elevated in all patients
without documented source of infection. No patient experienced
leucopenia. Thrombocytosis occurred in 7 patients who had
MOD.
Elevated liver transaminases were noticed in 8 patients (7
patients had MOD and 1 patient had single organ dysfunction).
C-reactive protein and creatine phosphokinase (CPK) values
were high in 7 patients who had MOD.
Results 104
Albumin, fasting blood sugar, creatinine phosphokinase
(CPK), serum creatinine and blood urea/nitrogen (BUN) levels
were within the normal values throughout the study.
Assessment of serum levels of cytokines interleukin-6 (IL-6)
and tumor necrosis factor-alpha (TNF-α) were done by EASIA
(Biosource Europe S.A., Belgium). Detection limits were of
80~2024 pg/ml for IL-6 assay and 50~1800 pg/ml for TNF-α
assay.
IL-6 assay results are listed in table (10) and TNF-α assay
results are listed in table (11).
Table (10): IL-6 assay results in pg/ml of second group:
Patients Preoperative
Day 3
rd Postoperative
day 7
th Postoperative
day 14
th Postoperative
day
1* 300 510 1000 510
2** 600 600 350 1450
3** 1200 2024 1900 2024
4** 1000 1100 700 2024
5** 500 510 800 510
6** 800 350 800 -
7** 500 200 250 300
8** 300 500 2024 2024
9** 700 600 900 -
10** 1250 2024 2024 -
11* 570 510 1000 800
12** 620 1300 2024 -
13* 600 2024 400 200
14* 570 700 400 100
Results 105
15* 650 350 600 200 * Survivor ** Non-survivor
Table (11): TNF-α assay results in pg/ml of second group:
Patients Preoperative
Day 3
rd Postoperative
day 7
th Postoperative
day 14
th Postoperative
day
1* 180 460 360 250
2** 360 400 900 1400
3** 840 400 1200 1400
4** 600 500 800 1200
5** 400 520 900 1400
6** 560 720 1200 -
7** 300 500 1600 1600
8** 180 500 1800 1800
9** 420 504 1600 -
10** 1000 600 900 -
11* 400 400 640 100
12** 370 500 1600 -
13* 360 600 260 200
14* 340 350 380 200
15* 520 300 370 100 * Survivor ** Non-survivor
Results 106
0
400
800
1200
1600
2000
Preop. 3rd P.O. 7th P.O. 14th P.O.
Postoperative days
IL- 6
assay (
pg
/ml)
Survivors
Non-survivors
0
400
800
1200
1600
2000
Preop. 3rd P.O. 7th P.O. 14th P.O.
IL- 6
assay (
pg
/ml)
Survivors
Non-survivors
0
400
800
1200
1600
2000
Preop. 3rd P.O. 7th P.O. 14th P.O.
Postoperative days
IL- 6
assay (
pg
/ml)
Survivors
Non-survivors
0
400
800
1200
1600
2000
Preop. 3rd P.O. 7th P.O. 14th P.O.
IL- 6
assay (
pg
/ml)
Survivors
Non-survivors
Chart 5; illustrates serum IL-6 assay levels of survivors and non-
survivors of second group at preoperative, 3rd, 7th and 14th
postoperative days. Analysis of data revealed significant higher
levels of IL-6 assay of non-survivors compared to survivors at 7th
(680+303 pg/ml for survivors, 1177+730 pg/ml for non survivors)
and 14th (362+289 pg/ml for survivors, 1643+796 pg/ml for non
survivors) postoperative days (ρ-value = 0.0710, 0.0027
respectively).
Error bars represent range Preop. day
(1)
3rd
PO day
(2)
7th
PO day
(3)
14th
PO day
(4)
Su
rviv
ors
Highest value 650 2024 1000 800
Lowest value 300 350 400 100
Mean + SD 538+137 819+685 680+303 362+289
No
n-
su
rviv
ors
Highest value 1250 2024 2024 2024
Lowest value 300 200 250 300
Mean + SD 747+313 921+667 1177+730 1643+796
(1) ρ-value = 0.2065 (2) ρ-value = 0.7679
(3) ρ-value = 0.0710 (4) ρ-value = 0.0027
Chart (5): IL-6 assay levels of survivors and non-survivors of second
group at preoperative, 3rd
, 7th
and 14th postoperative (PO) days.
Results 107
0
400
800
1200
1600
Preop. 3rd P.O. 7th P.O. 14th P.O.
Postoperative days
TN
F- a
lph
a a
ssa
y (
pg
/ml)
Survivors
Non-survivors
0
400
800
1200
1600
Preop. 3rd P.O. 7th P.O. 14th P.O.
Postoperative days
TN
F- a
lph
a a
ssa
y (
pg
/ml)
Survivors
Non-survivors
0
400
800
1200
1600
Preop. 3rd P.O. 7th P.O. 14th P.O.
Postoperative days
TN
F- a
lph
a a
ssa
y (
pg
/ml)
Survivors
Non-survivors
0
400
800
1200
1600
Preop. 3rd P.O. 7th P.O. 14th P.O.
Postoperative days
TN
F- a
lph
a a
ssa
y (
pg
/ml)
Survivors
Non-survivors
Chart 6; illustrates serum TNF-α assay levels of survivors and
non-survivors of second group at preoperative, 3rd, 7th and 14th
postoperative days. Analysis of data revealed significant higher
levels of TNF-α assay of non-survivors compared to survivors at 7th
(402 + 141 pg/ml for survivors, 1250 + 371pg/ml for non survivors)
and 14th (170 + 67 pg/ml for survivors, 1466 + 206 pg/ml for non
survivors) postoperative days (ρ-value < 0.0001, < 0.0001
respectively).
Error bars represent range Preop.
day(1)
3
rd PO
day(2)
7
th PO
day(3)
14
th PO
day(4)
Su
rviv
ors
Highest value 520 600 640 250
Lowest value 180 300 260 100
Mean + SD 360+122 422+115 402+141 170+67
No
n-
su
rviv
ors
Highest value 1000 720 1800 1800
Lowest value 180 400 800 1200
Mean + SD 503+252 514+92 1250+371 1466+206
(1) ρ-value = 0.2065 (2) ρ-value = 0.7753
(3) ρ-value < 0.0001 (4) ρ-value < 0.0001
Chart (6): TNF-α assay levels of survivors and non-survivors of
second group at preoperative, 3rd
, 7th
and 14th
postoperative (PO) days.
Results 108
0
400
800
1200
1600
2000
Preop. 3rd P.O. 7th P.O. 14th P.O.
Postoperative days
IL- 6
as
sa
y (
pg
/ml)
Group I
Group II
0
400
800
1200
1600
2000
Preop. 3rd P.O. 7th P.O. 14th P.O.
IL- 6
as
sa
y (
pg
/ml)
Group I
Group II
0
400
800
1200
1600
2000
Preop. 3rd P.O. 7th P.O. 14th P.O.
Postoperative days
IL- 6
as
sa
y (
pg
/ml)
Group I
Group II
0
400
800
1200
1600
2000
Preop. 3rd P.O. 7th P.O. 14th P.O.
IL- 6
as
sa
y (
pg
/ml)
Group I
Group II
III- Comparison between IL-6 assay levels of survivors in
both groups:
Chart 7; illustrates serum IL-6 assay levels of survivors in both
groups at preoperative, 3rd
, 7th
and 14th
postoperative days.
Analysis of data revealed no significant variations in levels of
IL-6 assay of first group survivors compared to second group
survivors (ρ-value > 0.4376).
Error bars represent range Preop. day
(1)
3rd
PO day
(2)
7th
PO day
(3)
14th
PO day
(4)
Gro
up
I
Highest value 800 2024 2024 1000
Lowest value 200 450 200 100
Mean + SD 555+147 973+629 896+568 450+336
Gro
up
II
Highest value 650 2024 1000 800
Lowest value 300 350 400 100
Mean + SD 538+137 819+685 680+303 362+289
(1) ρ-value = 0.6064 (2) ρ-value = 0.5185
(3) ρ-value = 0.4376 (4) ρ-value = 0.6064
Chart (7): IL-6 assay levels of survivors in both groups at
preoperative, 3rd
, 7th
and 14th
postoperative (PO) days.
Results 109
Group I
Group II
0
400
800
1200
1600
Preop. 3rd P.O. 7th P.O. 14th P.O.
Postoperative days
TN
F- a
lph
a a
ss
ay (
pg
/ml)
Group I
Group II
0
400
800
1200
1600
Preop. 3rd P.O. 7th P.O. 14th P.O.
Postoperative days
TN
F- a
lph
a a
ss
ay (
pg
/ml)
Group I
Group II
0
400
800
1200
1600
Preop. 3rd P.O. 7th P.O. 14th P.O.
Postoperative days
TN
F- a
lph
a a
ss
ay (
pg
/ml)
Group I
Group II
0
400
800
1200
1600
Preop. 3rd P.O. 7th P.O. 14th P.O.
Postoperative days
TN
F- a
lph
a a
ss
ay (
pg
/ml)
IV- Comparison between TNF-α assay levels of survivors in
both groups:
Chart 8; illustrates serum TNF-α assay levels of survivors in both
groups at preoperative, 3rd, 7th and 14th postoperative days.
Analysis of data revealed no significant variations in levels of
TNF-α assay of first group survivors compared to second group
survivors (ρ-value > 0.4376).
Error bars represent range Preop. day
(1)
3rd
PO day
(2)
7th
PO day
(3)
14th
PO day
(4)
Gro
up
I
Highest value 640 550 700 220
Lowest value 240 300 200 80
Mean + SD 403+118 450+75 406+187 148+50
Gro
up
II
Highest value 520 600 640 250
Lowest value 180 300 260 100
Mean + SD 360+122 422+115 402+141 170+67
(1) ρ-value = 0.6064 (2) ρ-value = 0.4376
(3) ρ-value = 0.8981 (4) ρ-value = 0.6064
Chart (8): TNF-α assay levels of survivors in both groups at
preoperative, 3rd
, 7th
and 14th
postoperative (PO) days.
Results 110
0
400
800
1200
1600
2000
Preop. 3rd P.O. 7th P.O. 14th P.O.
Postoperative days
IL- 6
assa
y (
pg
/ml)
Group I
Group II
0
400
800
1200
1600
2000
Preop. 3rd P.O. 7th P.O. 14th P.O.
IL- 6
assa
y (
pg
/ml)
Group I
Group II
0
400
800
1200
1600
2000
Preop. 3rd P.O. 7th P.O. 14th P.O.
Postoperative days
IL- 6
assa
y (
pg
/ml)
Group I
Group II
0
400
800
1200
1600
2000
Preop. 3rd P.O. 7th P.O. 14th P.O.
IL- 6
assa
y (
pg
/ml)
Group I
Group II
V- Comparison between IL-6 assay levels of non-survivors in
both groups:
Chart 9; illustrates serum IL-6 assay levels of non-survivors in
both groups at preoperative, 3rd, 7th and 14th postoperative days.
Analysis of data revealed no significant variations in levels of
IL-6 assay of first group non-survivors compared to second group
survivors (ρ-value > 0.4198).
Error bars represent range Preop. day
(1)
3rd
PO day
(2)
7th
PO day
(3)
14th
PO day
(4)
Gro
up
I
Highest value 1250 2024 2024 2024
Lowest value 500 200 850 2024
Mean + SD 773+219 779+637 1654+486 2024+0
Gro
up
II
Highest value 1250 2024 2024 2024
Lowest value 300 200 250 300
Mean + SD 747+313 921+667 1177+730 1643+796
(1) ρ-value = 0.8749 (2) ρ-value = 0.8749
(3) ρ-value = 0.4198 (4) ρ-value = 0.5676
Chart (9): IL-6 assay levels of non-survivors in both groups at
preoperative, 3rd
, 7th
and 14th
postoperative (PO) days.
Results 111
0
400
800
1200
1600
Preop. 3rd P.O. 7th P.O. 14th P.O.
Postoperative days
TN
F-a
lph
a a
ssa
y (
pg
/ml) Group I
Group II
0
400
800
1200
1600
Preop. 3rd P.O. 7th P.O. 14th P.O.
Postoperative days
TN
F-a
lph
a a
ssa
y (
pg
/ml) Group I
Group II
0
400
800
1200
1600
Preop. 3rd P.O. 7th P.O. 14th P.O.
Postoperative days
TN
F-a
lph
a a
ssa
y (
pg
/ml) Group I
Group II
0
400
800
1200
1600
Preop. 3rd P.O. 7th P.O. 14th P.O.
Postoperative days
TN
F-a
lph
a a
ssa
y (
pg
/ml) Group I
Group II
VI- Comparison between TNF-α assay levels of non-survivors
in both groups:
Chart 10; illustrates serum TNF-α assay levels of non-survivors
in both groups at preoperative, 3rd, 7th and 14th postoperative days.
Analysis of data revealed no significant variations in levels of
TNF-α assay of first group non-survivors compared to second
group survivors (ρ-value > 0.5806).
Error bars represent range Preop. day
(1)
3rd
PO day
(2)
7th
PO day
(3)
14th
PO day
(4)
Gro
up
I
Highest value 1000 1200 1800 1800
Lowest value 340 300 1200 1200
Mean + SD 563+250 650+350 1533+242 1500+424
Gro
up
II
Highest value 1000 720 1800 1800
Lowest value 180 400 800 1200
Mean + SD 503+252 514+92 1250+371 1466+206
(1) ρ-value = 0.7925 (2) ρ-value = 0.9578
(3) ρ-value = 0.5806 (4) ρ-value = 0.6132
Chart (10): TNF-α assay levels of non-survivors in both groups at
preoperative, 3rd
, 7th
and 14th
postoperative (PO) days.
Discussion 112
The Second World War was an important time
stone for management of severe burns. The idea of
down-to-fascia excision technique was elicited to
remove all devitalized tissues. In the early eighties, with
the advances in immunological studies of burn, another
technique that is tangential excision was introduced and
became the mainstay method of escharectomy.
Since this time, the technique and depth of burn
wound excision has been always controversial especially
in severe burn. However, the early escharectomy was
applied, by any of these two techniques, to restore
cellular and humoral immunity and modulates the stress
response in burned patients that leads to reduce the
incidence of SIRS and MOF.
Many previous studies compared the merits and
drawbacks of the tangential excision versus the down-to-
fascia excision in different points of view. Since, the
tangential excision technique has shown the advantages
of preserving subdermal fat over bony prominences for
Discussion 113
cosmetic reasons, as well as maintaining the integrity of
lymphatic drainage and cutaneous nerves. On the other
hand, the grafting onto subdermal fat and exaggerated
blood loss are eminent disadvantages of this technique
(Herndon et al., 1999).
On the contrary, down-to-fascia excision assures a
viable bed for skin grafting with minimal blood loss, but
it destroys the lymphatics, cutaneous nerves and
subcutaneous fat that compromise the cosmetic outcome
(Rode, 2001).
Recently, Chen and colleagues in 2000 suggested
that the accumulation and reabsorption of subeschar
tissue fluid (STF) likely contributes to the serologic
evidence of cell mediated immunological abnormalities
documented in severe thermal injury. They stated that
down-to-fascia excision may be better than tangential
excision because it removes larger amount of subeschar
tissue fluid.
Discussion 114
After revising literature, no study compared the
impact of each technique on alteration of immunological
profile of severely burned patients. Therefore, this work
aimed at comparing the effect of these two different
techniques of early burn wound excision on alteration of
immunological profile of severely burned patients.
Moreover, it could interpret the results to suggest
the impact of elimination of larger amount of subeschar
tissue fluids (STF) on altering the immunological profile
in burned patients. This would enable the burn surgeons
to decide the proper technique (i.e. proper depth) of
early burn wound excision that would decrease the
incidence of SIRS in order to decrease the morbidity,
improve clinical outcome and increase survival rate in
extensively burned patients.
For these aims, the study was designed to divide 30
acutely burned patients into two groups (each group
included 15 patients) according to technique of
escharectomy. We unified the patients‟ inclusion criteria
Discussion 115
for both groups to make the technique of excision as the
only variable that would have a possible effect on the
changes in serum levels of the most important
prognostic factors of SIRS, which are TNF-α and IL-6
cytokines.
Statistical analysis of both groups revealed no
significant difference in all parameters of the study.
Il-6 assay showed no difference between survivors
of both groups (ρ-value > 0.4376). Moreover, there was
also no significant difference in non-survivors of both
groups (ρ-value > 0.4198).
In addition, neither there was insignificant variation
in levels of TNF-α assay of survivors in both groups nor
non-survivors in both groups at all time points (ρ-value
> 0.4376, ρ-value > 0.5806 respectively).
These findings conclude the equal effect of
tangential excision and down-to-fascia excision
techniques on altering of immune response of severely
burned patients.
Discussion 116
Therefore, in deep dermal burns, there does not
appear to be any advantage to routinely performing a
down-to-fascia excision, since the immunological profile
changes are similar in both techniques of excision.
Conversely, many previous studies aimed at the
evaluation of the role of subeschar tissue fluids (STF) in
development of multiorgan failure (MOF). Ferrara in
1988 and Dyess in 1991 suggested that: STF may act as
both an immunologic barrier to microbial clearance in
otherwise viable subcutaneous tissue and a reservoir for
systemically reabsorbed immuno-suppressive factors.
Similar findings were encountered in the study of Chen
and colleagues in 2000 who suggested that STF might be
one of the inducing factors involved in the genesis of
SIRS and the development of MOF in the early postburn
stage.
However, Rong and colleagues in 2003 stated that
the cells and large molecules seems to be more difficult
to enter subeschar tissue fluid compared with small
Discussion 117
molecules and no marked local inflammatory response
occurs in subeschar tissue fluid during early stage of
severe burn, and subeschar tissue fluid has no lethal
effect.
Consequently, the results of this study disagreed
with the concept of “down-to-fascia excision may better
than tangential excision because it removes larger
amount of subeschar tissue fluid”. Additionally, it could
state that subeschar tissue fluid removal may has no role
in suppression of immune response in thermal induced
SIRS and MOF.
Moreover, there has been always a controversy in
the correlation between the IL-6 and TNF-α serum levels
and mortality rate in severely burned patients. Munster
in 1996 studied the correlation between serum levels of
IL-6 and MOD in severely burned patients. He
suggested that low serum level of IL-6 and high serum
level of TNF-α might be considered the most important
Discussion 118
poor prognostic factors related to SIRS and MOF
following thermal injury.
A similar conclusion was reached out in the study
of Deveci and colleagues in 2000 who stated that IL-6
inhibits the severity of the inflammatory response in the
early period of thermal injury by decreasing serum
levels of TNF-α.
However, Hack and co-workers in 1989, and Drost
and colleagues in 1993 found a positive correlation
between high IL-6 and TNF-α serum levels and
incidence of multiorgan failure (MOF) and consequently
mortality rates in severe thermal injuries.
Conversely, Rodriguez and colleagues in 1993
reported no association between mortality and IL-6.
By analysis of mean values of IL-6 assay and TNF-
α assay in another point of view, comparisons between
survivors and non-survivors of the same group were
established. The results showed significantly higher
levels of IL-6 assay and TNF-α assay of non-survivors
Discussion 119
compared to survivors in both group (ρ-value <0.0710
and <0.0004 respectively) especially at 7th and 14th
postoperative days.
The results confirmed the findings of previous
authors who emphasized that there were significant
higher levels of TNF-α assay of non-survivors compared
to survivors. However, it was found significant higher
levels of IL-6 assay also in non-survivors compared to
survivors, which disagreed with the suggestion of
previous authors.
An in-depth analysis of the results, the curves of
mean values of IL-6 assay and TNF-α assay in survivors
in both groups were compared. It was found that burn
wound excision normalized TNF-α serum levels, in both
groups. In contrast, the elevated serum levels of IL-6
were decreased by burn wound excision, but they did not
reach the normal levels.
These results were similar to the findings of
Schwacha and colleagues in 2000, who studied the
Discussion 120
impact of wound excision on the immunological profile.
Their study revealed that escharectomy and grafting
normalized TNF-α production, independent of which
procedure was applied. In contrast, the elevated
production of IL-6 post-burn was decreased by burn
wound excision and grafting but did not reach the
normal levels.
These results could be explained by the fact that the
half-life of some cytokines is different due to difference
in their renal clearance. Therefore, decline in levels of
cytokines in severe burn after escharectomy is not the
same.
Concerning the clinical outcomes, three parameters
were used to explore the possible impact of technique of
burn wound excision on the clinical outcome in severely
burned patients, namely, the Average Hospital Stay
(AHS), the incidence of multiorgan dysfunction (MOD)
in non-survivors of both groups and the Survival rate
(SR).
Discussion 121
The correlation between the technique of burn
wound excision and the Average Hospital stay (AHS)
revealed that the AHS of patients of group of tangential
excision was significantly higher than group of down-to-
fascia excision (ρ-value = 0.0674).
This could be explained by that in tangential
excision that the exaggerated blood loss needs more time
to resuscitate the operated patients even with careful
haemostasis before undergoing another session of
excision. Additionally, the accuracy of escharectomy is
surgeons‟ dependant factor so the bed after excision may
be unhealthy and need further debridement or the
grafting onto subdermal fat results in a lower success.
Moreover, infection rates are higher in tangential
excisions than those of down-to-fascia excisions due to
abundant vascularity of the bed in the second type of
escharectomy.
Taking the depth of excision into consideration, the
incidence of multiorgan dysfunction (MOD) in non-
Discussion 122
survivors in group of tangential excision (66.7%) was
statistically insignificant compared to that of group of
down-to-fascia excision (70%) (ρ-value = 0.6761). Thus,
it can clearly conclude that incidence MOD is not related
to depth of burn wound excision.
The Survival Rates (SR) of group of tangential
excision was not statistically significant compared to the
SR of group of down-to-fascia excision (ρ-value =
0.2714).
Many studies elaborated on the correlation between
the results of burn wound excision techniques on one
hand and the local outcomes on the other hand.
However, the issue of the value of the different
techniques of burn wound excision in improving the
general condition of severely burned patients, and hence
in the proper prediction of the average hospital stay and
survival rate has not been investigated by any burn
center. Therefore, to explain these results, further
detailed investigations are needed.
Discussion 123
On light of all these results, it was concluded that
both methods of excision, namely down-to-fascia and
tangential excision, affect immunological profile
similarly, STF is an inflammatory response to burn and
it may has no immunosuppressive effect, escharectomy
decline serum levels of both IL-6 and TNF-α and
escharectomy normalizes TNF-α serum levels and
decreases serum levels of IL-6 but not to normal levels.
Additionally, clinical outcomes of both techniques of
excision are similar, since, incidence of MOD and
survival rates. However, application of tangential
excision technique needs more hospital stay.
These conclusions recommend down-to-fascia
excision for full-thickness injury and tangential excision
through or below the dermis for deep dermal injury.
However, it is recommended that following initial
evaluation, wound excision could be carried beyond the
deepest level of injured tissue, according to surgeon‟s
preference, facilities and location of burn.
Discussion 124
Additionally, this piece of work recommend
changing protocol of Ain Shams University Burn Unit in
management of deep dermal burn to start with
escharectomy and avoid conservative management.
Finally, further study to backbone this study results
are needed.
Summary and Conclusion 125
This prospective comparative study was conducted in the Burn
Unit of Ain Shams University Hospitals, in the period from
January 2004 until March 2006.
It aimed to compare the effect of two different techniques of
early burn wound excision (tangential excision and down-to-
fascia excision) on alteration of interleukin-6 (IL-6) and tumor
necrosis factor-alpha (TNF-α) levels as indicators for the
immunological profile alterations.
The study included 30 acutely burned adult patients. All
patients were chosen irrespective to sex. The ages ranged
between 50 - 20 years, (29.2 + 9.8 years). The burned surface
area (BSA) ranged between 21 and 70%, (42.8 + 13.4 %). The
deep areas, (i.e. deep dermal) were ranging between 15 and 25%
of TBSA, (21.9 + 2.9%). Out of the 30 patients, 25 had flame
burns (83 %), 4 had scalds (13 %) and 1 had flash burns (3 %).
The 30 patients were divided prospectively into two groups
according to the technique of the excision:
First group (15 patients), included the patients who were
candidates for tangential early burn wound excision. This group
Summary and Conclusion 126
included 6 males and 9 females. The average hospital stay (AHS)
was 24.1 + 11.4 days. The survival rate was 60%; (the mortalities
were 6 of 15 [2 cases with single organ failure and 4 cases with
multiple organs failure]).
Second group (15 patients), included the patients who
were candidates for down-to fascia early burn wound excision.
This group included 9 males and 6 females. The average hospital
stay (AHS) was 17.2 + 8.2 days. The survival rate was 33.3%;
(the mortalities were 10 of 15 [3 cases with single organ failure
and 7 cases with multiple organs failure]).
For each patient in both groups the Resuscitation Protocols
were applied according to Ain Shams University – Burn Unit
protocols. Burn wound excision was started within 5th
post-burn
days and was completed within 11th
PBDs. Extent of excised area
ranged between 5% and 16% of TBSA per session. All the
excised areas were covered by allograft except in three cases,
where autograft was used.
Monitoring of the patients was done by Clinical Monitoring
(Systemic, Local) and Laboratory Monitoring; which included
routine laboratory investigations (e.g. CBC, PT, PTT, Random
Summary and Conclusion 127
blood sugar, Alb. and C-RP), Laboratory criteria of multiorgan
dysfunction (MOD) (e.g. ABG, Renal function [serum creatinine
and blood urea/nitrogen (BUN)], Hepatic function [SGOT,
SGPT] and cardiac functions as SGOT) and assay of serum
levels of cytokines IL-6 and TNF-α by EASIA.
By comparing the AHS, it was significantly higher in first
group than in second group (ρ-value = 0.0674). The incidence of
MOD in non-survivors in first group (66.7%) was not statistically
significant than that of second group (70%) (ρ-value = 0.6761).
By comparing the Survival Rates (SR) of both groups, the SR of
first group (60 %) was not statistically significant than the SR of
second group (33.3%) (ρ-value = 0.2714).
As regards, IL-6 assay for comparison between survivors and
non-survivors of the same group, the results showed significantly
higher levels of IL-6 assay of non-survivors compared to
survivors in both group at 7th
and 14th
postoperative days (for 1st
group, ρ-value = 0.0360 and 0.0004 respectively, and for 2nd
group, ρ-value = 0.0710 and 0.0027 respectively).
In addition, TNF-α assay for comparison between survivors
and non-survivors of the same group emphasized that there were
Summary and Conclusion 128
significant higher levels of TNF-α assay of non-survivors
compared to survivors in both group at 7th
and 14th
postoperative
days, (for 1st group, ρ-value = 0.0004, 0.0004 respectively, and
for 2nd
group, ρ-value < 0.0001, < 0.0001 respectively).
On the other hand, by comparing the curves of mean values of
IL-6 assay and TNF-α assay in survivors in both groups, it was
found that burn wound excision normalized TNF-α serum levels,
in both groups. In contrast, the elevated serum levels of IL-6
were decreased by burn wound excision, but they did not reach
the normal levels.
Concerning impact of depth of excision on serum levels of IL-
6 and TNF-α, analysis of data revealed insignificant variation in
levels of IL-6 assay of neither survivors in both groups nor non-
survivors in both groups at all time points (ρ-value > 0.4376, ρ-
value > 0.4198 respectively). In addition, neither there was
insignificant variation in levels of TNF-α assay of survivors in
both groups nor non-survivors in both groups at all time points
(ρ-value > 0.4376, ρ-value > 0.5806 respectively).
Summary and Conclusion 129
Consequently, these findings disagreed with the concept of
“fascial excision may better than tangential excision because it
removes large amounts of subeschar tissue fluid”.
On light of these results, it is concluded that in deep dermal
burns, there does not appear to be any advantage to routinely
performing a fascial excision, since the immunological profile
changes and clinical outcomes are similar in tangential and
fascial excision.
These finding clearly indicated that following initial
evaluation, wound excision is carried beyond the deepest
level of injured tissue, where fascial excision is used for
full-thickness injury and tangential excision is used in or
below the dermis for deep dermal injury.
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العربيالملخص أ
زخضش ف انحشق ال ؽك أ انجهذ ان
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ثبنزبن االعزئصبل . ؽبيهخ رؤد نهفبح
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انذ ي ز انذساعخ انمبسخ
ث طشمز ي طشق اعزئصبل انجهذ
العربيالملخص ج
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حز انغؾبء طشمخ االعزئصبل بع ان
ب ؾهي حش رأصش كال ي( انصفبل
انجبص انبؾ ثبعزخذاو انزغش ف
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٤٢انحشق ف رهك انحبالد رزشاح يبث
ثبنبئخ ي يغبحخ جهذ انشض ٠٠
رؾزم ؾه حشق ي انذسجخ انضبخ ثغجخ
ثبنبئخ ي يغبحخ ٤٠ ٢٠رزشاح يب ث
ي ؤالء انضالص حبنخ، جذ . جهذ انشض
العربيالملخص د
حبالد ٢حبنخ يصبثخ ثحشق نج ٤٠أ
حبنخ ( ثغبئم عبخ)يصبثخ ثحشق عهخ
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:شقانزخضش زجخ انح
٢٠اؽزهذ ؾه : انجؾخ األن
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، نمذ جذ انزخضش زجخ انحشق
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. ٢٢٤٢ + ٤٢٤٢ ألبيزى ثبنغزؾف
ثبنبئخ ٦٠أيب يؿذل انجمبء فكب
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العربيالملخص ه
٢٠اؽزهذ ؾه : انجؾخ انضبخ
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حز انغؾبء انصفبل االعزئصبل
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، أعجبة انفبح كبذ ٢٠انفبد
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(.ثؿذح أؾضبء ف ثبل انحبالد
لذ اعزخذيذ طشق اإلؿبػ نكم حبنخ ي
انجؾز طجمب نجشركل حذح انحشق
بد ثذأد ؾه. ثغزؾفبد جبيؿخ ؾ ؽظ
االعزئصبل خالل انخظ أبو األن ي انحشق
و األن ي حذ ؾؾشح اعزكهذ خالل األ
انحشق، رشاحذ يغبحخ األجضاء انغزأصهخ
بنبئخ ي يغبحخ جهذ ث ٢٦إن ٠يب ث
العربيالملخص و
انشض ف كم ؾهخ، رى اعزخذاو
أغجخ حخ يضم غؾبء األي نزغطخ
األجضاء انغزأصهخ ف كم انؿهبد ؾذا
صالس يب حش رى اعزخذاو سلؽ جهذخ ي
.انشض
رذ يزبثؿ انشعض، يزبثؿخ
ؾبيخ نحبنخ انشض يعضؿخ )إكهكخ
. بنزحبنم انطجخ يزبثؿخ ث( نهجشح
اؽزهذ األخشح ؾه انزحبنم انؿزبدح
يضم صسح دو كبيهخ عشؾخ انض )
انزجهط عكش ؾؾائ ثبنذو غجخ انضالل
انزحبنم انخبصخ ثبكزؾب فؾم ( ثبنذو
يضم غبصاد ثبنذو )ف غبئف األؾضبء
غبئف انكه غبئف انكجذ غبئف
–د كال ي إزشنك لبط يؿذال( انمهت
أنفب ثبنذو – ؾبيم ركشص انسو ٦
.كؤؽشاد نؿم انجبص انبؾ
العربيالملخص ز
ثزحهم انزبئج، جذ أ يؿذل
اإللبيخ ثبنغزؾف نهجؾخ األن أكضش
. ثمبسز ثػشح نهجؾخ انضبخ
ثمبسخ يؿذل حذس فؾم ثبألؾضبء كزنك
ذ أ ال يؿذل انجمبء ف انجؾز ج
.ثجذ اخزالفبد
أيب ثبنغجخ العزخذاو لبط يؿذالد
ثبنذو ،نهمبسخ ث ٦ –إزشنك
انحبالد انز رى ؽفبئب حبالد انفبد
ف انجؾخ اناحذح ي انجؾز، فمذ
أؽبسد انزبئج إن جد اخزال إحصبئ
ثى خبصخ ف انؿبد انخبصخ ثبنو
ثؽ ؾؾش ثؿذ انؿهخ انغبثؽ انشا
(.انمبعبد أؾه ف حبالد انفبد)
ثبإلعضبفخ نزنك، ؾذ اعزخذاو لبط يؿذالد
أنفب ثبنذو -ؾبيم ركشص انسو
،نهمبسخ ث انحبالد انز رى ؽفبئب
حبالد انفبد ف انجؾخ اناحذح ي
العربيالملخص ح
انجؾز، فمذ أؽبسد انزبئج إن جد
خبصخ ف انؿبد اخزال إحصبئ ثى
انخبصخ ثبنو انغبثؽ انشاثؽ ؾؾش ثؿذ
انمبعبد أؾه ف حبالد )انؿهخ
(.انفبد
ثمبسخ ؽكم انحبد انأخرح ي
يزعطبد انحغبثخ نزهك انمبعبد جذ أ
إصانخ انجهذ انزخضش ؤد نخفض يؿذالد
أنفب ثبنذو نغجخ يب –ؾبيم ركشص انسو
ق نك خفض يؿذالد إزشنك لجم انحش
ثبنذو نغجخ ألم أ ال رصم نغجخ يب ٦ –
.لجم انحشق
أيب ثبنغجخ العزخذاو لبط كال ي يؿذالد
– ؾبيم ركشص انسو ٦ –إزشنك
أنفب ثبنذو ،نهمبسخ ث انحبالد انز
رى ؽفبئب ف انجؾز كزنك حبالد
مذ أؽبسد انفبد ف انجؾز، ف
العربيالملخص ط
انزبئج إن ؾذو جد أ اخزال إحصبئ
.ثى ف جؽ انؿبد
ثبنزبن، رؾش رهك انزبئج نؿذو صحخ
حز أ االعزئصبل "انجذأ انزؿبس ؾه
أفضم ي االعزئصبل انغؾبء انصفبل
ألخ ضم كخ اكجش ي انؿبيالد بع ان
حشق انغججخ نفؾم األؾضبء انفبح ف ان
" انخطشح
ف " ف عضء ز انزبئج غزخهص أ
حز انحشق انؿمخ ال فبئذح ي االعزئصبل
كأجشاء سر حش أ انغؾبء انصفبل
حز انغؾبء انصفبل بع االعزئصبل ان
ؤصشا ثبنضم ؾه انجبص انبؾ
نهشض خبصخ أ يؿذالد انجمبء اإللبيخ
".سثخثبنغزؾف يزمب
نزا خهص ثأ ثؿذ انزصم نزؾخص أكذ
ؾ ؾك انحشق، رزى ؾهخ االعزئصبل نهجهذ
العربيالملخص ي
انزخضش ي انحشق نغز أؾك ي، فف
حشق انذسجخ انضبنضخ فك اعزخذاو
أيب حز انغؾبء انصفبل طشمخ االعزئصبل
ف حشق انذسجخ انضبخ فك ؾم
مخ األديخ ي خالل أ رحذ طجيبع اعزئصبل
.انجهذ انزخضش
دراسة أثر طريقتين مختلفتين لالستئصال المبكر وعامل ٦-رح الحرق على تغيير معدالت إنترليكينلج
في الحروق الشديدةبالدم ألفا -تنكرز الورم
Doctor Mohamed Ahmed El Rouby
Consultant of Plastic & Reconstructive Surgery
Ain Shams University – Cairo – Egypt
+2 0101556023
+2 0126531265
http://www.elroubyegypt.com
http://tajmeel.ohost.de
محمذ أحمذ الروبي. د
مصر -القاهرة - راحات التجميل واالصالح بجامعة عين شمسمذرس ج