md degree in plastic surgery thesis

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

[email protected]

[email protected]

[email protected]

[email protected]

محمذ أحمذ الروبي. د

مصر -القاهرة - مذرس جراحات التجميل واالصالح بجامعة عين شمس

http://www.elroubyegypt.com/

http://tajmeel.ohost.de/

mailto:[email protected]




To my Sons and family!

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


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


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


106

6 TNF-α assay levels of survivors and non-survivors of


, 7th

and 14th


107

7 IL-6 assay levels of survivors in both groups at

preoperative, 3rd

, 7th

and 14th


108

8 TNF-α assay levels of survivors in both groups at

preoperative, 3rd

, 7th

and 14th


109

9 IL-6 assay levels of non-survivors in both groups at

preoperative, 3rd

, 7th

and 14th


110

10 TNF-α assay levels of non-survivors in both groups at

preoperative, 3rd

, 7th

and 14th


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

IInnttrroodduuccttiioonn

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.

AAiimm ooff

TThhee WWoorrkk

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.

RReevviieeww ooff

LLiitteerraattuurree


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


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


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),


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).


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


C5a Complement C5 Mast cell degranulation

PMNL activation

PMNL and macrophage chemotaxis


Substance P Sensory nerve endings Vasodilatation


Histamine Mast cells, Basophils Increased microvascular permeability


Chemokinesis

5-Hydroxytryptamine

(5HT = serotonin)

Platelets , Mast cells Increased microvascular permeability


Platelet activating factor

(PAF)

PMNL, Macrophages,

Basophils



PGE2 Cyclooxygenase pathway PMNL activation

PGF2 Cyclooxygenase pathway Vasodilatation

LTB4 Lipoxygenase pathway Vasoconstriction , PMNL chemotaxis

LTD4 Lipoxygenase pathway Increased microvascular permeability


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


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,


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


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.


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.


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


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


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


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


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


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)


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


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.,


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


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


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.


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


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


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


(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


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,


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).


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


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


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)


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


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).


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


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


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,


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


(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


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


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.


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).


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.


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-


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


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-


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


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,


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).


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-


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


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).


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


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


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


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


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


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,


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.


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).


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


(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


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.,


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


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


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


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


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


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


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)


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


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


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


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).

PPaattiieennttss

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MMeetthhooddss


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


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).


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.


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.


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


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


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).


- 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


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,


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):


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).


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.


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.


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.

RReessuullttss

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


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


4 3rd

PBDs 12% 11 days Multiple N

5 3rd


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


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



Survivors

32

7

44 5

999

0

3

6

9

12

15

Group I Group II

Nu

mb

er

of



Survivors

Multiple 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:


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


IL- 6

as

sa

y (

pg

/ml)

-

Survivors

Non-survivors

0

400

800

1200

1600

2000


IL- 6

as

sa

y (

pg

/ml)

Post-operative Days

Survivors

Non-survivors

0

400

800

1200

1600

2000


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


Postoperative days

TN

F- a

lph

a a

ssa

y (

pg

/ml) Survivors

Non-survivors

0

400

800

1200

1600


Postoperative days

TN

F- a

lph

a a

ssa

y (

pg

/ml) Survivors

Non-survivors

0

400

800

1200

1600


Postoperative days

TN

F- a

lph

a a

ssa

y (

pg

/ml) Survivors

Non-survivors

0

400

800

1200

1600


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


, 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


, 7th


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:


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:


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


Postoperative days

IL- 6

assay (

pg

/ml)

Survivors

Non-survivors

0

400

800

1200

1600

2000


IL- 6

assay (

pg

/ml)

Survivors

Non-survivors

0

400

800

1200

1600

2000


Postoperative days

IL- 6

assay (

pg

/ml)

Survivors

Non-survivors

0

400

800

1200

1600

2000


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


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).


(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


, 7th


Results 107

0

400

800

1200

1600


Postoperative days

TN

F- a

lph

a a

ssa

y (

pg

/ml)

Survivors

Non-survivors

0

400

800

1200

1600


Postoperative days

TN

F- a

lph

a a

ssa

y (

pg

/ml)

Survivors

Non-survivors

0

400

800

1200

1600


Postoperative days

TN

F- a

lph

a a

ssa

y (

pg

/ml)

Survivors

Non-survivors

0

400

800

1200

1600


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


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


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


, 7th

and 14th

postoperative (PO) days.

Results 108

0

400

800

1200

1600

2000


Postoperative days

IL- 6

as

sa

y (

pg

/ml)

Group I

Group II

0

400

800

1200

1600

2000


IL- 6

as

sa

y (

pg

/ml)

Group I

Group II

0

400

800

1200

1600

2000


Postoperative days

IL- 6

as

sa

y (

pg

/ml)

Group I

Group II

0

400

800

1200

1600

2000


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).


(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


Results 109

Group I

Group II

0

400

800

1200

1600


Postoperative days

TN

F- a

lph

a a

ss

ay (

pg

/ml)

Group I

Group II

0

400

800

1200

1600


Postoperative days

TN

F- a

lph

a a

ss

ay (

pg

/ml)

Group I

Group II

0

400

800

1200

1600


Postoperative days

TN

F- a

lph

a a

ss

ay (

pg

/ml)

Group I

Group II

0

400

800

1200

1600


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.


TNF-α assay of first group survivors compared to second group



(1)

3rd

PO day

(2)

7th

PO day

(3)

14th

PO day

(4)

Gro

up

I


Lowest value 240 300 200 80

Mean + SD 403+118 450+75 406+187 148+50

Gro

up

II


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


Results 110

0

400

800

1200

1600

2000


Postoperative days

IL- 6

assa

y (

pg

/ml)

Group I

Group II

0

400

800

1200

1600

2000


IL- 6

assa

y (

pg

/ml)

Group I

Group II

0

400

800

1200

1600

2000


Postoperative days

IL- 6

assa

y (

pg

/ml)

Group I

Group II

0

400

800

1200

1600

2000


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.


IL-6 assay of first group non-survivors compared to second group



(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


Results 111

0

400

800

1200

1600


Postoperative days

TN

F-a

lph

a a

ssa

y (

pg

/ml) Group I

Group II

0

400

800

1200

1600


Postoperative days

TN

F-a

lph

a a

ssa

y (

pg

/ml) Group I

Group II

0

400

800

1200

1600


Postoperative days

TN

F-a

lph

a a

ssa

y (

pg

/ml) Group I

Group II

0

400

800

1200

1600


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.


TNF-α assay of first group non-survivors compared to second

group survivors (ρ-value > 0.5806).


(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


DDiissccuussssiioonn

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


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.

SSuummmmaarryy

aanndd

CCoonncclluussiioonn


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


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


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


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).


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.

RReeffeerreenncceess

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الملخص الملخص

العربيالعربي

العربيالملخص أ‌

زخضش ف انحشق ال ؽك أ انجهذ ان

انجبص انبؾ عضؿب انصذس انشئغ إل

نهشض ي خالل انغو انكخ ي ي

انكشثبد انز رزؿبؼ ؾهخ يب ؤد

ف انبخ نحذس فؾم ثبألؾضبء أ ح

ثبنزبن االعزئصبل . ؽبيهخ رؤد نهفبح

انجكش نزنك انجهذ انزخضش ضجط أداء

بؾ حغ ي انحبنخ انؿبيخ انجبص ان

ؾبدح يب زى . نهشض يب ؿجم ثؾفبئ

أ يبعاالعزئصبل ثطشمز أيب اعزئصبل

.حز انغؾبء انصفبل اعزئصبل

ثبنحفبظ ؾه بع زبص االعزئصبل ان

طجمخ يب رحذ األديخ انذ نزا

كزنك . فحبفع ؾه انؾكم انطجؿ نهجغى

ؾه األؾخ لؼ ي االعزئصبحبفع زا ان

ؿت زا . انهفبخ األؾصبة انحغخ

ؾذو اعزمشاس انشلؽ لانؼ ي االعزئصب

العربيالملخص ب‌

انجهذخ يؽ كضشح كخ انذو انفمد ي

.انشض أصبء انؿهخ

حز انغؾبء ثب زبص االعزئصبل

ثزاجذ طجمخ األنب انغهفخ انصفبل

هب انشلؽ نهؿضالد انز رغزمش ؾ

انجهذخ رمهم كخ انذو انفمد ي

زا نك ؿت. انشض أصبء انؿهخ

ؾذو انحفبظ ؾه طجمخ يب رحذ األديخ انؼ

انذ األؾخ انهفبخ األؾصبة

. انحغخ

لذ ألش انكضش ي لجم ؾه أ

أفضم ي حز انغؾبء انصفبل االعزئصبل

ألخ ضم كخ اكجش ي بعاالعزئصبل ان

انؿبيالد انغججخ نفؾم األؾضبء انفبح

.ف انحشق انخطشح

انذ ي ز انذساعخ انمبسخ

ث طشمز ي طشق اعزئصبل انجهذ

العربيالملخص ج‌

طشمخ االعزئصبل )انزخضش زجخ انحشق

حز انغؾبء طشمخ االعزئصبل بع ان

ب ؾهي حش رأصش كال ي( انصفبل

انجبص انبؾ ثبعزخذاو انزغش ف

ؾبيم ركشص ٦ –يؿذالد كال ي إزشنك

أنفب ثبنذو كؤؽشاد نؿم انجبص –انسو

.خطشحانبؾ ف يشعض انحشق ان

رذ ز انذساعخ ثحذح انحشق لذ

ثغزؾفبد جبيؿخ ؾ ؽظ ف انفزشح يب

اؽزهذ .٤٠٠٦ يبسط ٤٠٠٢ث بش

حبنخ ي حبالد انحشق انخطشح، ٠٠ؾه

رى اخزبس انحبالد ي كال انجغ ثأؾبس

عخ، كبذ غت ٠٠ ٤٠رزشاح يب ث

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

.احذح ثحشق نج زجخ ربس كشثبئ

نمذ رى رمغى انضالص حبنخ إن

اعزئصبل انجهذ خمطشيجؾز حغجب

:شقانزخضش زجخ انح

٢٠اؽزهذ ؾه : انجؾخ األن

يشض انز رى اعزخذاو طشمخ

عزئصبل انجهذ البع االعزئصبل ان

، نمذ جذ انزخضش زجخ انحشق

إبس، كب يؿذل ٩ركس ٦أى

. ٢٢٤٢ + ٤٢٤٢ ألبيزى ثبنغزؾف

ثبنبئخ ٦٠أيب يؿذل انجمبء فكب

، أعجبة انفبح ٦ؾذد انفبد )

كبذ فؾم ثؿض احذ ف حبنخ فؾم

(. ثؿذح أؾضبء ف ثبل انحبالد

العربيالملخص ه‌

٢٠اؽزهذ ؾه : انجؾخ انضبخ

يشض انز رى اعزخذاو طشمخ

حز انغؾبء انصفبل االعزئصبل

عزئصبل انجهذ انزخضش زجخ ال

٦ركس ٩، نمذ جذ أى انحشق

إبس، كب يؿذل ألبيزى

أيب يؿذل . ٢٤٤ + ٢٠٤٤ثبنغزؾف

ؾذد )ثبنبئخ ٠٠٤٠انجمبء فكب

، أعجبة انفبح كبذ ٢٠انفبد

فؾم ثؿض احذ ف صالس حبالد فؾم

(.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

[email protected]

[email protected]

[email protected]

[email protected]

محمذ أحمذ الروبي. د

‌مصر -القاهرة - راحات التجميل واالصالح بجامعة عين شمسمذرس ج

http://www.elroubyegypt.com/

http://tajmeel.ohost.de/





md degree in plastic surgery thesis

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