Điều Trị Bỏng Toàn Diện (Bản Expert Consult)

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Triage
Triage is the initial classification of casualties into priority
groups for treatment and is essential in the management of
large numbers of casualties. All first responders should take
into account their own safety. Remember that exposure to
radiation is reduced by distance and shielding. Therefore,
establish a perimeter beyond which those without shielding
should remain. The triage process begins after donning
personal protection equipment. Those patients unlikely
to survive should not be allowed to overwhelm available
resources, so that adequate treatment reaches those most
likely to survive. In most circumstances, ionizing radiation
is not immediately life-threatening and any associated injury
should be treated first. Exposure can be significantly reduced
by removing contaminated clothing.21 Once life-saving
measures have been carried out and the patient stabilized,
assessment of radiation exposure can proceed.
If large-scale casualties are encountered, triage may, of
necessity, seem to be draconian. In conventional warfare
with limited medical resources, 50% of soldiers with
thermal injuries of up to 70% TBSA will be expected to
survive (Table 42.3).
This survival rate should be bettered in a smaller civilian
major accident. Thus burns alone over 70% TBSA should
receive expectant treatment and those under 20% can have
their treatment delayed. If there has been a significant expo­
sure to radiation as well as a thermal injury, individuals with
over 30% TBSA burns are unlikely to survive without the use
of major resources.22
Treatment
The treatment of any burn requires massive support from a
dedicated team. This will be available for small accidents.
With larger accidents or a nuclear attack, the number of
victims could swamp the services; treatment facilities may be
destroyed; normal supply channels would be drastically
reduced, if present at all; production, distribution and trans­
portation of supplies may be greatly impaired and local care
workers may also be the victims.23
First aid
The victims must be evacuated from the source of radiation
in order to limit the exposure. Normal resuscitation proced­
ures must be followed (i.e. airway, breathing, circulation,
etc.). Contaminated clothing must be removed and the skin
wounds decontaminated by copious but gentle irrigation
with water or saline. The goal of decontamination is to dilute
telangiectatic and deeper vessels occluded. Obliterating
endarteritis results in fibrosis, atrophy and necrosis. Skin
cancers may be evident after months or years.
One of the most closely studied local effects of radiation
injury involves the treatment of breast cancer. It is well
known that radiation therapy improves postmastectomy
outcomes in women with multiple nodal involvement. This
outcome comes at a cost as evidenced by increased rates of
capsular contracture, soft tissue fibrosis, and an overall
poorer aesthetic outcome. Spear et al. reported significantly
increased rates of tissue contracture, hyperpigmentation,
and asymmetry following all types of reconstruction paired
with radiation.20 This local tissue destruction does not
abate with time and has changed the face of breast recon­
struction to avoid tissue expanders following treatment with
radiation.
The acute radiation syndrome
The physiological effects of whole-body radiation are
described as the acute radiation syndrome (ARS). The clini­
cal course usually begins within hours of exposure. Prodro­
mal symptoms include nausea, vomiting, diarrhea, fatigue,
fever and headache. There then follows a latent period, the
duration of which is related to the dose. Hematopoietic and
gastrointestinal complications follow this. The ARS can be
subdivided into three overlapping subsyndromes, which are
related to the dose exposure.
Hematopoietic syndrome
This may occur after an exposure of between 1 and 4 Gy.
The bone marrow is the most sensitive and pancytopenia
develops. Opportunistic infections result from the granulo­
cytopenia and spontaneous bleeding results from thrombo­
cytopenia. Hemorrhage and infection is the usual cause of
death.
Gastrointestinal syndrome
This requires a larger dose exposure usually in the range of
10 to 12 Gy. Severe nausea and vomiting associated with
bowel cramps and watery diarrhea occurs within hours of
irradiation. There is a shorter latent period of 5–7 days,
which reflects the turnover time of the gut epithelium (3–5
days). The epithelial damage results in loss of transport capa­
bility, bacterial translocation with sepsis, bowel ischemia
and bloody diarrhea. Large fluid imbalances can result in
hypovolemia, acute renal failure and anemia from both
bleeding and the loss of erythropoiesis. Critical exposure will
lead to rapid deterioration with unrelenting bloody diarrhea,
fever, refractive hypovolemic shock, sepsis and death.
Neurovascular syndrome
An exposure to a dose of 15–30 Gy or greater can cause an
immediate total collapse of the vascular system super­
imposed on the aforementioned syndromes. This may be
due to the massive release of mediator substances, nitric
oxide abnormalities or destruction of endothelium.13 This
syndrome can progress rapidly with variable neurological
symptoms, respiratory distress, cardiovascular collapse and
death.
Table 42.3  Survival rates with major resources available
Burn alone
<70% TBSA
50% survival
Burn alone
>70% TBSA
Probably fatal
Burn plus radiation
<30% TBSA
May survive
Burn plus radiation
>30% TBSA
Probably fatal
TBSA, total body surface area.

Radiation injuries and vesicant burns
465
Patients with thermal burns in excess of 40% TBSA or with
associated inhalation or major trauma should be treated
expectantly in the mass casualty situation. They should be
made comfortable, given adequate analgesia and/or seda­
tives if available and thought appropriate. Resuscitation
should be the same as that for an uncomplicated thermal
injury. Any resuscitation formula can be used, but it must
be closely monitored and altered as necessary to maintain
an adequate urine output. The fluid requirement will be
increased as fluid is sequestered into damaged internal
organs especially the gut. Fluid losses from diarrhea and
vomiting may also be excessive and need to be replaced.
Intravenous fluids may be limited and the victims may be
advised to take oral fluids consisting of balanced salt solu­
tions and maintain a large urine output.
Oral resuscitation
Studies in humans and animal models have shown that
intestinal absorption remains intact in burn patients. Kramer
et al. reviewed the use of oral resuscitation therapy in burn
care and found 12 reports, most of which show equal out­
comes to intravenous infusions. This solution should be
readily available, cheap, easy to transport, and palatable
(Table 42.4).27,28 Preliminary data by the authors shows a
reduction in intravenous fluid requirements when Parkland
formula-driven protocols are supplemented with oral resus­
citation (Fig. 42.1).
Care of the burn wound
The patient is bathed gently to remove loose non-viable skin,
the remnants of burnt clothing and any other external debris,
which may be contaminated with radioactive material. After
the patient has been cleaned, decontaminated and debrided,
the extent of any thermal burn and its depth can be ascer­
tained more accurately. The major problems that will be
experienced with a radiation burn and/or thermal injuries
are those associated with sepsis, fluid balance and the non-
healing wound. Mild erythema may require little treatment;
and neutralize particles without spreading them to unex­
posed areas. Thus patients should not be immersed in tubs.
Irrigation should be continued until a dosimeter such as a
Geiger–Müller counter indicates a steady state or minimum
radiation count has been reached.
Intact skin may also be irrigated with a soft brush or surgi­
cal sponge preferably under a stream of warm tap water. If
this is inadequate, a second scrubbing with mild soap or
detergent (pH 7) for 3–4 min is recommended. This is fol­
lowed by application of povidone-iodine solution or hex­
achlorophene soap, which is then rinsed again for 2–3 min
and dried. If the patient is known to have had <100 rem he/
she can be followed as an outpatient. Exposures >100 rem
require full evaluation in hospital. Patients with exposures
>200 rem or who have symptoms of ARS should preferably
be sent to specialist centers with facilities to treat bone
marrow failure.24
Assessment
The assessment of thermal injury has been covered in pre­
ceding chapters. Exposure to radiation can be estimated
clinically, by noting the onset of symptoms of ARS, sup­
ported by biological parameters. A complete blood count,
including platelets and differential count, should be per­
formed immediately and repeated at 12–24 h if indicated by
a change in the absolute lymphocyte count. If the patient
sustains a fall in lymphocyte count of 50% or a count less
than 1 × 109/liter in a time period of 48 h post exposure, a
moderate dose of radiation has been encountered.25 Levels
of serum amylase and diamine oxidase (produced by intes­
tinal villi) may be useful biological dosimeters of the future.
Amylase levels are only reliable when the salivary glands
have been exposed and diamine oxidase has not yet been
fully assessed in humans. Lymphocyte chromosomal analy­
sis allows very accurate measurement even at low levels
of exposure. However, the need for the test to be performed
in cell cultures in laboratories over 48 h incubation
would render this test impractical with large numbers of
casualties.26
General care of the irradiated patient
Where possible a history should be obtained from the
patient or others. Factors such as age, concurrent medical
problems, smoke inhalation and multiple trauma will
affect the prognosis. With this in mind a full physical
examination is carried out to exclude other injuries. Victims
of radiation exposure may not appear to differ clinically
from the thermally injured and should receive the same
care. Those exposed to lethal doses of radiation will exhibit
early signs of radiation sickness and should be triaged
accordingly.
All patients should be given adequate analgesia. Opiates
or opioids are the drugs of choice. They must be titrated to
effect and administered by the intravenous route. Early
nausea and vomiting will be distressing and must be treated
with available antiemetic drugs. Prochlorperazine has to be
given by intramuscular injection but the newer agent,
ondansetron, may prove successful as it is used against the
similar symptoms encountered in radiotherapy and chemo­
therapy. It can also be used in children.
Table 42.4  Oral resuscitation formulas
Formula
Na
Cl
K+
Buffer
Use
WHO ORS (1975)
90
80
20
30
Diarrhea
WHO ORS (2002)
75
65
20
10
Diarrhea
Fox’s sodium lactate
161
0
0
161
Burns
Moyer’s citrated NaCl
85
63
0
29
Burns
Monafo’s HLS
300
200
0
100
Burns
Liquidsorb
60
44
4
28
Burns
Jiang’s burn drink
48
28
0
20
Burns
Ricelyte
50
45
25
34
Burns
Ceralyte 90
90
80
20
30
Diarrhea/
Burns
Adapted from Kramer et al. 2010,27 with permission from ePlasty.

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466
hands. Treatment options typically include local wound
control with surgical excision as well as wound care using
Diethylene triamine pentaacetic acid (DTPA) and intra­
venous administration of DTPA. DTPA acts as a chelating
agent to bind the irradiated material and reduce biologic
exposure.34
Treatment of complications
Hematological
Blood and platelets are administered to maintain an ade­
quate hemoglobin concentration and a platelet level of
20 × 109 per liter. If surgery is contemplated, this level should
be raised to 75 × 109 per liter. All blood products should be
irradiated to avoid graft-versus-host disease.
Bone marrow transplantation is the treatment of choice
following total body irradiation. It should be performed
between 3 and 5 days post-exposure as the immunosuppres­
sion is at its peak.
An important goal of medical treatment is to stimulate the
proliferation and differentiation of residual hematopoietic
stem and progenitor cells (HSPC). Administration of anti-
apoptotic cytokine combinations such as stem cell factor,
Flt-3 ligand, thrombopoietin, and interleukin-3, may assist
recovery, if administered early.35 Moreover, hematopoietic
growth factors such as granulocyte colony-stimulating factor
(G-CSF) and granulocyte–macrophage colony-stimulating
factor (GM-CSF) have also been recommended36,37 based on
demonstration of improved survival in irradiated primates
and reduced neutropenia in humans following accidental
irradiation.
Infection
The immunosuppression associated with irradiation makes
the victim susceptible to exogenous and endogenous patho­
gens. Exogenous infection can be limited by adequate aseptic
technique and nursing the patient in a sterile environment.
Monitoring the patient adequately will allow the early diag­
nosis of sepsis and its treatment before it becomes well
established. The antibiotic chosen should reflect the current
pattern of susceptibility and nosocomial infections in that
particular unit at that time. Combination therapy will be
required where there is a profound neutropenia. With the
large fluid losses and shifts, gentamicin is not recommended
unless there is no other choice. Therapeutic levels will be
difficult to obtain without risking toxicity and there are now
safer broad-spectrum antibiotics (imipenem, ceftazidime
and ciprofloxacin). If Gram-positive infection is suspected,
vancomycin or the newer teicoplanin should be adminis­
tered. If there is an inadequate response, an antifungal agent
must be added. The use of fresh frozen plasma, gamma
globulin solutions and monoclonal antibodies is at present
speculative, but if resources allow and the patient’s condition
is not stabilizing, these agents should be considered.
Cardiovascular collapse
This complication may occur due to the exposure, sepsis,
fluid loss or hemorrhage. The patient should be given
adequate fluid resuscitation, the airway must be protected
and oxygen therapy instituted. Sedation and mechanical
however, it is important to avoid further irritation of the skin
by exposure to abrasive decontamination, irritating solu­
tions and sunlight. With a slightly higher radiation dose
causing dry desquamation, a bland lotion and loose clothing
to alleviate itching may be all that is required. Deeper burns
with moist desquamation are treated like conventional
thermal injuries. Topical chemotherapeutic agents can be
used and regularly applied as described elsewhere. Burns are
best treated closed because of the high risk of sepsis in
immunosuppressed patients whose wounds are susceptible
to dehydration, colonization and portal entry of organisms.
Early tangential excision and split skin grafting provides
early wound closure, decreased burn wound colonization
and sepsis and shortened hospital stay.29,30 This technique is
recommended by the authors and probably has advantages
where the potential to develop septic wounds is great. Infor­
mation regarding the grafting of radiation burns is not yet
available but is probably best delayed. Dubos et al.31 per­
forming early excision and grafting of burns in irradiated
monkeys have shown that healing occurred fully by the end
of the second week, although histologically there was a slight
delay in the healing process. The procedure however is not
without risks. Blood loss in excess of 300 mL/% TBSA excised
presents an increased anesthetic hazard. In irradiated tissue
that is severely injured, definitive management usually
involves resection of damaged tissue and replacement with
well-vascularized non-radiated tissue, usually from a distant
site. There is research ongoing to suggest that injections of
human mesenchymal stem cells may have a role in the treat­
ment of local radiation-induced tissue injury.32
Hyperbaric oxygen therapy (HBO) may be combined with
surgical treatment potentially to enhance wound healing in
irradiated tissue. The mechanism of action is not certain but
appears to be related to the creation of a high oxygen gradi­
ent across the irradiated tissues, which stimulates capillary
ingrowth. Hyperbaric oxygen treatments have been devised
using an empirical approach.33 A single treatment or ‘dive’
consists of 90 min in the chamber breathing an oxygen-rich
mixture at 2.4 ATA (atmosphere absolute). Soft-tissue defects
are usually treated with 30 dives. When combined with
surgery a ‘20/10 protocol’ is used in which the operative
procedure is ‘sandwiched’ between 20 preoperative and 10
postoperative dives.
Workers who deal with irradiated material, such as pluto­
nium, can become exposed through small cuts on their
Figure 42.1  The addition of oral resuscitation reduces overall intravenous
fluid requirements. (Pilot data collected by authors.)
7000
2000
3000
4000
5000
6000
1000
0
8 hours
16 hours
24 hours
IVF
Ceralyte
Parkland estimate
Urine
Volume (mL)
Time post-burn

Radiation injuries and vesicant burns
467
and with accuracy, because of the delay between exposure
and appearances of lesions, and because of hidden lesions
in underlying tissues. Medical treatment deals with inflam­
mation, moist desquamation, and chronic pain; the most
favorable time for surgical intervention is difficult to specify.
Full intensive care support is needed for whole-body irradia­
tion causing ARS, and is available only if small numbers are
involved. Oral replacement therapy may be a feasible alter­
native to IV resuscitation of burns and could potentially save
many lives in mass casualty situations. Those who survive
and show signs of regeneration of tissues will warrant late
surgical intervention. Aplastic anemia, immunosuppression,
hemorrhage, and sepsis will be major problems for survi­
vors. The improving therapy of bone marrow transplantation
is the treatment of choice. Large numbers of casualties will
necessitate expectant treatment only. In the event of a radia­
tion mass casualty, resources will be limited and treatment
may depend on oral routes of resuscitation to maintain
intravascular volume. Evacuation of survivors will take days
and a natural selection will take place.
Vesicant burns
Vesicant agents are characterized by their ability to produce
cutaneous blisters resembling ‘burns.’ They have posed a
major military threat since the use of sulfur mustard [bis
(2-chloroethyl) sulfide] in the trenches of World War I. Since
this time various nations have deployed chemical weapons
and terrorist organizations have used it in public places.38
More recently, the conflict between Iraq and Iran in the
1980s displayed the most open and widespread use of chem­
ical weapons on a battlefield in recent decades. Chemical
weapons were believed to have been deployed by Iraq in the
1990 Persian Gulf War when nerve gas and blister agent were
detected in the theater of operations.39,40 Although sulfur and
nitrogen mustard is the most important vesicant militarily,
the vesicant category includes other agents, such as lewisite
and phosgene oxime. These compounds affect not only skin
but all epithelial tissue with which they come into contact,
particularly the eyes and respiratory tract. Although most
physicians are unlikely to encounter casualties of chemical
weapons, the proliferation of these agents has increased the
risk to both military and civilian populations. They are likely
to require expertise found in burn centers and for this reason,
an account of the management of these injuries is included
in this text.41
Mechanisms of action
The mechanism of action of mustard has eluded identifica­
tion; however, most of the toxic effects are believed to be
related to alkylation of DNA and critical target molecules.
The DNA cross-links, which prevent replication and repair
of DNA, ultimately lead to cell death. The dermal epidermal
separation, which causes the skin lesions, is believed to be
due to release of proteases and other enzymes. Breakage of
anchoring filaments connecting the basal cell layer to the
basement membrane results in a blister with the basement
membrane on its dermal side. There are three main hypo­
theses to explain the biochemical processes leading to
enzyme release.
ventilation will decrease the oxygen debt that will inevitably
occur. Inotropic support may become necessary and should
be started as early as possible accompanied by the relevant
cardiovascular monitoring. Invasive cardiovascular monitor­
ing will aid in the treatment of volume replacement, but
invasive intravenous lines must be inserted in aseptic
conditions, kept meticulously clean, changed regularly and
removed when no longer indicated. Agents that manipulate
the release of nitric oxide may become available in the near
future and may turn out to be the agents of choice in the
treatment of septic shock.
Occupational exposure
In clinical practice there are concerns that relatively low
levels of radiation delivered over a long period of time might
induce cancer and/or exert genetic or teratogenetic effects.
The radiation dose can be limited by reducing the duration
of exposure or by increasing the distance from the source of
radiation. Since distance and radiation intensity obey the
inverse square law, the latter is particularly effective. While
the efficacy of shielding devices will be determined by the
type and thickness of the material and the energy and type
of radiation, Table 42.5 illustrates the effectiveness of these
devices when used at diagnostic X-ray energies. It should be
noted that the bodies of others provide very effective
shielding.
Cumulative doses of radiation can be recorded on radia­
tion badges containing photographic emulsion. The person­
nel dosimeter is relatively cheap and accurate but has
limitations. The smallest exposure that can be measured is
10 millirem; film badges can be exposed by heat, giving false
readings, and they are analyzed only at monthly intervals.
Summary
Treatment of radiation injury, whether or not it is combined
with other injuries, requires specialized knowledge and
resources. The combination of radiation injury with associ­
ated injuries appears to have a synergistic effect on outcome.
Significant increases in mortality occur because of immuno­
suppression secondary to radiation exposure in patients
already vulnerable to infections. For localized radiation
injury, it is often difficult to assess the level of severity quickly
Table 42.5  The effectiveness of shielding devices
Device
Transmission (%)
Lead apron
<10
Thyroid shield
<10
Leaded glasses
<10
Unleaded glasses
50
Human body
1
Human body wearing lead apron
0.1
Portable lead shields
<1

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468
blindness. Inhalation causes irritation and coughing, hyper­
secretion, and pulmonary edema.
Ghanei et al. reviewed 355 survivors and 108 deaths from
exposure to sulfur mustard during an attack on Sardasht,
Iran in July of 1987. Their data revealed that mortality from
exposure to this agent occurs in two waves. Initial deaths
happened in the first 2–3 days after contact and were due
mostly to respiratory involvement. The second wave of
deaths occurred 1–3 weeks after contact and were attributed
to respiratory distress syndrome or infection (pneumonia,
septic shock, or wound infections). The authors suggest that
patients should be kept in the ICU setting for the initial 4
weeks following contact and that antibiotic therapy be kept
for at least the first 2 weeks of treatment.49 Figure 42.2 dem­
onstrates numerous vesicles and a crusting rash following
exposure to a sulfur mustard agent.
Treatment for exposure to a vesicant agent
The only prophylaxis against these agents is butyl rubber
gloves, boots and a respirator. The clothing of a victim must
either be removed or decontaminated with Fuller’s earth
powder. Eyes can be irrigated with water but, if available,
1.26% sodium bicarbonate solution or 0.9% saline should
be used. Upon reaching a treatment facility, patients must
have all their clothing removed if this has not already been
done, and all the exposed areas must be cleansed with
copious water lavage. Attendants should also be suitably
protected and contaminated clothing must be placed in
special bags.
Current treatment of vesicant agents centers around symp­
tomatic relief. Itching can be treated with sedatives (benzo­
diazepines or phenothiazines), and antipruritic agents.
Dimercaprol (British antilewisite), a chelating agent, is a
specific antidote for lewisite poisoning. It is of note that it
is incompatible with silver sulfadiazine. It is available as an
ointment for skin lesions, as drops for eye applications
(5–10% in oil), and in an intramuscular preparation for
systemic toxicity. Other chelating agents are:
The first proposes that strand breaks in the DNA activate
the nuclear DNA repair enzyme poly (ADP-ribose) polymer­
ase. This initiates a cascade of reactions in which cellular
stores of nicotinamide adenine dinucleotide (NAD) are
depleted, glycolysis is inhibited, and the hexose monophos­
phate shunt is stimulated. This is thought to lead to induc­
tion and secretion of proteases.42
The second hypothesis proposes a mechanism based on
an interaction between mustard and the intracellular scaven­
ger glutathione (GSH).43 This is thought to inactivate thiol
proteins, including calcium and magnesium adenosine
triphosphatases, which regulate calcium levels. Elevation of
cytosolic calcium concentration activates production of
proteases, phospholipases and endonucleases, which break
down membranes, cytoskeleton and DNA, leading to cell
death. A separate consequence of depleted GSH could also
be lipid peroxidation with the formation of lipid peroxides
toxic to cell membranes.44
The third hypothesis involves lipid peroxidation where the
principal toxic consequence of GSH depletion is the forma­
tion of toxic lipid peroxides with resulting cell membrane
disruption.
The exact mechanism of action of the other agents
is unknown although lewisite has been shown to inhibit
several important enzyme systems, such as the pyruvate
dehydrogenase complex.
Clinical features
Early symptoms ascribed to mustard gas include an ocular
burning sensation and a feeling of suffocation associated
with a burning throat.45 After 4 h, erythema is seen; in 12–
48 h, blistering appears accompanied by severe pruritus
which has a predilection for moist areas such as the axilla
and perineum. The blisters tend to rupture, discharging an
amber serous fluid and leaving painful shallow ulcers.
Greater exposure produces coagulative necrosis of skin, with
either no blistering or ‘doughnut blisters’ surrounding a
central necrotic zone.46 This will be accompanied by severe
conjunctivitis, corneal erosion and necrotizing bronchitis. A
secondary respiratory infection may develop over the next
few days which coupled with associated marrow suppression
could prove fatal. Following absorption of large amounts of
mustard other systems may be affected. Severe stem cell sup­
pression may lead to pancytopenia, and involvement of the
gastrointestinal tract can have effects ranging from nausea
and vomiting to severe hemorrhagic diarrhea. Excitation of
the CNS, resulting in convulsions, has been reported.47
Mustard may also affect other organs, but rarely do these
produce clinical effects.
Lewisite (2-chlorovinyl-dichlorarsine) is the best known
arsine. It is more powerful than the mustards and symptoms
occur sooner. Eye irritation is produced immediately and
sneezing, salivation and lacrimation occur sooner. Non-
lethal chronic exposure may lead to arsenical poisoning.
Exposure to phosgene oxime, the commonest halogenated
oxime, has the immediate effect of stinging, and is likened
to that of contact with a stinging nettle.48 Within a minute,
the affected area becomes swollen and solid lesions resem­
bling urticaria are seen. An eschar will form after 1 week, but
healing is often delayed beyond 2 months. Contamination
of the eyes is extremely painful and may result in permanent
Figure 42.2  Photograph of child injured in the attack on Sardasht in 1987.
(Photograph taken from Ghanei et al. 2003,49 with permission from ePlasty, formerly Journal
of Burns and Wounds.)

Radiation injuries and vesicant burns
469
Acute and severe exposure can also lead to chronic skin
ulceration, scar formation and the development of skin
cancer.
Recurrent or persistent corneal ulceration can occur
after latent periods of 10–25 years. Chronic conjunctivitis
and corneal clouding may accompany this delayed
keratopathy.58
Clinical follow-ups on 200 Iranian soldiers who suffered
injuries from mustard during the Iran–Iraq War indicate that
about one third had experienced varied respiratory ailments,
such as chronic bronchitis, asthma, recurrent pneumonia,
bronchiectasis and even tracheobronchial stenosis, more
than 2 years after exposure. Some 12% of all British soldiers
exposed to mustard in World War I were awarded disability
compensation for respiratory disorders believed to have
been due to mustard exposures during combat.59
Summary
The vesicant agents are perhaps poorly named since they
have the ability to affect all epithelial surfaces, particularly
the eyes and respiratory surfaces, and not just the skin. The
most important vesicant is sulfur mustard, which acts as an
alkylating agent, causing a series of clinical reactions ranging
from vesicles to severe skin necrosis. Systemic effects are seen
with high doses, and the combination of depressed bone
marrow activity and respiratory involvement often proves
fatal. There is no effective antidote, and treatment depends
on prevention of contact and local therapy to achieve wound
healing, which tends to be slow. There is no risk to the care­
giver from the blister fluid which contains no active agent.
Treatment may require respiratory care in an ICU setting for
upwards of 4 weeks, as well as several weeks of intravenous
antibiotic therapy.
Further reading
Graham JS, Chilcott RP, Rice P, et al. Wound healing of cutaneous
sulfur mustard injuries: strategies for the development of improved
therapies. J Burns Wounds. 2005;4:e1.
Kramer GC, Michell MW, Oliveira H, et al. Oral and enteral
resuscitation of burn shock: the historical record and implications
for mass casualty care. Eplasty. 2010;10:pii, e56.
Kucan JO. Hiroshima and Nagasaki: Review of the consequences:
implications in the post 9/11 world. J Burns Surg Wound Care
[serial online]. 2004;3(1):8.
Nenot JC. Medical and surgical management for localized radiation
injuries. Int J Radiat Biol. 1990;57:784.
Young L, Orosco R, Milner S. Double fire tragedy of Kenya. Eplasty.
2009;10:e3.
•
DMSA – mesodimercaptosuccinic acid,
•
DMPS – 2,3-dimercapto-1 propanesulfonic acid
sodium, and
•
DMPA – N-(2,3-dimercaptopropyl) phthalamidic acid.
These have a higher therapeutic index, are water soluble,
and are effective orally. There is no specific antidote to
mustard poisoning and no pretreatments or treatments exist
that provide practical or effective protection against mustard
toxicity.50
There are also no standardized methods for the treatment
of mustard injury. For patients experiencing cutaneous
injuries, erythema requiring more than 5% TBSA in non-
critical areas (face, hands, perineum) require hospitaliza­
tion. The systemic fluid derangement is less than that seen
with thermal burns; however, patients should be carefully
monitored. Fluid requirements in Iranian casualties during
the Iran–Iraq war appeared to have been relatively independ­
ent of TBSA.
Blisters should be deroofed and dressed with topical anti­
microbials. The mustard blister fluid is harmless.51
Favorable outcomes have now been demonstrated in the
pig model by use of various debriding techniques and resur­
facing with split-thickness skin grafts. Such methods have
included laser, dermabrasion, sharp surgical excision, and
enzymatic debridement.52–56
Proposed strategies for the development of improved ther­
apies have been discussed in detail by Graham et al.54
Affected eyes should be irrigated, treated with antibiotics,
and inspected at the earliest time by an ophthalmologist.
Respiratory injury requires symptomatic treatment according
to its severity. Inhalation of high-dose steroids is controver­
sial at present. Severe exposure will lead to agranulocytosis
or aplastic anemia.57 The pancytopenia seen after 7 days with
the Iranian casualties did not appear to be helped by transfu­
sion of relevant blood products. Bone marrow transplanta­
tion may prove useful, although of little practical value with
large numbers of casualties. The effect of bone marrow stim­
ulants such as oxymetholone and lithium carbonate is
unknown but may be considered. Fluid replacement may be
carried out dynamically with adequate cardiovascular moni­
toring. The maximum fluid loss occurs during blister forma­
tion and not necessarily in the first 24 hours.
Long-term effects of acute exposure
Individuals who sustain mustard injury may experience dif­
ficulties even after the initial effects of the injury have sub­
sided. Destruction of melanocytes leaves hypopigmented
areas, otherwise hyperpigmentation tends to predominate.
 
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Radiation injuries and vesicant burns
469.e1
© Copyright 2012 Elsevier, Inc. All rights reserved.
References
1. Daniel J. The X-rays. Science. 1896;3:562-563.
2. Hirsch EF, Bowers GJ. Irradiated trauma victims: the impact of
ionizing radiation on surgical consideration following a surgical
mishap. World J Surg. 1992;16:918.
3. Mahesh M. NCRP Report Number 160: its significance to medical
imaging. J Am Coll Radiol. 2009;6(12):890-892.
4. Rubin P, Casarett GW. Clinical radiation pathology. Philadelphia:
WB Saunders; 1968:15.
5. Mettler FA, Kelsey CA. Fundamentals of radiation accidents.
In: Mettler FA, Kelsey CA, Ricks RC, eds. Medical management of
radiation accidents. Boca Raton: CRC; 1990:2.
6. DOE/REAC/TS Radiation Accident Registries, personal
communication and unpublished data, June 2010.
7. Eisman B, Bond V. Surgical care of nuclear casualties. Surg Gynecol
Obstet. 1978;146:877-883.
8. Kucan JO. Hiroshima and Nagasaki: Review of the consequences:
implications in the post 9/11 world. J Burns Surg Wound Care
[serial online]. 2004;3(1):8.
9. Zimmerman PD. Dirty bombs: the threat revisited. Def Hor.
2004;38:1-11.
10. Ron E. Cancer risks from medical radiation. Health Phys.
2003;85(1):47-59.
11. Goodman TR. Understanding the cancer-CT conundrum. J Clin
Gastroenterol. 2010;44(7):469-474.
12. Lewis KN. The prompt and delayed effect of nuclear war. Sci Am.
1979;241(1):35-47.
13. Kelleher D. Acute effects of ionizing radiation. In: United States
Navy. Royal Navy workshop on nuclear warfare combat casualty
care. US Navy 1983:71-80.
14. Brooks JW, Evans EI, Han WT, et al. The influence of external
body radiation on mortality from thermal burns. Ann Surg.
1953;136(3):533-534.
15. Glasstone S, Dolan PJ. The effects of nuclear weapons. United States
Department of Defense and the United States Department of
Energy; 1977:541-628.
16. Oughterson AW, Warren S. Medical effects of the atomic bomb in
Japan. New York: McGraw-Hill; 1956.
17. Need JV. Update on the genetic effects of ionizing radiation.
JAMA. 1991;32:698.
18. Fisher DE, James WD. Indoor tanning–science, behavior, and
policy. N Engl J Med. 2010;363(10):901-903.
19. Nenot JC. Medical and surgical management for localized
radiation injuries. Int J Radiat Biol. 1990;57:784.
20. Spear SL, Ducic I, Low M, et al. The effect of radiation on
pedicled TRAM flap breast reconstruction: outcomes and
implications. Plast Reconstr Surg. 2005;115(1):84-95.
21. Salame-Alfie A, et al. Handbook for responding to a radiological
dispersal device: first responder’s guide – the first 12 hours.
CRCPD 06–06; September 2006:88.
22. Becker WK, Buescher TM, Cioffi WG, et al. Combined radiation
and thermal injury after nuclear attack. In: Browne D, Weiss JF,
MacVittie, et al, eds. Treatment of radiation injuries. New York:
Plenum; 1990:10.
23. Hirsch EF, Bowers GJ. Irradiated trauma victims: the impact of
ionizing radiation on surgical considerations following a nuclear
mishap. World J Surg. 1992;16:918.
24. Radiation Injury. American Burn Association advanced burn life
support course. provider’s manual. Chicago: American College of
Surgeons; 1999:(Appendix 1)66.
25. Browne D, Weiss JF, MacVittie, et al, eds. Consensus summary:
treatment of radiation injuries. New York: Plenum; 1990.
26. Walden TL, Farzaneh MS. Biological assessment of radiation
damage. In: Walker RI, Cerveny TJ, eds. Textbook of military
medicine – medical consequences of nuclear warfare. Virginia: TMM,
Office of The Surgeon General; 1989:85-104.
27. Kramer GC, Michell MW, Oliveira H, et al. Oral and enteral
resuscitation of burn shock: the historical record and implications
for mass casualty care. Eplasty. 2010;10:pii, e56.
28. Young L, Orosco R, Milner S. Double fire tragedy of Kenya.
Eplasty. 2009;10:e3.
29. Burke JF, Bondoc CC, Quinby WC. Primary burn excision and
immediate grafting: a method shortening illness. J Trauma.
1974;14:389-395.
30. Gray D, Pine R, Harnar T, et al. Early surgical excision versus
conventional therapy in patients with 20 to 40 percent burns.
Am J Surg. 1982;189:147-151.
31. Dubos M, Neveux Y, Monpeyssin M, et al. Impact of ionizing
radiation on response to thermal and surgical trauma. In: Walker
RI, Gruber DF, MacVittie TJ, et al, eds. The pathophysiology of
combined injury and trauma. Baltimore: University Park Press;
1985:19-25.
32. Müller K, Meineke V. Advances in the management of localized
radiation injuries. Health Phys. 2010;98(6):843-850.
33. Kindwall EP. Hyperbaric oxygen’s effect on radiation necrosis.
Clin Plast Surg. 1993;20:473-483.
34. Schadilov AE, Belosokhov MV, Levina ES. A case of wound intake
of plutonium isotopes and 241Am in a human: application and
improvement of the NCRP wound model. Health Phys. 2010;
99(4):560-567.
35. Herodin F, Drouet M. Cytokine-based treatment of accidentally
irradiated victims and new approaches. Exp Hematol. 2005;33:
1071-1080.
36. Waselenko JK, MacVittie TJ, Blakely WF, et al. Medical
management of the acute radiation syndrome: recommendations
of the Strategic National Stockpile Radiation Working Group. Ann
Intern Med. 2004;140(12):1037-1051.
37. Dainiak N, Waselenlso JK, Armitage JO, et al. The hematologist
and radiation casualties. Hematol. 2003;1:473-495 Online.
Available at:
full/2003/1/473 (Accessed 15 March 2005).
38. Sidell FR, Urbanetti JS, Smith WJ, et al. Vesicants. In: Zajtchuk R,
Bellamy RF, eds. Textbook of military medicine – medical aspects of
chemical and biological warfare. Washington DC: Office of The
Surgeon General, Department of the Army; 1997:197-228.
39. New York Times News service. 20 000 troops may have faced gas.
The Sun. 23 Oct 1996:A-1.
40. Eddington PG. Gassed in the Gulf. Washington: Insignia; 1997:
72-82, xiii.
41. Graham JS, Chilcott RP, Rice P, et al. Wound healing of cutaneous
sulfur mustard injuries: strategies for the development of
improved therapies. J Burns Wounds. 2005;4:e1.
42. Papirmeister B, Feister AJ, Robinson SI, et al, eds. Molecular
mechanisms of cytotoxicity. In: Medical defense against mustard gas:
toxic mechanisms and pharmacological implications. Boca Raton:
CRC; 1990:155-197.
43. Orrenius S, McConkey DJ, Nicotera P. Biochemical mechanisms
of cytotoxicity. Trends Pharmacol Sci Fest Suppl. 1985;15:18-20.
44. Somani SM. Toxicokinetics and toxicodynamics of mustard. In:
Somani SM, ed. Chemical warfare. San Diego: Academic Press;
1992:13-45.
45. Willems JL. Clinical management of mustard gas casualties. Ann
Med Milit (Belg). 1989;3(Suppl):1-61.
46. Papirmeister B, Feister AJ, Robinson SI, et al. The sulfur mustard
injury: description of lesions and resulting incapacitation.
In: Medical defense against mustard gas: toxic mechanisms
and pharmacological implications. Boca Raton: CRC; 1990:
13-34.
47. NATO. Vesicants (blister agents), mustard and nitrogen mustards.
In: NATO handbook on the medical aspects of NBS defensive
operations. Vol 3. Washington DC: US Army, US Navy, US Air
Force; 1984:12-15.
48. McManus J, Huebner K. Vesicants. Crit Care Clin. 2005;21(4):
707-718.

Total Burn Care
42
469.e2
© Copyright 2012 Elsevier, Inc. All rights reserved.
49. Ghanei M, Aslani J, Khateri S, et al. Public health status of the
civil population of Sardasht 15 years following large-scale
wartime exposure to sulfur mustard. J Burns Surg Wound Care
[serial online]. 2003;2(1):7.
50. Papirmeister B, Feister AJ, Robinson SI, et al. Pretreatments
and therapies. In: Medical defense against mustard gas: toxic
mechanisms and pharmacological implications. Boca Raton: CRC;
1990:243-287.
51. Sultzberger MB, Katz JH. The absence of skin irritants in the
contents of vesicles. US Navy Med Bull. 1943;43:1258-1262.
52. Graham JS, Schomacker KT, Glatter RD, et al. Efficacy of laser
debridement with autologous split-thickness skin grafting in
promoting improved healing of deep cutaneous sulfur mustard
burns. Burns. 2002;28(8):719-730.
53. Rice P. The use of dermabrasion to accelerate the naturally slow
rate of epidermal healing mustard injuries in pigs. Proceedings of
the 1995 NATO Research Study Group-3 meeting on prophylaxis
and therapy against chemical agents. CTC No. AD-B209142.
Porton Down, Salisbury, UK: Chemical and Biological Defense
Establishment; 1995.
54. Graham JS, Schomacker KT, Glatter RD, et al. Bioengineering
methods employed in the study of wound healing of sulfur
mustard burns. Skin Res Technol. 2002;8(1):57-59.
55. Eldad A, Weinberg A, Breitman S, et al. Early nonsurgical removal
of chemically injured tissue enhances wound healing in partial-
thickness burns. Burns. 1988;24(2):166-172.
56. Chilcott RP, Rice P, Milner SM, et al. Wound healing of cutaneous
sulfur mustard injuries: strategies for the development of
improved therapies. J Burns Wounds [serial line]. 2005;4(1):1.
Online. Available at: url://
57. Anslow WP, Houck CR. Systemic pharmacology and pathology of
sulfur and nitrogen mustards. In: Chemical warfare agents and
related chemical problems. DTIC No AD-234-AD-249. Summary
technical report of division 9. Washington DC: National Defense
Research Committee of the Office of Scientific Research and
Development; 1946:Pts 3-4.
58. Blodi FC. Mustard gas keratopathy. Int Ophtalmol Clin. 1971;2:1.
59. Gilchrist HL. A comparative study of world war casualties from gas
and other weapons. Washington DC: Government Printing Office;
1928.

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©2012 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2786-9.00043-6
Exfoliative diseases of the integument
and soft tissue necrotizing infections
Shawn Fagan, Jiake Chai, Marcus Spies, Maureen Hollyoak, Michael J. Muller,
Cleon W. Goodwin, David N. Herndon
Introduction
Acute, severe exfoliative, and necrotizing diseases of skin and
underlying structures may cause significant morbidity in the
afflicted patient. The problems associated with these dis­
eases, such as wound infection, sepsis, inadequate nutrition,
and pain, are similar to those seen in patients with major
burns. Burn centers provide expertise in the treatment and
management of critically ill patients with skin loss from all
causes, not solely from thermal injury. This chapter describes
the pathophysiological processes of severe exfoliative skin
disorders, their diagnosis, and the specialized treatment
offered by burn units.
Severe exfoliative disorders
Erythema multiforme minor (EM), Stevens–Johnson syn­
drome (SJS), and toxic epidermal necrolysis (TEN) are severe
exfoliative diseases of skin and mucous membranes. There
is great controversy on the classification of these exfoliative
skin disorders and the terminology is confusing. Erythema
multiforme minor is characterized by skin lesions isolated
to no more than one mucosal surface. Erythema multiforme
major involves two or more mucous membranes and may
affect internal organs with systemic symptoms. However,
most authors consider erythema multiforme major, SJS, and
TEN to be the same disease entity, differing only by the area
of involved skin. In this classification, SJS is considered to
affect <10% total body surface area (TBSA), whereas TEN
covers >30% TSBA, leaving a zone of overlap between 10%
and 30% TBSA, which is referred to as SJS/TEN.1,2 The most
common characteristics of these disease entities are defined
in Table 43.1.3,4 The incidence of TEN is estimated at 0.4–1.2
cases per million persons per year. The incidence of SJS has
been reported to be 1–7 cases per million persons per year.5–9
These exfoliative disorders occur in all age groups; however,
the incidence is increased in the elderly and females.3,10–13 In
addition, TEN is seen more often in patients with HIV infec­
tion14 and in bone marrow transplant recipients.15 Mortality
of TEN ranges from 25 to 80%. However, reports are variable
and usually based only on small patient populations.16–18
Death may occur early in the course of the disease, with
sepsis being the most frequent cause. Pseudomonas aeruginosa
and Staphylococcus aureus are the predominant organisms
involved.16 Pulmonary embolism and gastrointestinal hem­
orrhage are other causes of death.10,16 The prognosis of SJS/
TEN is worse than that of a burn victim with the same extent
of skin loss.16 Mortality is increased significantly in those
patients at the extremes of age, and in relation to the percent­
age of denuded skin and serum urea nitrogen levels.16,19
Cartotto et al. created a scoring system (SCORTEN) to
predict mortality in the first 20 hours of individuals present­
ing with TEN.20 The scoring system evaluates seven para­
meters at presentation but recently has been challenged as
to its true accuracy. SJS is associated with a mortality rate of
0–38%.11,20 Erythema multiforme rarely causes death.21
Etiology
TEN and SJS both appear to be caused by immunological
reactions to foreign antigens. TEN, as the more severe entity,
has a much higher percentage associated with antecedent
drug therapy. Drugs are implicated in 77–94% of cases of
TEN.6,22 Antibacterials and antifungals (36%), anticonvul­
sants (24%), analgesics and non-steroidal anti-inflammatory
agents (38%), and even corticosteroids (14%) have been
implicated.22,23 Attempts to identify drugs suspected of
having caused exfoliative necrolysis by skin test and labora­
tory tests seldom have been rewarding.16 Upper respiratory
tract infections, pharyngitis, otitis media, or viral illness are
frequently reported.10–12,24–26 Mycoplasma pneumoniae and
herpes viruses (cytomegalovirus, Epstein–Barr virus, herpes
simplex, and varicella zoster) have been implicated in the
cause of EM and SJS, but not TEN.11,27,28 It can be difficult to
differentiate some prodromal symptoms as due to viral or
other infectious agents, or due to the primary disease process.
Recently, the incidence of HIV infection in patients with
toxic epidermal necrolysis has risen.14,29 Whether this increase
is due to their immunocompromised state or to the increased
prescription of high-risk drugs, particularly sulfonamides, is
debated. No history of drug ingestion or preceding illness
may be noted in these patients. Many of these cases may
actually suffer from lack of patient recall of current medica­
tion because of the severity of the underlying disease or the
patient’s age. Idiopathic cases, not related to drugs, accounted
for only 3–4% of TEN.6,7
CHAPTER 43 
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IN THIS CHAPTER
PowerPoint Presentation Online

Total Burn Care
43
472
Epidermal and dermoepidermal suppressor/cytotoxic
T-lymphocytes in addition to dermal infiltrates of helper
T-lymphocytes have been demonstrated.31–33 Hertl has con­
firmed that these epidermal cells are cytotoxic T-cells.34 Lang­
erhans cells appear to be reduced in the epidermis, although
numerous dermal macrophages are observed.35 A more
intense dermal cell infiltrate is present in SJS, especially in
postherpetic cases.27,31 Dendritic lymphoid cells are observed,
opposed to damaged dermal macrophages and necrotic
keratinocytes. Further, at the point where the cytoplasmic
processes contact the keratinocyte, the plasma membrane of
the keratinocyte is absent.35 Aberrant expression of HLA-
DR on keratinocytes has been observed, a phenomenon
which has been observed in many other inflammatory
skin disorders.32,36
Immunofluorescence microscopy has demonstrated IgM
and C3 along the dermoepidermal junction and dermal
vessels in cases of postherpetic SJS and EM.27,31 There have
been only two reports of basal cell immunofluorescence
in TEN.35,37 The pathogenesis of TEN is not completely
understood. Type IV delayed hypersensitivity reaction, type
II cytotoxic reaction, keratinocyte cytotoxicity mediated by
lymphocytes, drug-related non-immunological mechanisms,
and keratinocyte apoptosis mediated by receptors of the TNF
superfamily are possible mechanisms which amplify predis­
posing factors of infection and genetic susceptibility.14,38–40
Positive patch tests in patients with TEN have been used to
support the delayed hypersensitivity hypothesis.33 This view
is somewhat at odds with the fact that HIV patients display
increased frequency of TEN.14,41
Suppression/cytotoxic T-cell infiltrates are observed in the
epidermis in TEN33,35 and graft versus host disease.42 It is
hypothesized that cytotoxic T-cells recognize drug metabo­
lites which are complexed with the MHC-I molecule on
the surface of keratinocytes, migrate into the epidermis,
react with keratinocytes, and cause epidermal necrolysis.
Table 43.1  Characteristics of erythema multiforme, SJS, and TEN
Erythema multiforme
Stevens–Johnson syndrome
Toxic epidermal necrolysis
Prodrome
Absent
High fever, malaise
High fever, malaise
Acute phase
4–8 days
4–8 days
Sensation of skin burning or tenderness
Sudden onset, 1–2 days
Sensation of skin burning or tenderness
Skin lesions
Symmetrical, primarily located on
the extremities, some target
lesions without blisters
Variable distribution, individual vesicles
on an erythematous base <10%
TBSA
Nikolsky’s positive
Diffuse generalized epidermal
detachment, absence of target
lesions, large confluent plaques
>30% TBSA
Nikolsky’s positive
Mucosal
involvement
Limited to one surface, usually oral
Severe, two or more surfaces involved
Severe, two or more surfaces involved
Histopathology
Dermoepidermal separation,
mononuclear perivascular cell
infiltrate, small areas of epidermal
detachment associated with
target lesions
Dermoepidermal separation, more
intense dermal infiltrate, areas of
epidermal detachment
Epidermal necrosis, dermoepidermal
separation, minimal dermal
inflammatory infiltrate, large areas of
epidermal detachment
Recovery
1–4 weeks
1–6 weeks
1–6 weeks
Mortality
0%
0–38%
25–80%
Figure 43.1  Toxic epidermal necrolysis (TEN) is characterized by massive
sloughing of the epidermal tissue.
Morphology/histopathology
An early skin biopsy is essential for diagnosis. Skin manifes­
tations vary from patient to patient and with the age of the
lesion (Fig. 43.1). Skin lesions may evolve to different stages
of development with recurrent attacks of EM in a single
patient.30 Advancing edges of the target lesions show scat­
tered necrotic keratinocytes in the epidermis and only mild
dermal inflammation. In older lesions and central zones of
target lesions, the dusky appearance corresponds to areas
of extensive keratinocyte necrosis, often with the formation
of subepidermal bullae and dermoepidermal separation.
The surrounding erythematous zone shows papillary dermal
edema, vascular dilation with endothelial cell swelling, and
perivascular mononuclear cell infiltrate.13 Extravasated ery­
throcytes may be seen in the surrounding papillary dermis.
The reticular dermis is normal.

Exfoliative diseases of the integument and soft tissue necrotizing infections
473
membrane erosions may result in cicatricial lesions causing
phimosis in men and vaginal synechiae in women. Oropha­
ryngeal involvement is common and often results in severe
dysphagia (Fig. 43.3).48 Although mucocutaneous erosions
are the most common features of TEN/SJS, the disease
may present with multisystem involvement. The onset of
The occurrence of sicca syndromes in patients with TEN and
graft versus host disease further supports the autoimmune
theory.43 The observation of blebbing of the keratinocyte
plasma membrane in TEN is considered a reliable morpho­
logical finding of cytotoxic T-lymphocyte cytolysis.35 Further,
the observation that cyclophosphamide aids TEN patients
supports this theory, as cyclophosphamide is known to
inhibit cytotoxic T-lymphocyte activity.35 Type II cytotoxic
reactions involve the binding of either IgG or IgM antibodies
to a cell-bound antigen. The antigen–antibody complex then
activates the complement cascade and results in the cell
destruction. This mechanism is not generally supported
since nuclear fragmentation, common to keratinocytes of
toxic epidermal necrolysis patients, is not a consequence of
complement-mediated cytolysis.35,37,44 Keratinocyte apopto­
sis as the primary mechanism in the pathogenesis of TEN
has been favored recently.39 This event is thought to be medi­
ated by ligand/receptor interaction of the tumor necrosis
factor (TNF) superfamily (as TNFα/TNF receptor or FasL/Fas
interaction).39,45 In SJS, keratinocyte DNA fragmentation has
been found in about 90% of cases associated with dermal
perforin-positive lymphocytes.40 Non-immunological mech­
anisms include keratinocyte injury by either drug, drug
metabolite, or toxic products derived from a drug in the
epidermis.14,29,46
Clinical features
A prodromal phase of TEN/SJS is identified frequently and
usually consists of low-grade fever, malaise, and cough, all
of which may suggest a respiratory tract infection. These
symptoms may precede any cutaneous manifestation by
1–21 days, but usually last for 2–3 days.2,11 Additionally,
patients may present with conjunctivitis, sore throat, and
generalized, tender erythema. This may evolve from morbil­
liform eruptions or discrete erythematous or purpuric
macules.38 Later, vesicles and large bullae emerge from areas
of erythema. Patients may exhibit diffuse red erythema
immediately followed by epidermolysis.16 On light digital
pressure, the epidermis desquamates in sheets: Nikolsky’s
sign is positive (Fig. 43.2). Generally, a lag period of 1–3
weeks is observed from initiation of drug until skin eruption,
which may be shorter on reexposure of a previously sensi­
tized individual.1,2
Two or more areas of mucosa involvement are typical of
SJS or TEN. Mucosal involvement precedes skin lesions by
1–3 days in one-third of cases.13,47 Several sites are usually
affected, in the following order of frequency: oropharynx,
ocular, genitalia, and anus. Most TEN patients have multiple
mucosal lesions, and they generally persist longer than cuta­
neous lesions.16
Complications
Toxic epidermal necrolysis is frequently associated with
serious complications. The skin re-epithelializes from the
dermal elements without scarring. Some patients experience
hemodynamic instability and shock, and secondary full-
thickness necrosis of the skin may develop; however, abnor­
mal pigmentation is common. Nail plates are frequently lost
and nail regrowth may be abnormal or absent.13 Mucosal
Figure 43.2  (a–c) Nikolsky’s sign. Epidermal separation induced by gentle
pressure on the skin surface.
A
bB
cC

Total Burn Care
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474
Management
Toxic epidermal necrolysis is a life-threatening disease. Such
a patient is best managed in a burn intensive care unit where
goal-directed fluid resuscitation, nutritional support, wound
care, physical therapy, and social services are provided rou­
tinely utilizing a multidisciplinary approach.10,12,17,18,24,25,38
Surgical approach
Debridement of necrotic epidermis and coverage of the
large wound surface with biological or synthetic dressings
are essential.10,54–56 Sloughed epidermis should be removed
in order to reduce bacterial growth and the risk for
infection. The exposed and tender dermis should be
covered. Debridement is best undertaken under general
anesthesia as soon as diagnosis by histology is established.
Blood loss associated with debridement is minimal, so
over-resuscitation must be avoided. Synthetic dressings,
such as Biobrane™, and bio­logical dressings, such as hom­
ograft (cadaver allograft) and porcine xenograft skin,
greatly reduce the pain, decrease fluid loss, promote
healing, and reduce the risk of wound infection and
sepsis.10,54–57 Biobrane™ is readily available as a com­mercial
shelf product; however, in our own experience it is associ­
ated with increased local infection when covering greater
than 40% TBSA wound areas. Porcine xenograft adheres well
to the skin and is commercially available in large quanti­
ties.55,56 Homograft is more likely to become vascularized
and therefore reduces the number of graft changes.10,58
However, this must be weighed against the potential poor
cosmetic results of vascularized homograft (Fig. 43.5).
Grafted areas must be immobilized and protected from
shear forces. In children, Steinmann pins to suspend
extremities may be useful.55 In both adults and children,
continuous rotation or air fluidized (Clinitron) beds fre­
quently are used.
intestinal symptoms generally occurs concurrently with the
cutaneous lesions.49 Epidermal and epithelial sloughing
may extend into the gastrointestinal mucosa, and may
induce esophagitis with frequent subsequent stricture for­
mation.46 Gastrointestinal erosions macroscopically resem­
ble ulcerative or pseudomembranous colitis and massive
hemorrhage requiring resection has been reported.10,16,24
Intestinal involvement worsens the prognosis.16,49 Respira­
tory tract involvement occurs and is associated with increased
mortality.48,50 These complications include diffuse erythema
to extensive confluent tracheal and bronchial erosion
covered by fibrinous exudate.38,48 Epiglottal swelling, neces­
sitating intubation, has been reported.48 Desquamation of
alveolar lining cells also has been reported and these patients
require frequent tracheobronchial toilet.49 Subclinical inter­
stitial edema is often noticed and 30% of cases progress to
frank pulmonary edema and respiratory decompensa­
tion.13,51 Bronchopneumonia was found to be the most fre­
quent complication, occurring in 50% of patients.21,24,50
Pulmonary embolism is an important cause of death in
patients with TEN.16 Renal manifestations like glomerulone­
phritis and acute tubular necrosis,52 as well as hepatitis and
hepatocellular necrosis, have been described.13,38 Hypoalbu­
minemia, asymptomatic hyperamylasemia, increased eryth­
rocyte sedimentation rate, leukocytosis, thrombocytopenia,
and normochromic and normocytic anemia are not uncom­
mon.21,48 Leukopenia is a frequent and poor prognostic
sign.12,13,16,24 This is due, in part, to depletion of the T-helper/
inducer lymphocyte population (CD4+).53 Ocular sequelae
are the most severe long-term complications and occur in
half of the survivors. Pseudomembranous or membranous
conjunctivitis resulting from coalesced fibrin and necrotic
debris can lead to opacification, secondary infection, and
blindness (Fig. 43.4).4 Conjunctival scarring may result in
lacrimal duct destruction, leading to reduced tear produc­
tion and keratoconjunctivitis sicca, a Sjögren-like syndrome.
Ectropion, entropion, trichiasis, and symblepharon can
also occur.11,43
Figure 43.3  TEN patient demonstrating significant oropharyngeal
involvement.
Figure 43.4  Ocular involvement in TEN is common and can lead to
blindness. Early and aggressive ocular care must be initiated to prevent
pseudomembranes. (Arrows demonstrate membranous conjunctivitis.)

Exfoliative diseases of the integument and soft tissue necrotizing infections
475
briefly review the literature with regards to use of corticos­
teroids, cyclosporine A, intravenous immunoglobins, and
thalidomide.
Corticosteroid therapy
Corticosteroid treatment of toxic epidermal necrolysis has
produced much controversy. In regard to the delayed hyper­
sensitivity reaction or antibody-dependent cytotoxicity theo­
ries of pathogenesis, corticosteroids would seem to be an
appropriate form of medical therapy.38,59 However, the prac­
tice of administering continuous high-dose corticosteroid in
an attempt to stop the progression of the disease is widely
rejected.11–13,38,42,46,60,61 Rational assessment of the benefit of
corticosteroids administration is not possible due to the lack
of randomized, controlled, prospective trials. Many authors
feel that steroids enhance the risk of sepsis,24,55 increase
protein catabolism, delay wound healing,16 cause severe
gastrointestinal bleeding,16,24 prolong hospitalization,61
and increase mortality.12,24,62 Lyell states that the indication
for the use of steroids in the treatment of toxic epidermal
necrolysis is vague.46
One study found no decrease in the progression of SJS
with steroids, but instead found significant morbidity.62 In
a prospective, although not randomized, study, increased
survival (66%) was seen in matched patients who did not
receive steroids compared to only 33% survival in those
who did receive steroids.24 Pediatric SJS patients treated
with steroids had a longer hospital stay and a complica­
tion rate of 74% compared to 28% in those without
steroids.61 Another study demonstrated 80% mortality
associated with steroid therapy, which was reduced to 20%
when steroids were withheld.12 In several studies, patients
with antecedent glucocorticoid therapy before the onset of
TEN showed no significant survival benefit,63,64 and corti­
costeroid use itself has been linked to an increased risk for
developing TEN.23 Currently, the body of evidence suggests
that the treatment of TEN with corticosteroids has no
significant benefit and may in fact be detrimental.60,65
Therefore corticosteroids cannot be recommended in the
treatment of TEN.
Cyclosporin A
Cyclosporin A is an agent that has the properties of both
being a powerful immunosuppressant and antiapoptotic.
The mechanism of action is inhibition of the synthesis of
interleukin-2 by selective inhibition of calcineurin, thus
arresting the proliferation of T helper cells. To date, there
have been nine individual cases and one case series of the
use of cyclosporin A in the treatment of TEN.66 In the only
case series, Arevalo et al. observed a significantly shorter time
to disease arrest (24–36 h) and time to re-epithelialization
when compared to historical controls.66 Although intriguing,
the currently published studies do not have similar metho­
dologies, varying with regards to the dosage administered,
route of administration, and duration of therapy. Further­
more, cyclosporin A therapy has been associated with a
septicemia rate of 55%.65 Therefore; a well-performed pro­
spective clinical trial is warranted prior to advocating the
use of cyclosporin A in the treatment of TEN.
Topical therapy
As separation occurs at the dermal–epidermal junction,
varying depths of viable dermis remain. If this dermis can
be protected from toxic detergents, desiccation, mechanical
trauma, and wound infection, then rapid re-epithelialization
by proliferation of basal keratinocytes from the skin append­
ages will occur.54 However, bacterial proliferation on the
unprotected wound surface with invasive infection leads to
full-thickness skin necrosis. Hydrotherapy and topical anti­
microbials provide debridement and infection control which
should be initiated early in the course of the disease.11,26
Effective topical antimicrobial agents include silver sulf­a­
diazine cream,30 silver nitrate solution,13,24,26 chlorhexidine
gluconate solution,13 and polymyxin-bacitracin ointment.11
Silver sulfadiazine is widely used but may exacerbate the
disease process due to its sulfonamide component. Addi­
tionally, an inhibitory effect on epithelialization and leuko­
penia requiring discontinuation has been observed. Silver
nitrate solution does not contribute to the ongoing drug
reaction, and epithelialization is not inhibited. However,
silver nitrate solutions are hyponatremic, and thus associ­
ated with approximately 350 mmol of sodium loss per day/
m2 treated. Therefore, serum electrolytes and osmolarity
must be carefully monitored. For patients with contami­
nated wounds due to delayed initiation of treatment, silver
nitrate soaks can reduce contamination and prepare the
wound for eventual biological dressing. Chlorhexidine
gluconate and polymyxin ointment are effective against
Gram-negative organisms, including P. aeruginosa, with low
incidence of sensitivity. Moreover, chlorhexidine gluconate
also shows bactericidal effects against Gram-positive
organisms.
Immunomodulation therapy
As mentioned previously, the pathophysiology of TEN
appears to be initially immunologic. Therefore, it is logical
to consider immunosuppressive therapy as an early
treatment modality for TEN. The following sections will
Figure 43.5  Homograft vascularization occurring over a second-degree
thermal injury, resulting in a poor cosmetic result.

Total Burn Care
43
476
placebo-controlled clinical trials. Despite the failure of tha­
lidomide, investigators are still exploring the use of tumor
necrosis factor A antagonists and inhibitors (infliximab
etanercept, etc.), in the treatment of TEN. Unfortunately,
these new therapies have only been reported in case reports
and thus cannot be supported for routine use in this
patient population.
Until these treatment modalities have proven their efficacy
in controlled trials, the Gold Standard of treatment for TEN
patients consists of a multidisciplinary approach, such as
used in severe burns, focusing on wound care, infection
control, and prevention of complications. The specific
requirements of these patients are best met in a burn inten­
sive care unit, so early referral to a burn center is strongly
recommended. Guidelines for the transfer decision may rely
on the referral criteria for severe burn injury established by
the American Burn Association (see also Fig. 43.6). The
multidisciplinary burn team for specialized treatment of
patients with extensive skin loss with trained critical care
physicians, surgeons, critical care nursing specialists, respira­
tory therapists, and physical and occupational therapists is
able to provide the best acute care as well as early and
adequate rehabilitation.
General management
Drugs suspected of having initiated the disease should be
discontinued immediately. Administration of pain medica­
tion is of high priority and antipyretic agents may be required.
The empirical use of broad-spectrum antibiotics may be nec­
essary if neutropenia exists, as these patients are prone to
septic complications. The white blood cell count generally
returns to normal levels after 2–5 days. The cause of this
immunosuppression is unclear; it may be part of the primary
disease or a secondary event.59 Neutropenia is the only com­
plication in which ‘prophylactic’ antibiotics are indicated.
Otherwise, systemic antibiotics only should be used for
documented infections or suspected sepsis. Oral nystatin
Intravenous immunoglobulin
It has been suggested that the Fas-Fas ligand interaction may
be responsible for the apoptosis seen in TEN.67 Through a
series of experiments, Viard et al. observed, in vitro, that TEN
patients expressed lytically active Fas ligand and that the
action of this ligand could be blocked by both a monoclonal
antibody and human immunoglobins.68 These observations
suggest that human immunoglobins may contain a Fas
blocking antibody and therefore may be useful in the treat­
ment of TEN. Unfortunately, clinical data are less impressive,
with some case series suggesting a benefit while others dem­
onstrate less encouraging results.69–71 This trend appears to
be continuing with a new report from Yang et al. demon­
strating no survival benefit but perhaps some beneficial
affects on morbidity.72 As in the case with cyclosporin A, a
controlled multicenter clinical trial is required prior to advo­
cating the use of human immunoglobins routinely in the
treatment of TEN.
Thalidomide
The primary mechanism in the pathogenesis of TEN is
keratinocyte apoptosis. Accordingly, tumor necrosis factor
A has been implicated in the pathogenesis of TEN. Thalido­
mide, a potent inhibitor of tumor necrosis factor A, would
appear to be a logical therapeutic agent in the treatment of
TEN. Unfortunately, Wolkenstein et al.73 had to prema­
turely terminate a randomized clinical trial of thalidomide
versus placebo in the treatment of TEN due to excess mor­
tality in the treatment group. Ten of 12 patients expired in
the thalidomide group compared to three of 10 in the
control group. The authors theorized that thalidomide may
have paradoxically increased the production of tumor
necrosis factor in the treatment group, a previously reported
phenomenon of thalidomide administration. Therefore,
thalidomide as a treatment for TEN should not be initi­
ated, owing to the detrimental effects, but does demon­
strate the usefulness of randomized, double-blinded,
Figure 43.6  Algorithm for management of
SJS/TEN.
Clinical and histologic
diagnosis of SJS/TEN
Early transfer to burn center
Cease suspected drug
No corticosteroids
Fluid replacement
In burn center
Debridement
Biologic or synthetic dressings
Antibiotics
Enteral nutrition
Respiratory care
Ophthalmologic care
Rehabilitation
Children or age >60
>20% TBSA involved
Progression
Preexisting medical disorder
(Diabetes mellitus, vascular
disease, liver failure, renal
failure, pulmonary
failure, organ
transplantation, HIV)
Yes
No
No
No
Yes
Yes
Yes
Yes

Exfoliative diseases of the integument and soft tissue necrotizing infections
477
post-traumatic stress disorder are all well described. With the
trend towards goal directed therapy, early and repeated
evaluations and prompt intervention should help, if not
prevent, long-term psychiatric complications. This manage­
ment should continue well into the outpatient phase.
Nutritional support
Enteral nutrition should be started on admission. Due to the
frequent presence of oral mucosal ulcerations, patients may
be reluctant to take nutrition orally, and thus require a
nasogastric tube placement. Unlike burned patients who
have significantly elevated metabolic rate, these patients
appear to have metabolic rates only slightly above basal
requirements.54,59 Weight stabilization and a positive nitro­
gen balance have been achieved in adults with 2500 kcal/
day.54 If gastrointestinal function becomes impaired or
sepsis intervenes, requirements may increase. Total parenteral
nutrition should be avoided, but initiated if enteral intoler­
ance persists.
Soft-tissue infections and degenerative
skin disorders
Staphylococcal scalded skin syndrome, necrotizing fasciitis,
and purpura fulminans are examples of a group of condi­
tions characterized by extensive soft-tissue loss, rapid onset
of critical illness, and death. Early, accurate diagnosis is
essential to initiate appropriate action, such as extensive
surgical excision in the case of necrotizing fasciitis or
crepitant soft-tissue infections. Burn care centers with their
acute and reconstructive capacities have much to offer
these patients with extensive skin loss.
Staphylococcal scalded skin syndrome
Staphylococcal scalded skin syndrome is the severe condi­
tion caused by exfoliative staphylococcal toxins and is char­
acterized by systemic signs and symptoms and generalized
involvement of the skin (Fig. 43.7). It is important to make
prevents intestinal overgrowth of Candida and decreases the
risk of Candida sepsis.24,59 Frequent monitoring of urinary
tract, respiratory tract, skin, and catheters allows early detec­
tion of systemic infection and identification of organisms.
Intravenous replacement of fluid losses through the
exposed body surface is required. However, as patients do
not develop the massive edema and fluid losses evident
in burn patients, fluid resuscitation formulas commonly
employed in the management of thermal injuries overesti­
mate the actual need.13,38,54–56 Ringer’s lactate solution is
given at a rate determined by close monitoring of the patient’s
condition and urine output. Once wound coverage is accom­
plished, fluid requirements usually decrease. Central line
placement should be avoided, if possible, to reduce the risk
of infection and sepsis. To further minimize this risk, lines
should be placed in areas of uninvolved skin. Invasive
devices are removed as soon as possible, and oral and
nasogastric routes are utilized at earliest convenience. Envi­
ronmental temperature should be raised to 30–32°C to
reduce metabolic energy expenditure. Heat shield and infra­
red lamps are beneficial in patients’ rooms, bathrooms, and
operating rooms.
Stress ulceration prophylaxis is advisable. Mouth erosion,
resulting in severe dysphagia, can be alleviated by the use of
viscous lidocaine or cocaine rinses, and thus ease oral
administration of nutrients and fluids. Oral debris should
be removed and the mouth sprayed with antiseptic several
times a day.60 Pulmonary involvement requires close super­
vision, with careful toileting including bronchoscopy,
incentive spirometry, mobilization, and coughing to prevent
infections and complications. If mechanical ventilatory
support is necessary, the prevention of bronchopulmonary
infection gains even more importance. Daily monitoring by
blood assessment, including blood gas analysis, chest X-ray,
and bacteriological culture, are required to initiate timely
antibiotic therapy or ventilatory support. Measures to prevent
thromboembolism, such as low-dose or low-molecular-
weight administration of heparin, should be instituted on
admission.
Ocular involvement should be assessed daily by an oph­
thalmologist. Conjunctival crusting can be minimized by the
application of saline eye drops every hour. Any adhesions
should be broken using a blunt instrument, and bland eye
drops or ointment applied frequently.11,54 Documented
ocular infections are treated with organism-specific anti­
biotic therapy. New reports have been published regarding
the use of cryopreserved amniotic membrane as a biologic
dressing. The placement appears to suppress inflammation
and prevent the cicatricial complications.74 Regardless of the
therapy employed, special long-term ophthalmological
follow-up is needed to prevent and address ocular long-term
sequelae. Lacrimal duct obstruction may be detected early by
performing Schirmer’s test.11,60
During hospitalization, patients with TEN and SJS may
demonstrate limitations in mobility, decreased strength,
postural and gait deviation, contractures, and impaired
coordination. Therefore, patients should be treated and
closely followed throughout the course of the disease by a
physiotherapist.65
Along with intensive physical and occupational therapy,
this patient population requires psychiatric evaluation.
Similar to the burn population, depression, anxiety and
Figure 43.7  Staphylococcal scalded skin syndrome is characterized by
diffuse, erythematous lesions with bullae formation (see left forearm).
Epidermis is shed in sheets with minimal abrasion. The wounds are
partial-thickness and heal without surgical intervention.

Total Burn Care
43
478
Until skin barrier function is restored, patients should
receive appropriate wound dressings to prevent secondary
wound infection. Topical agents are soothing and bacterio­
static. It needs to be pointed out that the wound initially is
not colonized or infected, so alternatively, large areas can be
more effectively managed with biological or synthetic dress­
ings. They have the advantage of eliminating the need for
frequent dressing changes which can be particularly trau­
matic for young children. Mortality usually is low, but may
occur in very young and adult patients, usually from sepsis
or electrolyte imbalance on the basis of underlying disease.77
Complete wound healing is usually observed within 7 days,
and scarring and altered pigmentation are not common.
Necrotizing fasciitis and bacterial myonecrosis
Necrotizing fasciitis is a soft-tissue infection which is char­
acterized by widespread necrosis of fascia and subcutaneous
tissue which may progress to muscle and skin necrosis.
Overall mortality may still be as high as 50%.76,81 Most cases
of necrotizing fasciitis are due to polymicrobial infection
including both anaerobic Gram-positive cocci and Gram-
negative bacilli.81 Streptococcus, Staphylococcus, Enterococcus,
and Bacteroides are commonly found. Infection with many
bacterial species may result in bacterial myonecrosis.
However, gas gangrene by Clostridia spp. results in severe
systemic toxicity and higher mortality than necrotizing fas­
ciitis. A deep contaminated wound frequently precedes the
severe soft-tissue infection. Streptococcal myositis has a
mortality rate of between 80% and 100%.82 Risk factors for
both necrotizing fasciitis and bacterial myonecrosis have
been identified as diabetes mellitus, intravenous drug use,
age greater than 50 years, hypertension, and malnutrition/
obesity. The presence of three or more of these risk factors
was found to give a predictive mortality rate of 50%
(Fig. 43.8)83.
Diagnosis
Early diagnosis is of extreme importance and consequence.
Initial presentation is deceptive as the findings may be local­
ized pain and edema without discoloration of the skin. Later,
induration and erythema may be evident. Paresthesia of
overlying skin and eventual dusky discoloration and local
blistering may occur in the later course. Severe toxemia may
develop, usually out of proportion to the local signs. Severe
systemic alterations are characteristic of myonecrosis. Gas
inclusion may be evident in subcutaneous tissues on X-ray.
CT and MRI may help in the diagnosis and provide informa­
tion on the nature and extent of the infection.84 Frozen
section biopsies may provide early histological evidence of
infection.85 Gram stains and microbiological testing are very
important diagnostic tools and guide antibiotic treatment.
However, a definite distinction between necrotizing fasciitis,
myonecrosis, and other soft-tissue infections often can only
be established during surgery.
Management
The key to successful management of necrotizing infections
is early diagnosis and radical surgical intervention. Surgical
exploration involves complete excision of all necrotic tissues.
a diagnosis early, particularly to differentiate it from TEN,
which has a different management and much greater mortal­
ity. Staphylococcal scalded skin syndrome is predominantly
a disease of infancy (Ritter’s disease) and early childhood,
with most cases occurring before the age of 5 years.75
Newborn nurseries are often the sites of outbreaks. Attend­
ant staff may be infected or colonized with Staphylococcus
aureus strains producing epidermolytic toxin, thus emphasiz­
ing the importance of standard hygienic measures. Adult
staphylococcal scalded skin syndrome is rare and usually
associated with compromised renal function. Mortality is
generally only 4%, but can be much higher in adults (40%),
depending on underlying diseases.75,76
Two distinct epidermolytic toxins (ETA and ETB), are
responsible for the blistering in staphylococcal scalded skin
syndrome.46 ETA is heat-stable, whereas ETB is heat-labile
and encoded by a bacterial plasmid. Most toxigenic strains
of S. aureus are identified as group 2 phage.77 The exfoliative
toxin is metabolized and excreted by the kidneys, leading to
a predisposition of patients with renal immaturity (children)
or renal compromise. The exfoliative toxins produce blister­
ing by disrupting the epidermal granular cell layers through
interdesmosomal splittings but without epidermal necrosis
and with very few inflammatory cells. The exact mechanism
of action of the toxins has not been determined, although it
is felt that the toxins directly affect desmosomes. One might
be proteolytic disruption of desmosomes with the toxin or
part of its sequence acting as a serine protease.75,78,79
Diagnosis of staphylococcal scalded skin syndrome can be
made rapidly with a skin biopsy. The characteristic intraepi­
dermal level of splitting is seen, with the split occurring at
the granular layer level (stratum granulosum) with no epi­
dermal necrosis or inflammatory cells in the corium.77
Immunofluorescent studies of the skin are negative.77 A
Tzanck preparation from a scraping of the base of a freshly
denuded area will reveal the affected cell population, i.e.
acanthocytic keratinocytes.77 Bullae, denuded skin and blood
are usually sterile, however, and staphylococci can usually be
cultured from nares, conjunctiva, or pharynx.80
Management
Onset may be marked by fever, malaise, and irritability.
Scarlatiniform erythema is often accentuated in flexural and
periorificial areas.75 The skin is generally tender to touch,
and sheets of skin may peel away in response to minor
trauma (Nikolsky’s sign). Blisters appear within 24–48 h of
rupture, leaving a characteristic moist erythematous epider­
mal base. Severe mucosal involvement is not a typical
feature. With diagnosis antibiotics should be started, and
semisynthetic penicillinase-resistant penicillin analogs are
indicated (e.g. methicillin or oxacillin), since the majority
of group 2 staphylococci show resistance to penicillin.
Administration of steroids to these patients is contraindi­
cated.77 After screening for colonization, decontamination
of colonized areas, especially the nasopharyngeal region in
patients and nursing staff, may be advisable to prevent
further spread. Fluid resuscitation is usually required at a
lesser volume compared to a burn patient with a similar
involved body surface area. Fluid substitution should be
guided by urine output, hemodynamic parameters, electro­
lyte, and colloid status.

Exfoliative diseases of the integument and soft tissue necrotizing infections
479
if available, should not delay radical surgical debridement
and should be used as an adjunct to radical surgery and
antibiotic therapy.89,91
Purpura fulminans
Purpura fulminans is a term that describes an acute syn­
drome of rapidly progressive hemorrhagic necrosis of the
skin due to dermal vascular thrombosis associated with vas­
cular collapse and disseminated intravascular coagulation
(DIC).92 It may occur in individuals with dysfunction of the
protein C anticoagulant system, with acute severe infection,
or idiopathically without any coagulation dysfunction or
infection.
It has been associated with systemic infection by Meningo­
coccus, Gram-negative bacilli, Staphylococcus, Streptococcus,
and Rickettsia organisms. Skin necrosis begins in a region of
dermal discomfort, which rapidly progresses to evanescent
flush, followed by petechiae. Hemorrhagic bullae progress to
frank skin necrosis. The process generally involves the skin
and subcutaneous tissues, without involvement of muscle.
Skin involvement is frequently an early manifestation of the
disease process. Skin biopsy will, therefore, allow an earlier
diagnosis.92 Mortality in the acute phase is 18–40%.93
Management is directed at halting progression of the
underlying infectious disease, preventing secondary infec­
tions, and removing non-viable tissue. Early heparin
administration and replacement of clotting factors have
proven useful to stop intravascular clotting.93 Shock from
blood extravasation and sepsis require extensive volume
If more than one operation for debridement of infected
necrotic tissue is needed, mortality increases from 43% to
71%; this outcome drastically highlights the importance of
adequate initial necrosectomy.86 In patients with many risk
factors, early amputation of the extremity, especially in cases
of myonecrosis, should be considered. Broad-spectrum anti­
biotics are started preoperatively, although high-dose peni­
cillin is appropriate for clostridial infections. However,
antibiotic treatment is no substitution for surgical interven­
tion. Adequate fluid resuscitation and nutritional support
are also required. Wounds are packed open with antiseptic-
soaked dressings, which need to be changed frequently.
Kaiser and Cerra have reported unsatisfactory results with
either early application of porcine xenografts or burn wound
topical antimicrobials.87 Complete control of local and sys­
temic infection is required before wound closure is addressed.
As in burns, secondary infections must be prevented by
proper wound management, Biological or synthetic dress­
ings offer the advantages of decreased pain, decreased fluid
loss, and prevention of secondary infection. Frequently, large
areas of skin and soft-tissue loss result from this disease and
will eventually require extensive surgery to achieve adequate
closure. Some authors advocate the use of hyperbaric oxygen
and claim that it results in decreased mortality and reduced
need for debridement; however, most of these reports are
case reports or uncontrolled trials and adequate prospective
controlled trials in patients are still lacking.88,89 In animals,
hyperbaric oxygen therapy alone did not improve survival or
bacterial colonization, but did show adjuvant effects to anti­
biotic treatment.90 In summary, hyperbaric oxygen therapy,
Figure 43.8  Flowchart of management of exfoliative and necrotizing conditions of the integument.
Partial-thickness necrosis
Full-thickness necrosis
Exfoliative or necrotizing skin loss
Separation at
dermo-epidermal
level
SJS/TEN
No corticosteroids
Fluid resuscitation
Discontinue suspected drug
Biological and synthetic
dressings
Care to mucosal surfaces
Separation at
intra-epidermal
level
Staphylococcal
scalded skin
syndrome
Systemic and topical
antibiotics
Biological and
synthetic dressings
Dermal
vascular
thrombosis
Purpura
fulminans
Antibiotics
Restore clotting factors
Surgical debridement
Biological and
synthetic dressings
Deeper tissue levels involved
Primary
fascia
infection
Primary
muscle
infection
Necrotizing
fasciitis
Bacterial
myonecrosis
Urgent surgical debridement
Antibiotics
‘Open wound’
Biological and
synthetic dressings
and controlled infection

Total Burn Care
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480
While first described by Bryant and White in 1898 and
later investigated by Selye in 1962, it was not until 1976 that
the true clinical significance of the syndrome was formally
recognized by Gipstein et al. The clinical syndrome of cal­
ciphylaxis is characterized by:96,97
1. Painful purpuric cutaneous lesions (Fig. 43.10)
2. Histological evidence of systemic medial calcifications
of arteries; tunica media
3. Histological evidence of small vessel mural calcification
with or without endovascular fibrosis leading to
vascular thrombosis and tissue necrosis.
As previously stated, the exact pathophysiology of cal­
ciphylaxis is unknown, though the best theory was offered
by Selye et al. in 1962. Utilizing a rat model, he suggested
that calciphylaxis was a condition of hypersensitivity caused
by exposure to ‘sensitizing agents’ (nephrectomy/PTH) and
‘challengers’ (egg albumin/metallic salts) over a defined
period of time.96 Simply stated, calciphylaxis appears to be
a clinical syndrome induced by a series of events that pre­
disposes the patient to extraskeletal calcifications.
Clinically, calciphylaxis affects approximately 1–4% of the
population with underlying end-stage renal disease.98 The
condition has been reported in age groups ranging from
6 months to 83 years of age. The condition appears to affect
predominantly Caucasian women with a female to male
ratio of 3 : 1. Unfortunately, the mortality rate associated
Figure 43.9  Early Calciphylaxis lesion. (Courtesy of Dr Shawn Fagan.)
Box 43.1  Conditions associated with non-uremic calciphylaxis
•
Primary hyperparathyroidism
•
Breast cancer + chemotherapy
•
Liver cirrhosis
•
Cholangiocarcinoma
•
Crohn’s disease
•
Rheumatic arthritis
•
Systemic lupus erythematosus.
Figure 43.10  Proximal Calciphylaxis. (Courtesy of Dr Shawn Fagan.)
replacement. Limb vascular and compartmental pressure
should be monitored closely to enable early escharotomy
and/or fasciotomy, when needed. Skin lesions resulting only
in blisters should be treated with topical antimicrobials (e.g.
silver sulfadiazine) to prevent secondary infection. Non-
viable tissue should be removed as soon as the patient’s
condition allows. Small areas can be covered with autografts
but, as large areas are frequently involved, allograft or
xenograft skin coverage may be required. Limb amputations
may be frequently required due to vascular compromise, as
well as revisions for progression of disease.94 Isolation of the
affected patient, as well as monitoring and prophylactic
treatment of patients and staff, may be necessary to prevent
further spread and outbreaks of the disease, especially in case
of meningococcal infection.
Calciphylaxis
Calciphylaxis is a rare condition that is characterized by the
development of extraskeletal calcifications resulting in tissue
necrosis. While the exact etiology is unknown, the condition
appears to be most commonly associated with disorders that
alter calcium/phosphate homeostasis. Thus, the condition is
usually diagnosed in individuals undergoing renal replace­
ment therapy or who have recently undergone renal trans­
plantation. Despite the close association with renal failure,
Nigwekar et al. have identified a subgroup of individuals
with the same pathological condition but without end stage
renal failure and coined the term ‘non-uremic calciphylaxis’
(Fig. 43.9, Box 43.1).95

Exfoliative diseases of the integument and soft tissue necrotizing infections
481
without evidence of disease progression prior to definitive
closure.
Conclusion
Inflammatory and infectious conditions of the skin and
underlying tissues represent a major diagnostic and thera­
peutic challenge. The team approach to their care is essential,
and wound management is paramount. Burn units are
ideally suited to deal with patients with these conditions and
should be considered as the appropriate site of referral for
these critically ill patients.
Further reading
Becker DS. Toxic epidermal necrolysis. Lancet. 1998;351:1417-1420.
Cartotto R, Mayich M, Nickerson D, et al. SCORTEN accurately
predicts mortality among toxic epidermal necrolysis patients
treated in a burn center. J Burn Care Res. 2008;29(1):141-146.
Koh MJ, Tay YK. An update on Stevens–Johnson and toxic epidermal
necrolysis in children. Curr Opin Pediatr. 2009;21:505-510.
Weenig RH, Sewell LD, Davis MD, et al. Calciphylaxis: natural history,
risk factors, outcome. J Am Acad Dermatol. 2009;61(1):73-79.
Wilkins J, Morrison L, White CR. Oculocutaneous manifestations of
the erythema multiforme/Stevens–Johnson syndrome/toxic
epidermal necrolysis spectrum. Dermatol Clin. 1992;10:571-582.
with calciphylaxis is as high as 60–80% and appears to be
related to the distribution of cutaneous lesions.95 Distal
lesions have a reported mortality rate of 42%, where more
proximal lesions (trunk, abdomen, buttocks and proximal
extremities) have a reported mortality rate approaching
72%. The association between mortality rates and lesion
distribution may in fact be related to the degree of systemic
involvement. The overall mortality rate from calciphylaxis
appears to be closely related to the extent of internal organ
involvement and development of sepsis from infected cuta­
neous lesions.
The diagnosis of calciphylaxis should be suspected in any
patient with painful cutaneous lesions and a history sup­
portive of the clinical syndrome. While diagnostic laborato­
ries and imaging are not helpful, the diagnosis can be
formally established with a tissue biopsy.
Once the diagnosis is established, the treatment should
be initiated in a multidisciplinary approach. The treatment
should be based on improving the underlying condition
such as reformulation in hemodialysis or potentially
administering sodium thiosulfate which acts as an antioxi­
dant and chelator of cations. Unfortunately, despite the
best medical efforts, treatment usually becomes supportive
from an analgesic and wound standpoint. Wound manage­
ment should be aggressive to avoid local wound infections.
The primary goal is to establish a healthy wound bed
 
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Exfoliative diseases of the integument and soft tissue necrotizing infections
481.e1
© Copyright 2012 Elsevier, Inc. All rights reserved.
References
1. Rasmussen JE. Erythema multiforme. Should anyone care
about the standards of care? Arch Dermatol. 1995;131:
726-729.
2. Becker DS. Toxic epidermal necrolysis. Lancet. 1998;351:
1417-1420.
3. Patterson R, Dykewicz MS, Gonzales A, et al. Erythema
multiforme and Stevens–Johnson syndrome: descriptive and
therapeutic controversy. Chest. 1990;98:331-336.
4. Wilkins J, Morrison L, White CR. Oculocutaneous manifestations
of the erythema multiforme/Stevens–Johnson syndrome/toxic
epidermal necrolysis spectrum. Dermatol Clin. 1992;10:
571-582.
5. Chan HC, Stern RS, Arndt KA, et al. The incidence of erythema
multiforme, Stevens–Johnson syndrome and toxic epidermal
necrolysis. Arch Dermatol. 1990;126:43-47.
6. Roujeau JC, Guillaume JC, Fabre JP, et al. Toxic epidermal
necrolysis (Lyell syndrome): incidence and drug etiology in
France, 1981–1985. Arch Dermatol. 1990;126:37-42.
7. Schoepf E, Stuehmer A, Rzany B, et al. Toxic epidermal necrolysis
and Stevens–Johnson syndrome: an epidemiologic study from
West Germany. Arch Dermatol. 1991;127:839-842.
8. Naldi L, Locasti F, Marchesi, et al. Incidence of toxic epidermal
necrolysis in Italy. Arch Dermatol. 1990;126:1103-1104.
9. Strom BL, Carson JL, Halpern AC, et al. A population-based study
of Stevens–Johnson syndrome: incidence and antecedent drug
exposures. Arch Dermatol. 1991;127:831-838.
10. Halebian P, Corder V, Herndon D, et al. A burn center experience
with toxic epidermal necrolysis. J Burn Care Rehabil. 1983;4:
176-183.
11. Prendiville JS, Hebert AA, Greenwald MJ, et al. Management of
Stevens–Johnson syndrome and toxic epidermal necrolysis in
children. J Pediatr. 1987;115:881-887.
12. Kim PS, Goldfarb IW, Gaisford JC, et al. Stevens–Johnson
syndrome and toxic epidermal necrolysis: a pathophysiologic
review with recommendations for a treatment protocol. J Burn
Care Rehabil. 1983;4:91-100.
13. Roujeau JC, Chosidow O, Saiag P, et al. Toxic epidermal necrolysis
(Lyell syndrome). J Am Acad Dermatol. 1990;23:1039-1058.
14. Saiag P, Caumes E, Chosidow O, et al. Drug-induced toxic
epidermal necrolysis (Lyell syndrome) in patients infected with
the human immunodeficiency virus. J Am Acad Dermatol.
1990;26:567-574.
15. Villada G, Roujeau J, Cordonnier C, et al. Toxic epidermal
necrolysis after bone marrow transplantation: study of nine cases.
J Am Acad Dermatol. 1990;23:870-875.
16. Revuz J, Penson D, Roujeau JC, et al. Toxic epidermal necrolysis:
clinical findings and prognostic factors in 87 patients. Arch
Dermatol. 1987;123:1160-1166.
17. Murphy JT, Purdue GF, Hunt JL. Toxic epidermal necrolysis. J Burn
Care Rehabil. 1997;18:417-420.
18. McGee T, Munster A. Toxic epidermal necrolysis syndrome:
mortality rate reduced with early referral to regional burn center.
Plast Reconstr Surg. 1998;102:1018-1022.
19. Scully MC, Frieden IJ. Toxic epidermal necrolysis in early infancy.
J Am Acad Dermatol. 1992;27:340-344.
20. Cartotto R, Mayich M, Nickerson D, et al. SCORTEN
accurately predicts mortality among toxic epidermal necrolysis
patients treated in a burn center. J Burn Care Res. 2008;29(1):
141-146.
21. Ruiz-Maldonado R. Acute disseminated epidermal necrosis
type 1, 2 and 3: study of sixty cases. J Am Acad Dermatol. 1985;
13:623-635.
22. Guillaume JC, Roujeau JC, Revuz J, et al. The culprit drugs in 87
cases of toxic epidermal necrolysis (Lyell syndrome). Arch
Dermatol. 1987;123:1166-1170.
23. Roujeau JC, Kelly JP, Naldi L, et al. Medication use and the risk of
Stevens–Johnson syndrome or toxic epidermal necrolysis. N Engl J
Med. 1995;333:1600-1607.
24. Halebian PH, Madden MR, Finkestein JL, et al. Improved
burn center survival of patients with toxic epidermal
necrolysis managed without corticosteroids. Ann Surg.
1986;204:503-511.
25. Adzick NS, Kim SH, Bondoc CC, et al. Management of toxic
epidermal necrolysis in a pediatric burn center. Am J Dis Child.
1985;139:499-502.
26. Yetin J, Bianchini JR, Owens JA. Etiological factors in Stevens–
Johnson syndrome. South Med J. 1980;73:599-602.
27. Howland WW, Golitz LE, Weston WL, et al. Erythema multiforme:
clinical histopathologic, and immunologic study. J Am Acad
Dermatol. 1984;10:438-446.
28. Avakian R, Flowers FP, Araulo OE, et al. Toxic epidermal
necrolysis: a review. J Am Acad Dermatol. 1991;25:69-79.
29. Goldstein SM, Wintroub BW, Elias PM, et al. Toxic epidermal
necrolysis: unmuddying the waters. Arch Dermatol. 1987;123:
1153-1155.
30. Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: a
critical review of characteristics, diagnostic criteria and causes. J
Am Acad Dermatol. 1983;8:763-775.
31. Merot Y, Gravallese E, Guillen FJ, et al. Lymphocyte subsets and
Langerhans’ cells in toxic epidermal necrolysis. Arch Dermatol.
1986;122:455-458.
32. Villada G, Roujeau JC, Clerici T, et al. Immunopathology of
toxic epidermal necrolysis. Keratinocytes, HLA-DR expression,
Langerhans cells and mononuclear cells: an immunopathologic
study of five cases. Arch Dermatol. 1992;128:50-53.
33. Miyauchi H, Hosokawa H, Akaeda T, et al. T-cell subsets in
drug-induced toxic epidermal necrolysis. Arch Dermatol.
1991;127:851-855.
34. Hertl M, Merk HF, Bohlen H. T-cell subsets in drug-induced toxic
epidermal necrolysis. Arch Dermatol. 1992;128:272.
35. Heng MC, Allen SG. Efficiency of cyclophosphamides in toxic
epidermal necrolysis: clinical and pathophysiologic aspects. J Am
Acad Dermatol. 1991;25:778-786.
36. Roujeau JC, Huynh TN, Bracq C, et al. Genetic susceptibility
to toxic epidermal necrolysis. Arch Dermatol. 1987;123:
1171-1173.
37. Stein KM, Schlappner OL, Heaton CL, et al. Demonstration of
basal cell immunofluorescence in drug-induced toxic epidermal
necrolysis. Br J Dermatol. 1972;86:246-252.
38. Parson JM. Toxic epidermal necrolysis. Int J Dermatol. 1992;31:
749-768.
39. Paul C, Wolkenstein P, Adle H, et al. Apoptosis as a mechanism
of keratinocyte death in toxic epidermal necrolysis and
Stevens–Johnson syndrome. Br J Dermatol. 1996;134:
710-714.
40. Inachi S, Muizutani H, Shimuzu M. Epidermal apoptotic cell
death in erythema multiforme and Stevens–Johnson syndrome.
Contribution of perforin positive cell infiltration. Arch Dermatol.
1997;133:845-849.
41. Correia O, Chosidow O, Saiag P, et al. Evolving pattern of
drug-induced toxic epidermal necrolysis. Dermatology.
1993;186:32-37.
42. Paller AS, Nelson A, Steffen L, et al. T-lymphocyte subset in the
lesional skin of allogenic and autologous bone marrow transplant
patients. Arch Dermatol. 1988;124:1795-1801.
43. Roujeau JC, Philippoteau C, Koso M, et al. Sjögren-like
syndrome following toxic epidermal necrolysis. Lancet. 1985;1:
609-611.
44. Hensen EJ, Claas FHJ, Vermeer BJ. Drug-dependent binding of
circulating antibodies in drug-induced toxic epidermal necrolysis.
Lancet. 1981;2:151-152.
45. Haake AR, Polaskowska RR. Cell death by apoptosis and
epidermal biology. J Invest Dermatol. 1993;101:107-112.

Total Burn Care
43
481.e2
© Copyright 2012 Elsevier, Inc. All rights reserved.
46. Lyell A. Toxic epidermal necrolysis (the scalded skin syndrome):
a reappraisal. Br J Dermatol. 1979;100:69-86.
47. Rasmussen J. Toxic epidermal necrolysis. Med Clin N Am.
1980;64:901-920.
48. Wahle D, Beste D, Conley SF. Laryngeal involvement in toxic
epidermal necrolysis. Otolaryngol Head Neck Surg. 1992;6:
796-799.
49. Chosidow O, Delchier JC, Chaumette MT. Intestinal involvement
in drug-induced toxic epidermal necrolysis. Lancet. 1991;
337:928.
50. Lebargy F, Wolkenstein P, Gisselbrecht M, et al. Pulmonary
complications in toxic epidermal necrolysis: A prospective clinical
study. Intensive Care Med. 1997;23:1237-1244.
51. Mclvor R, Zaidi J, Peters W, et al. Acute and chronic respiratory
complications of toxic epidermal necrolysis. J Burn Care Rehabil.
1996;17:237-240.
52. Krumlovsky F, Del Greco F, Herdson P, et al. Renal disease
associated with toxic epidermal necrolysis (Lyell’s disease).
Am J Med. 1974;57:817-825.
53. Roujeau JC, Moritz S, Guillaume JC, et al. Lymphopenia
and abnormal balance of T-lymphocyte subpopulation
in toxic epidermal necrolysis. Arch Dermatol Res. 1985;
277:24-27.
54. Heimbach DM, Engrav LH, Marvin JA, et al. Toxic epidermal
necrolysis: a step forward in treatment. JAMA. 1987;257:
2171-2175.
55. Marvin JA, Heimbach DM, Engrav LH, et al. Improved
treatment of the Stevens–Johnson syndrome. Arch Surg.
1984;119:601-605.
56. Taylor JA, Grube B, Heimbach DM, et al. Toxic epidermal
necrolysis: a comprehensive approach. Clin Pediatr. 1989;28:
404-407.
57. Sowder LL. Biobrane wound dressing used in the treatment of
toxic epidermal necrolysis: a case report. J Burn Care Rehabil.
1990;11:237-239.
58. Birchall N, Langdon R, Cuono C, et al. Toxic epidermal
necrolysis: an approach to management using cryopreserved
allograft skin. J Am Acad Dermatol. 1987;16:368-372.
59. Halebian PH, Shires GT. Burn unit treatment of acute, severe
exfoliating disorders. Ann Rev Med. 1989;40:137-147.
60. Revuz J, Roujeau JC, Guillaume JC, et al. Treatment of toxic
epidermal necrolysis: Creteil’s experience. Arch Dermatol.
1987;123:1156-1158.
61. Ginsburg CM. Stevens–Johnson syndrome in children. Pediatr
Infect Dis. 1982;1:155-158.
62. Rasmussen JE. Cause, prognosis and management of toxic
epidermal necrolysis. Compr Ther. 1990;16:3-6.
63. Rzany B, Schmitt H, Schoepf E. Toxic epidermal necrolysis in
patients receiving glucocorticosteroids. Acta Derm Venereol.
1991;71:171-172.
64. Guibal F, Bastuji-Garin S, Chosidow O, et al. Characteristics of
toxic epidermal necrolysis in patients undergoing long-term
glucocorticoid therapy. Arch Dermatol. 1995;131:669-672.
65. Chave TA, Mortimer NJ, Sladden MJ, et al. Toxic epidermal
necrolysis: current evidence, practical management and future
directions. Br J Dermatol. 2005;153(2):241-253.
66. Arevalo JM, Lorente JA, Gonazlez-Herrada C, et al. Treatment of
toxic epidermal necrolysis with cyclosporin A. J Trauma.
2000;48(3):473-478.
67. Bachot N, Revuz J, Roujeau JC. Intravenous immunoglobulin
treatment for Stevens–Johnson syndrome and toxic epidermal
necrolysis: a prospective noncomparative study showing no
benefit on mortality or progression. Arch Dermatol. 2003;
139(1):33-36.
68. Viard I, Wehrli P, Bullani R, et al. Inhibition of toxic
epidermal necrolysis by blockade of CD95 with human
intravenous immunoglobulin. Science. 1998;282(16):
490-493.
69. Shortt R, Gomez M, Mittman N, et al. Intravenous
immunoglobulin does not improve outcome in toxic epidermal
necrolysis. J Burn Care Rehabil. 2004;25(3):246-255.
70. Stella M, Cassano P, Bollero D, et al. Toxic epidermal necrolysis
treated with intravenous high-dose immunoglobulins: our
experience. Dermatology. 2001;203(1):45-49.
71. Prins C, Vittorio C, Padilla RS, et al. Effect of high-dose
intravenous immunoglobulin therapy in Stevens–Johnson
syndrome: a retrospective, multicenter study. Dermatology.
2003;207(1):96-99.
72. Yang Y, Xu J, Li F, et al. Combination therapy of intravenous
immunoglobulin and corticosteroid in the treatment of epidermal
necrolysis and Steven–Johnson syndrome: a retrospective
comparative study in China. Int J Dermatol. 2009;48(10):
1122-1128.
73. Wolkenstein P, Latarjet J, Roujeau JC, et al. Randomised
comparison of thalidomide versus placebo in toxic epidermal
necrolysis. Lancet. 1998;352(9140):1586-1589.
74. Koh MJ, Tay YK. An update on Stevens-Johnson and toxic
epidermal necrolysis in children. Curr Opin Pediatr. 2009;21:
505-510.
75. Resnick SD. Staphylococcal toxin-mediated syndromes in
childhood. Semin Dermatol. 1992;11:11-18.
76. Canoso JJ, Barza M. Soft tissue infections. Rheum Dis Clin North
Am. 1993;15:235-239.
77. Elias PM, Fritsch P, Epstein EH. Staphylococcal scalded skin
syndrome: clinical features, pathogenesis, and recent
microbiological and biochemical developments. Arch Dermatol.
1977;113:207-219.
78. Dancer SJ, Garratt R, Sanhanha J, et al. The epidermolytic toxins
are serine proteases. FEBS Lett. 1990;268:129-132.
79. Vath GM, Earhart CA, Rago JV, et al. The structure of the
superantigen exfoliative toxin A suggests a novel regulation as a
serine protease. Biochemistry. 1997;36:1559-1566.
80. Itani O, Crump R, Minouni F, et al. Ritter’s disease (neonatal
staphylococcal scalded skin syndrome). Am J Dis Child.
1992;146:425-426.
81. Patino JF, Castro D. Necrotizing lesions of soft tissue: a review.
World J Surg. 1991;15:235-239.
82. Steven DL. Invasive group A streptococcal infections. Clin Infect
Dis. 1992;14:2-13.
83. Francis KR, Lamaute HR, Davis JM, et al. Implications of risk
factors in necrotizing fasciitis. Am J Surg. 1993;59:304-308.
84. Sharif HS, Clark DC, Aabed MY, et al. MR imaging of thoracic
and abdominal wall infections: comparison with other imaging
procedures. AJR Am J Roentgenol. 1990;154:989-995.
85. Stamenkovic I, Lew PD. Early recognition of potentially fatal
necrotizing fasciitis: the use of frozen-section biopsy. N Engl J
Med. 1984;310:1689-1693.
86. Freischlag JA, Ajalat G, Busuttil RW. Treatment of necrotizing soft
tissue infection: the need for a new approach. Am J Surg.
1985;149:751-757.
87. Kaiser RE, Cerra FB. Progressive necrotizing surgical infections:
a unified approach. J Trauma. 1981;24:349-352.
88. Risemann JA, Zamboni WA, Curtis A, et al. Hyperbaric oxygen
therapy for necrotizing fasciitis reduces mortality and the need for
debridement. Surgery. 1990;108:847-850.
89. Green RJ, Dafoe DC, Raffin TA. Necrotizing fasciitis. Chest.
1996;110:219-229.
90. Zamboni WA, Mazolewski PJ, Erdmann D, et al. Evaluation of
penicillin and hyperbaric oxygen in the treatment of streptococcal
myositis. Ann Plast Surg. 1997;39:131-136.
91. McHenry CR, Piotrowski JJ, Petrinic D, et al. Determinants of
mortality for necrotizing soft-tissue infections. Ann Surg.
1995;221:558-565.
92. Adcock DM, Hicks MJ. Dermatopathology of skin necrosis
associated with purpura fulminans. Semin Thromb Hemost.
1990;16:283-292.

Exfoliative diseases of the integument and soft tissue necrotizing infections
481.e3
© Copyright 2012 Elsevier, Inc. All rights reserved.
93. Chasan PE, Hansbrough JF, Cooper ML. Management of
cutaneous manifestations of extensive purpura fulminans in a
burn unit. J Burn Care Rehabil. 1992;13:410-413.
94. Genoff MC, Hoffer MM, Achauer B, et al. Extremity amputation
in meningococcemia induced purpura fulminans. Plast Reconstr
Surg. 1992;89:878-881.
95. Nigwekar SU, Wolf M, Sterns RH, et al. Calciphylaxis from
nonuremic causes: a systematic review. Clin J Am Soc Nephrol.
2008;3(4):1139-1143.
96. Selye H. Calciphylaxis. Chicago, Ill: University of Chicago Press;
1962.
97. Gipstein RM, Coburn JW, Adams DA, et al. Calciphylaxis
in man. A syndrome of tissue necrosis are in 11 patients
with chronic renal failure. Arch Intern Med. 1976;136(11):
1273-1280.
98. Weenig RH, Sewell LD, Davis MD, et al. Calciphylaxis: natural
history, risk factors, outcome. J Am Acad Dermatol. 2009;61(1):
73-79.

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©2012 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2786-9.00044-8
The burn problem: a pathologist’s
perspective
Hal K. Hawkins
Introduction
‘Burns are not a simple injury, but a very complicated disease.’
This statement, dating from 1840, holds true with additional
force in 2012.1 Massive destruction of skin tissue and smoke-
induced injury to the airways both stimulate complex reac­
tions which are still only partly understood. Malfunction of
every organ system frequently complicates the responses of
patients to large burns. The nature of this malfunction is
often clarified by examination of the body after death. Post­
mortem examination also may reveal unsuspected infections
or adverse effects of therapy. In addition, postmortem exami­
nation leads to review of the circumstances of injury and
of the causal sequence in which complications occurred, in
order to determine the manner of death. Analysis of an
entire case from the point of view of pathogenesis often
clarifies the nature of the patient’s most significant problems.
This chapter systematically reviews some of the observations
made at autopsy in patients who have died after burn injury.
It also surveys experimental evidence that bears on patho­
genetic mechanisms relevant to disease processes seen at
autopsy. The observations reviewed here are drawn from our
experience of 253 autopsies performed on burned children
who died at the Shriners Burns Hospital in Galveston, Texas,
from 1971 to the present.
To introduce the sections that follow, the major medical
problems that complicate burn injury are summarized here.
The degree of disruption of normal physiologic processes
after burn injury is extreme. Immediately after burn injury,
massive loss of intravascular fluid into the burned tissue
begins to occur.2,3 Unless this fluid loss is replaced by the
physician very promptly and carefully, serious hypovolemia
develops.4–6 Hypovolemia and the resulting reduction of
tissue perfusion to levels less than that necessary to maintain
cellular homeostasis, which is defined as ischemia, causes
necrosis of certain cells, typically those with the greatest
oxygen demand within a tissue. The neural and endocrine
responses to the traumatic injury may lead to recognizable
lesions in the stomach and the heart. Ischemia may lead
to necrosis of pancreatic acinar epithelium and acute pan­
creatitis. Thermal injury to skeletal muscle, or lack of per­
fusion of muscle, may lead to local exudation of fluid and
development of such high pressure in fascial compartments
that arterial perfusion is prevented. This ‘compartment
syndrome,’ unless relieved by prompt surgical intervention,
leads to necrosis of muscle throughout the entire compart­
ment.7 The consequences of massive necrosis of muscle often
include secondary injury to the lungs, owing to release of
reactive oxygen species, and myoglobinuria with secondary
renal damage.8 At the time of injury, patients frequently
inhale sufficient carbon monoxide to compromise the
oxygen-carrying capacity of the blood. The resultant tissue
hypoxia can cause death at the scene, and if the patient sur­
vives it can be sufficient to lead to irreversible neuronal
injury, cerebral edema and brain death. Hypoxia, sometimes
related to carbon monoxide intoxication, also contributes to
cardiac and renal injury. In addition, when fires occur in
closed spaces, the ‘flashover’ process consumes all available
oxygen, so that the patient’s environment may contain too
little oxygen to sustain life. Occasionally a burn victim is
found without pulse or respiratory effort, probably as a con­
sequence of hypoxia, and is revived by cardiopulmonary
resuscitation. In such cases ischemic and hypoxic injury may
be profound in multiple organs, and there may be significant
‘ischemia–reperfusion injury’ to the lungs after resuscitation.
Patients injured in house fires often suffer injury to the res­
piratory tract caused by inhalation of toxic products of com­
bustion.9 This smoke inhalation injury stimulates an intense
inflammatory reaction, which can lead to obstruction of
airways and further tissue injury. This problem is discussed
below in the section on the respiratory system. Infection is
the next major risk experienced by patients after burn injury.
Necrotic skin provides an excellent environment for prolif­
eration of bacteria and fungi, and as long as necrotic tissue
remains, the risk of infection remains high. Immunosup­
pression contributes to this risk, so that burn patients
develop serious infections with agents otherwise usually
encountered in patients treated with immunosuppressive
drugs after transplantation. The mechanisms of this immu­
nosuppression are still under investigation, but include
excessive secretion of glucocorticoids and abnormal cytokine
signaling. Injury to the intestinal epithelium by hypoxia or
ischemia leads to translocation of intestinal bacteria into the
portal circulation. Coagulopathy may be a very serious com­
plication of burn injury. It may lead directly to tissue ischemia
after vascular thrombosis, or the resultant hemorrhage may
lead to secondary hypovolemia. Patients often require trans­
fusion of very large quantities of blood products during their
treatment and are subject to all the risks of transfusion.
CHAPTER 44 
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IN THIS CHAPTER
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Total Burn Care
44
484
and washing for several days generally arrive at this institu­
tion with large quantities of multiple microorganisms
growing in the necrotic skin. The bacteria appear to pro­
liferate initially in areas which have insufficient circulation
to develop a significant inflammatory response. As large
numbers of bacteria accumulate, those with high pathogenic
capacity invade the adjacent viable tissue, produce further
necrosis, and gain access to the circulation. This is the condi­
tion of burn wound sepsis, which historically has been the
leading cause of death in burn patients. In Linares’ series of
115 autopsies, sepsis was present in 73%, as documented by
positive blood culture and demonstration of invasive infec­
tion of viable tissue.14,15 When pneumonia was found at
autopsy in such a case, the cause of death was classified as
burn wound sepsis, with pneumonia as a contributing cause.
In 80% of these fatal cases of sepsis the burn wound was the
source of the infection. The most important pathogens were
Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneu­
moniae, Escherichia coli, Enterobacter, and Candida species.
More recently, antibiotic-resistant Acinetobacter species have
emerged as a frequent cause of fatal sepsis. Burn wound
sepsis is suspected clinically when a burn wound is the site
of proliferating microorganisms exceeding 105/g of tissue,
and there is histologic evidence of active invasion of sub­
jacent unburned tissue.16 In our institution, the wounds
of burn patients, especially the open areas, are routinely
sampled for quantitative culture and for histologic study
when excision and grafting procedures are done, and when­
ever clinical examination suggests the possibility of tissue
infection. The histologic classification used and its rationale
are discussed below under the integumentary system. Once
septicemia occurs, there is a generalized reaction which often
includes hypotension, tachycardia, increased hyperthermia
or hypothermia, and poor perfusion of the intestines and
other viscera.17 In the case of Gram-negative bacteria, the
endotoxin stimulates monocytes via their CD14 receptors
to become activated and set up a cascade of release of pro-
and anti-inflammatory mediators which affect all organs and
tissues in the body.18–20 Coagulopathy is also an important
complication of sepsis.21 In addition, once bacteria have
gained entrance to the general circulation, it becomes pos­
sible for foci of tissue infection to develop at distant sites.
This is most likely to occur in sites of tissue necrosis, on
cardiac valves, or in the lungs. Abscesses in distant organs
can allow the infection to resist eradication by specific anti­
biotics, and thus allow sepsis to persist despite appropriate
therapy. One recent case demonstrated clearly the route of
dissemination of fatal burn wound sepsis. The patient was
admitted in a clinically septic condition 2 weeks after suffer­
ing a large burn, and died in spite of aggressive therapy. At
the time of autopsy there were many areas of bacterial pro­
liferation within the burn wound, invasion of viable tissue
deep to the burn eschar, and thrombosis of blood vessels
invaded by bacteria at the margin of the necrotic zone. Septic
emboli with fibrous organization were seen in pulmonary
artery branches in all lobes of the lungs. There were foci of
necrosis throughout the lungs in which bacterial prolifera­
tion was visible within the walls of arteries, and these necrotic
areas were surrounded by massive pulmonary hemorrhage
and edema. A direct hematogenous route of spread of infec­
tion from the skin to the lungs seemed clear in this case. On
the other hand, airway obstruction is known to predispose
Disease processes involving multiple
organ systems
Hypoxia and ischemia
All cells require a constant supply of oxygen and metabolic
substrates to remain viable. In tissue hypoxia, when
the supply of oxygen is insufficient to meet metabolic
demand, cells generate a limited amount of metabolic energy
by anaerobic glycolysis, releasing lactic acid. With tissue
ischemia, when the flow of blood is insufficient, this meta­
bolic perturbation is complicated by a lack of supply of
glucose and other substrates, and the extracellular fluid com­
position may change dramatically. In general, tissues with
the greatest metabolic activity are the first to lose viability
under conditions of hypoxia and ischemia, including the
neurons of the central nervous system, cardiac myocytes,
small intestinal epithelial cells and the proximal tubular
epithelium of the kidney. The location and extent of necrosis
in these organs depends on the severity and duration of the
ischemic or hypoxic injury.
After ischemia and hypoxia have led to irreversible injury
and death of selected cell types or whole segments of organs
(infarcts), responses are generated which may lead to further
injury of remote organs. Cellular necrosis stimulates an
intense acute inflammatory reaction, probably initiated by
activation of the complement cascade, degranulation of mast
cells, and other processes. This reaction surrounds an infarct,
or proceeds throughout a region of tissue injury if the local
circulation is sufficient. In the skin, the tissues at the base
of the zone of necrosis become acutely inflamed. Monocytes
recruited to the regions of injury secrete cytokines in
large quantities, and polymorphonuclear neutrophils acti­
vate their antibacterial mechanisms. Cytokines have effects
throughout the body, the most important probably being
TNF-α, and superoxide released by neutrophils has impor­
tant distant effects. In addition, in endothelial cells injured
by hypoxia the enzyme xanthine dehydrogenase is converted
to xanthine oxidase, which releases superoxide during deg­
radation of adenosine, which in turn is released by necrotic
cells.10,11 Superoxide, released into the circulation by this
metabolic process and by neutrophils, can injure the lung by
damaging both endothelial and epithelial cells and allowing
protein-rich fluid to exude into alveoli. The inflammatory
reaction to thermal tissue injury also stimulates an intense
influx of neutrophils, which undoubtedly contributes to this
injury by releasing superoxide. In experimental models of
burn injury, as well as in models of ischemia–reperfusion
injury, the lungs have been shown to be injured by these
processes.12 Endogenous antioxidants such as glutathione
are depleted, and conjugated dienes appear, indicating that
cell membrane injury due to lipid peroxidation has occurred
in the lung.13
Infection and sepsis
The skin normally provides a highly effective barrier against
invasion by infectious agents. Necrotic tissue, in the skin as
elsewhere, is ineffective as a barrier to infection and indeed
provides an excellent culture medium. Patients who are
treated for deep burn injury with traditional debridement

The burn problem: a pathologist’s perspective
485
of adhesion molecules on neutrophils and endothelial
cells.30 Generation of fibrin degradation products may be
sufficient to interfere with normal thrombosis, and throm­
bocytopenia can develop in response to abnormal intravas­
cular fibrin generation.31 Activation of the kinin system can
stimulate further abnormal vascular permeability and hypo­
tension.20 Consumption of coagulation factors can lead to
abnormal bleeding, which can cause extensive tissue injury
secondarily. It is important to note that the acute-phase
response to burn injury includes increased synthesis of
fibrinogen and factor VIII. During the first 3–10 days after
burn injury, patients often have greater than normal clotting
activity. This may increase their susceptibility to the develop­
ment of DIC, especially if sepsis supervenes. It also implies
that laboratory testing of levels of fibrinogen and factor VIII
may yield normal values even in the presence of abnormal
consumption of these factors. When disseminated intravas­
cular coagulation occurs, coagulation factors are depleted,
including antithrombin.32 There is evidence that admini­
stration of recombinant antithrombin is beneficial when
administered early in the course of treatment of severe
burns.33 When disseminated intravascular coagulation
occurs in the patient’s terminal course, microscopic fibrin
thrombi are seen in many organs at the time of autopsy,
most commonly in the lungs, the skin, the kidneys and the
gastrointestinal tract.14,34
Integumentary system
The skin is the site of initial injury in burn patients, and
many of the events that lead to dysfunction or failure of
other organs begin in the skin. Thermal injury rapidly pro­
duces irreversible injury and cell death in epidermal kerati­
nocytes, in the epidermal appendages, including hair follicles
and their attached sebaceous glands and sweat glands, and
in the connective tissue cells of the dermis. In many cases
the burn wound excised within 48 hours of injury shows that
the entire dermis and all of the hair follicles are necrotic, but
that much of the subcutaneous adipose tissue remains
viable. It appears that the greater insulating capacity of
adipose tissue protects it to some extent. In some cases, of
course, the necrosis of the initial thermal injury may extend
deep into the subcutaneous tissue. In extreme cases, the
underlying skeletal muscle may become necrotic as a result
of thermal injury. Necrosis of skeletal muscle is especially
prominent in the case of electrical injury, in which more heat
may be generated adjacent to bone than near the body
surface. An interesting observation is that there is often a
band-like infiltrate of degenerating polymorphonuclear neu­
trophils in the midst of a totally necrotic dermis. This sug­
gests that the boundary between necrotic and viable tissue
may have extended deeper after the initial burn injury and
its inflammatory response. There is experimental evidence
that burn wounds often evolve from an initial level of necro­
sis to a deeper level, even from second to third degree, as a
result of poor perfusion of the tissue immediately deep to
the initial burn injury.35 This process of vascular stasis deep
to the burn is undoubtedly due in part to the rapid loss of
intravascular fluid from the damaged capillaries and venules
just below the necrotic burn wound. In addition, there is
evidence that neutrophils contribute to this process of burn
wound extension, most likely by adhering to endothelium
to pneumonia acquired through the airways, by preventing
normal clearance of bacteria from the airways and by provid­
ing a favorable medium for bacterial growth. Multiple foci
of airway obstruction are almost always seen at autopsy in
burn patients.22 In another recent case, although pneumonia
was not present, there was invasion of antibiotic-resistant
Pseudomonas directly into the wall of a bronchus. The risk of
infection is proportional to the extent of severe burns, the
time elapsed before initiation of fluid therapy, the presence
of metabolic alterations, the development of immunologic
deficiency, the concurrence of trauma, the local evolution of
wounds, and the age of the patient. An infection may begin
in a burn wound, the respiratory system, the gastrointestinal
tract, the urinary tract, the blood vessels, or from localized
infection in any other area of the body. Although most
serious infections in burn patients appear to be due to
endogenous flora, and many derive from wound infections
present at the time of admission, nosocomial infection is a
constant hazard.23,24
The problem of burn wound sepsis is amenable to therapy.
The strategy of excision of the potentially infected burn
wound as early as possible, together with judicious admini­
stration of effective antibiotics, has greatly reduced the
number of deaths due to infection. Coincidentally with the
institution of early excision and grafting of burn patients in
our institution, the incidence of burn wound sepsis as a
cause of death declined dramatically. However, the problem
of sepsis persists despite the best efforts in prevention and
treatment. Certain organisms can evade the best current
efforts at management, and have caused death in recent
cases, including bacteria resistant to all available antibiot­
ics.25 Those patients who are referred for therapy more than
1 week after burn injury often have extensive invasive wound
infection and sepsis, which may be difficult or impossible
to eradicate. Other microorganisms also can cause life-
threatening infection in burn patients. Fungal infection is a
continuing problem in patients with large burns, despite the
development of more effective systemic antifungal agents.26
In one recent case of apparent systemic fungal infection,
invasive and systemic dissemination of a pseudofungus of
the genus Oomyces was demonstrated.27 Molecular methods
(RT-PCR) were used to identify the organism in this case. It
seems likely that the increased availability of molecular diag­
nostic testing of infectious agents may lead to recognition of
additional previously unrecognized causes of invasive infec­
tion in burn patients. We have also experienced cases in
which acquisition or reactivation of herpes virus infections
led to major tissue injury. The risks of infection of a victim
of a large burn are somewhat similar to those of an immu­
nosuppressed transplant patient.
Coagulopathy
The burn wound has procoagulant effects and may induce
coagulation throughout the circulation (DIC, disseminated
intravascular coagulation).28,29 Tissue necrosis, particularly
lethal injury to endothelial cells with exposure of suben­
dothelial collagen, and release of tissue thromboplastin, can
activate coagulation and lead to coagulopathy. Generation
of thrombin within the circulation leads to generation of
fibrin peptides and stimulates acute inflammatory reactions,
including increased vascular permeability and upregulation

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486
somewhat different pattern, in that there is often a wavefront
of necrosis that accompanies fungal invasion (Fig. 44.2).
Thus the presence of fungal hyphae extending to a boundary
between necrotic and viable tissue is considered evidence of
fungal invasion of viable tissue. On this basis, infections
identified within burn wounds are reported as surface colo­
nization, invasion of necrotic tissue, which may be superfi­
cial or deep, and invasion of viable tissue. The responsible
surgeon is called immediately when invasion of viable tissue
is found. If the level of clinical suspicion is especially high,
frozen sections have been found useful for this determina­
tion, using a tape transfer device to facilitate handling of
these difficult specimens, with confirmation of the results
with routine sections on the following day. Diagnosis of viral
infection of the skin is achieved most efficiently by prepara­
tion of smears from scrapings of freshly opened vesicular
lesions or the bases of recently ruptured vesicles, and direct
immunofluorescence testing.
A fortunately rare complication involving the skin of
patients with large burns is the development of squamous
cell carcinoma during the late phase of recovery. This
so-called ‘Marjolin ulcer’ shows extensive local invasion but
generally can be controlled with adequate local excision.37–39
Respiratory system
Respiratory failure, defined as inability to maintain adequate
oxygen saturation while administering 100% oxygen by ven­
tilator, has been found to be the immediate cause of death
in some burn patients. The causes and mechanisms of res­
piratory failure are multiple and will be addressed separately,
although in many cases more than one mechanism operates.
Direct thermal injury to the trachea and bronchi probably
does not occur, except in patients exposed to large amounts
of steam. In addition to the problems listed below, patients
may develop problems related to the airways such as
pneumothorax or interstitial emphysema, aspiration of
gastric contents, pulmonary embolism, and non-specific
and to each other, with resulting obstruction of the
microvasculature.36
It is important to assess the presence and extent of infec­
tion within the burn wound, both by examination of wounds
excised therapeutically and by biopsy of suspicious areas in
open foci after grafting procedures. A high index of suspicion
serves the burn patient well. All biopsy and excision speci­
mens in our institution are sampled and studied histologi­
cally with stains for bacteria (Brown and Hopps) and fungi
(methenamine silver). In large excision specimens, samples
are taken from sites of especially deep tissue injury and sites
that show abnormal discoloration of dermal or subcutan­
eous tissue. When infectious microorganisms are found, it is
important to determine their location with respect to the
boundary between living and necrotic tissue. This boundary
may be irregular. It is generally distinct and marked by
inflammation in wounds several days old, but may be some­
what indistinct in very fresh specimens, as karyolysis takes
some time to develop in burn wounds. As noted above,
wound infections generally begin with colonization of the
skin surface and proliferation of organisms on the surface,
often with extension into hair follicles, followed by growth
within the necrotic tissue. Both the coagulum on the surface
and the necrotic epidermis and dermis are considered part
of the burn eschar. Growth within necrotic tissue is consid­
ered evidence of tissue infection, however, and potentially
more dangerous than growth on the surface of necrotic skin,
under a layer of fibrin and debris. Even when quantitative
cultures show more than 105 bacteria per gram of tissue,
when careful histologic study shows that the organisms are
limited to the skin surface or the superficial necrotic tissue,
the risk of sepsis appears to be low. Such growth on or in
necrotic tissue, however, does set the stage for invasion of
viable tissue. The finding of clusters of bacteria or fungi
within viable tissue implies a serious risk of sepsis and
further tissue invasion. Bacterial invasion of viable tissue is
quite apparent by histologic study of appropriate tissue
samples (Fig. 44.1). Invasive fungal infection presents a
Figure 44.1  This micrograph shows a dense cluster of filamentous
Gram-negative rods within necrotic skin in a patient with severe wound
infection from whom Pseudomonas aeruginosa was recovered in culture.
Tissue Gram stain.
Figure 44.2  This micrograph shows fungal hyphae within necrotic tissue
extending close to the boundary with intact, viable dermal tissue. Periodic
acid–Schiff (PAS) stain.

The burn problem: a pathologist’s perspective
487
similar to that of ecthyma gangrenosum of the skin.42,43 A
similar angioinvasive pattern of pulmonary infection can be
seen with generalized infection due to Aspergillus or similar
filamentous fungi.
Diffuse alveolar damage
This process affects the pulmonary parenchyma in all
lobes, although it is often patchy in distribution and begins
with exudation of protein-rich fluid into alveolar spaces.
This proteinaceous exudate, representing the vascular phase
of the acute inflammatory reaction, is a consequence of
damage to or increased permeability of both capillary
endothelial cells and the epithelial type I cells of the alveolar
lining. Within hours the exudates form hyaline membranes,
which are a histologic hallmark of this disease process
(Fig. 44.6). Within a few days the exudate begins to undergo
pulmonary edema due related to increased venous pressure.
Lesions of the lungs, which may be multiple, are often found
at autopsy in burn patients.40
Infection
In patients who have clinical evidence of sepsis at the time
of death, extensive infection of the lungs is commonly
present and may represent a terminal event. Fatal pneumo­
nia is most often seen as a consequence of infection with a
highly resistant bacterial strain, an invasive fungus, or in a
compromised host with renal failure or some other cause of
severe immunodeficiency. Virulent and antibiotic-resistant
strains of Pseudomonas may produce an angioinvasive infec­
tion in the lung, with massive proliferation of bacteria within
the walls of pulmonary arteries and ischemic necrosis of
segments of lung tissue (Figs 44.3–44.5).41 This pattern is
Figure 44.3  This photograph is a slice of the upper lobe of the lung taken
at autopsy from a patient who showed clinical signs of sepsis when he
developed disseminated infection after multiple wound cultures of open
wounds yielded multiple antibiotic-resistant Pseudomonas.
Figure 44.4  This micrograph, taken at low magnification, shows a small
round pale area of necrotic lung tissue in which no nuclei are staining,
surrounded by a zone of congestion and hemorrhage, with very little acute
inflammatory reaction. H&E stain.
Figure 44.5  This high magnification micrograph shows short Gram-
negative rods growing profusely within the wall of a small pulmonary artery
branch. Brown–Hopps tissue Gram stain.
Figure 44.6  This section of lung tissue shows bright pink, homogeneous
hyaline membranes attached to alveolar walls and septa of alveolar ducts.
This is from a 2-year-old patient who died 8 days after a large scald burn.
This represents the exudative phase of diffuse alveolar damage, which may
be seen in the absence of smoke inhalation injury. H&E stain.

Total Burn Care
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488
oxygen in high concentration within the lung can itself lead
to injury, and this injury can be manifest in the form of
diffuse alveolar damage.53–55 Despite this plethora of mecha­
nisms that can lead to pulmonary injury in burn patients,
many patients with massive burn injury do not develop
clinically apparent respiratory difficulty. The conditions
that seem to be most strongly associated with this form of
pulmonary injury are delayed fluid resuscitation, limb
ischemia, and, of course, sepsis.
Smoke inhalation injury
Patients often inhale products of combustion in house fires,
and the toxic effects of these gases and fumes directly injure
tissues in the lung. These patients are recognized during
bronchoscopy by observing prominent hyperemia of the tra­
cheobronchial mucosa, and small particles of carbonaceous
soot within the airways. Associated findings include facial
burns and singed nasal hairs. These patients usually do not
require ventilator therapy for several days, but are at high
risk of developing respiratory failure, which responds poorly
to ventilator therapy and may prove fatal even when the
burn injury is small. The mortality of burn injury has been
found to be substantially increased when inhalation injury
also is present.56–60 Experimental studies in sheep and dogs
have partially clarified the mechanisms of smoke inhalation
injury.61–64 In animals the immediate reactions to inhalation
of toxic smoke include detachment of numerous ciliated
columnar cells from the tracheobronchial epithelium, secre­
tion of all stored mucus by secretory cells, and a dramatic
increase (more than 10-fold) in tracheobronchial blood
flow.65–67 Within a few hours an intense acute inflammatory
reaction develops, with exudation of numerous neutrophils
into the airways, and release of protein-rich fluid that may
coagulate within airways, forming occlusive ‘casts’ contain­
ing mucus and desquamated cells (Fig. 44.8). After 48 hours
the exudate of neutrophils, which is most intense in the
trachea at earlier times, fills many terminal bronchioles, and
organization by spindle-shaped fibroblasts within alveolar
spaces (Fig. 44.7), and collagenous fibrosis develops, which
obliterates alveoli and greatly thickens the septa between
alveoli and extends between capillaries and the alveolar
surface. Macrophages accumulate within alveoli, and alveo­
lar epithelial type II cells multiply. In the late stages there is
severe interstitial fibrosis.
There are multiple pathogenetic mechanisms that may be
responsible for this process, and despite extensive research
it is not yet clear which of these are most significant in
patients with burn injury.44,45 The burn injury itself stimu­
lates activation of complement, liberating peptides includ­
ing C5a and C3a, which despite their short half-lives could
stimulate vascular leakage in the pulmonary bed. These and
many other peptides are thought to activate circulating neu­
trophils, which produce secondary injury to the vascular and
epithelial membranes in the lung.46,47 Conversion of xan­
thine dehydrogenase to xanthine oxidase in the burn wound
can cause release of superoxide into the venous circulation,
stimulating endothelial injury and oxidative stress in the
lung.10 The neutrophils reacting to the burn wound undergo
an oxidative burst, with release of superoxide into the circu­
lation. This process is greatly enhanced if the patient’s course
is complicated by ischemic injury to muscle compartments,
limbs or other organs. Lipid peroxidation is a recognized
consequence of burn injury. Superoxide can also react with
nitric oxide, produced in the wound or the lung, to form
peroxynitrite, a highly toxic substance.48 Thrombin peptides,
released during thrombosis of blood vessels in the wound,
can also activate neutrophils and stimulate endothelial cells
to express adhesion molecules.49 The kinin system can be
activated during thermal injury, with its systemic conse­
quences. When patients develop sepsis, additional pulmo­
nary damage can be produced by release of proinflammatory
cytokines and augmentation of the processes that lead to
inflammatory injury of the lung.14,50 Neuropeptides includ­
ing substance P and CGRP may have a role in increasing
vascular leakage in the airways.51,52 Finally, the presence of
Figure 44.7  This micrograph shows numerous elongated cells resembling
fibroblasts occupying alveolar spaces and secreting connective tissue
matrix. This abnormality represents the proliferative phase of diffuse alveolar
damage. This patient died 1 month after a large flame burn and had clinical
evidence of smoke inhalation injury and acute respiratory distress syndrome
(ARDS). H&E stain.
Figure 44.8  This is a micrograph of sheep trachea sampled 3 hours after
experimental smoke inhalation injury by insufflation of cooled cotton smoke
under anesthesia. Numerous polymorphonuclear neutrophils (PMN) appear
to be flowing into the tracheal lumen from a gap in the epithelial lining.
H&E stain.

The burn problem: a pathologist’s perspective
489
including Alcian blue and MUC5b, are found in small bron­
chioles and lung parenchyma in almost all patients studied
at autopsy.22
Multiple mechanisms may be responsible for the respira­
tory disease evoked by inhalation of toxic smoke.69 As in the
case of diffuse alveolar damage, the available evidence indi­
cates that neutrophils may be responsible for much of the
injury, but the locus of injury appears to be different, cen­
tered on the airways rather than the pulmonary parenchyma.
Factors that may be likely to lead to selective damage to the
airways include local release of neuropeptides by afferent
C-fibers in the airways and activation of vagal reflexes and
activation of proinflammatory processes in reaction to injury
to the airway mucosa, particularly local production of inter­
leukin (IL)-8.70–73 Local production of nitric oxide and other
reactive nitrogen species has significant deleterious effects in
this form of acute lung injury, according to large animal
experiments.74,75 Local activation of thrombin during the for­
mation of fibrin clots, and local production of endothelin-1
may further enhance the inflammatory reaction in the
airways.76,77 Secretory cells appear to be especially sensitive
to smoke inhalation injury. Experimental studies in sheep
have demonstrated that activation of poly-adenosyl-ribose
polymerase (PARP) contributes to lung injury after burn and
smoke inhalation injury.78 Obstruction of small bronchi and
bronchioles is thought to lead to failure of ventilation of
multiple small segments of lung tissue, and inappropriate
vasodilation in these poorly ventilated segments may well
contribute to the failure of adequate oxygenation.79 Treat­
ment with nebulized heparin or tissue plasminogen activa­
tor has been found to reduce the degree of airway injury in
the ovine model, demonstrating the importance of fibrin
polymerization in this model.80,81 Segmental atelectasis and
prominent vasodilation in focal areas are features of smoke
inhalation injury seen in experimental animals, and also in
patients examined at autopsy after burn injury and smoke
inhalation injury. Obstruction of bronchi and bronchioles
by mucus, fibrin and cell debris contributes to respiratory
malfunction in experimental animals, and similar obstruc­
tive material is seen in human lung tissue at autopsy.22,79,82–84
As is the case with diffuse alveolar damage, deficient clear­
ance of airway secretions and the toxic effects of high con­
centrations of oxygen may complicate the reaction to injury.
The literature contains widely differing estimates of the
extent to which smoke inhalation injury contributes to mor­
tality in patients with burns. A recent review of more than
40 years’ experience at the Shriners Burns Hospital in Galve­
ston found that although clinical evidence of smoke inhala­
tion injury was present in only 14% of patients admitted for
recent burns, such evidence was recorded in 66% of the
patients who died.
Cardiovascular system
Despite the tachycardia and increased output common to
patients with burn injury, structural lesions of the heart have
been uncommon in our autopsies done on a pediatric popu­
lation of patients. However, cardiac hypertrophy is a con­
sistent finding at autopsy.85 Cardiac dilation and clinical
evidence of poor myocardial contractility do develop in
some patients after burn injury. Bacterial endocarditis occurs
in occasional patients with sepsis complicating burn injury.
begins to extend into the lung parenchyma (Fig. 44.9).
Studies using markers of upper airway mucus demonstrate
the presence of this material in small peripheral airways and
alveoli, demonstrating that the obstructive material moves
from larger to smaller, more peripheral airways.68 This
inflammatory reaction resolves in the experimental animal,
and the epithelium slowly regenerates. However, autopsy
evidence suggests that exudation of neutrophils and protein
into the airways resolves more poorly in humans, and may
persist for weeks (Fig. 44.10). The loss of airway epithelium,
which may be extensive, does not regenerate for long periods.
Perhaps because of failure of the mucociliary escalator,
mucus can be seen to accumulate around terminal bronchi­
oles focally. Markers of the mucus produced by bronchial
glands as opposed to goblet cells in more distal bronchioles,
Figure 44.9  This micrograph shows neutrophils (PMN) filling the lumen of
a small bronchiole in a sheep 48 hours after experimental smoke inhalation
injury. H&E stain.
Figure 44.10  This micrograph shows a bronchiole in human lung tissue
obtained at autopsy 7 days after a large flame burn. The lumen is almost
completely obstructed by a mixture of fibrin, mucus and neutrophils.
H&E stain.

Total Burn Care
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490
Urinary system
Patients with extensive burn injury, if resuscitated adequately
during the first few hours, may have normal renal function
throughout their hospital course. It is not uncommon,
however, especially when the initial fluid resuscitation was
not optimal, or when patients develop episodes of sepsis, for
acute renal failure to develop. In such cases the autopsy
frequently reveals evidence of acute tubular necrosis, the
morphologic expression of which depends on the timing of
the injury.40,88 The morphologic features of acute tubular
necrosis include edema of the entire kidney, with a substan­
tial increase in weight, and necrosis of proximal tubular cells
with karyolysis, karyorrhexis and sloughing of the injured
cells from the tubular basal lamina. Within 48 hours these
events are followed by evidence of regeneration of surviving
cells of the renal tubule, which flatten, become basophilic,
and undergo mitosis as they migrate to reconstitute the
epithelial lining. Clinical renal failure was an independent
factor associated with increased mortality in the analysis of
prognostic factors in patients with >80% TBSA burns in our
institution.89 Patients with renal failure seem to be at espe­
cially high risk for the infectious complications of burn
injury.
Digestive system and hepatobiliary tract
The association of duodenal ulcers with burn injury,
described by Curling, is a classic lesion that still occurs in
patients with burn injury, although its incidence is low,
probably as a result of routine treatment of burn patients
with inhibitors of gastric acid secretion.90 Local mucosal
necrosis and hemorrhage, an early manifestation of this
process, is seen with some frequency. Such defects in the
mucosa are often multiple, typically small and round, and
can be associated with significant hemorrhage from the
exposed blood vessels deep to the lesion. They heal rapidly
and rarely lead to serious complications.
The intestinal tract is especially susceptible to ischemic
and hypoxic injury, and lesions related to poor perfusion are
often found at the time of autopsy. Decreased blood flow in
the splanchnic circulation is a well-established physiologic
consequence of endotoxemia.16,91 Thus sepsis is associated
with an increased risk of intestinal injury. Hypoxic or
ischemic injury of the intestinal epithelium, which may be
very limited, can lead to translocation of intestinal flora into
the mesenteric lymphatic circulation and into the portal
venous circulation.92–95 Additional factors favoring the escape
of bacteria from the intestine include alterations in the bac­
terial ecology of the gut.96 Thus hypotension and hypoxia
can also be causes of sepsis. In our autopsy experience the
formation of abscesses or foci of tissue infection in the
intestinal tract was uncommon, except when many organs,
including the skin, were heavily infected in patients with
generalized sepsis. The intestinal lesion most commonly
seen at autopsy is transverse streaks of hemorrhage in the
small intestine in a ‘ladder’ pattern, associated with focal
necrosis of folds of mucosa. This is called superficial hemor­
rhagic necrosis (Fig. 44.13).97 Perhaps surprisingly, perfora­
tion of the intestinal tract is an uncommon occurrence in
patients with burn injury. Occasional patients develop pseu­
domembranous colitis or ‘typhlitis,’ typically a consequence
Non-bacterial thrombotic endocarditis (marantic endocardi­
tis) has also been seen, and may also give rise to embolic
complications (Fig. 44.11). When the endocardial region of
the left ventricle is examined at autopsy, small foci of necro­
sis associated with local hemorrhage are often observed (Fig.
44.12). Contraction band necrosis is sometimes the only
evidence of myocardial injury. These lesions may represent
poor perfusion of a tissue with high metabolic demands
during terminal episodes of hypotension. In some cases they
may represent the effects of endogenous or exogenous adren­
ergic agents. Rona and his associates have demonstrated that
β-adrenergic agents, at high doses, stimulate the develop­
ment of small foci of myocyte necrosis and hemorrhage in
the subendocardial region of the heart.86,87 This mode of
injury is potentially preventable in burn patients.
Figure 44.12  This high-magnification micrograph of heart tissue shows
the presence of multiple contraction bands in cardiac myocytes, seen as
refractile dark red bands running across muscle fibers. This is an early
irreversible change that is seen early after ischemic injury causes lethal cell
injury, especially when the tissue is reperfused with blood. It can also be
seen in the setting of beta-adrenergic toxicity. H&E stain.
Figure 44.11  This micrograph of an H&E-stained cardiac valve shows a
deposit of fibrin on the tricuspid valve of a patient who died of sepsis and
had nonbacterial thrombotic (marantic) endocarditis diagnosed at autopsy.
Gram stains did not reveal any bacteria.

The burn problem: a pathologist’s perspective
491
be a consequence of reduced splanchnic blood flow in
patients with sepsis. Intracellular cholestasis is commonly
observed in patients with burn injury. The basis for this
abnormality is not clear, although multiple physiologic
derangements could be expected to lead to cholestasis.99–101
Acute pancreatitis is found at autopsy in a sizable minority
of cases of fatal burns. Often necrosis and hemorrhage
appear out of proportion to the extent of acute inflamma­
tion. The pancreas is particularly vulnerable to the reduced
splanchnic blood flow that accompanies sepsis (Fig. 44.16).
Increased clinical suspicion of pancreatitis has led to assess­
ment of circulating amylase and lipase. On this basis, clinical
pancreatitis is not rare in our patient population, but is often
transient.
of infection by toxin-producing Clostridium difficile (Fig.
44.14). This complication can be minimized by judicious
use of antibiotics and screening for the toxin in stool when
pseudomembranous colitis is suspected.
The liver is enlarged in most autopsies of children who
succumb to burn injury, often to double or triple its normal
weight. Occasionally such hepatomegaly is thought to com­
promise ventilation.98 Steatosis is often found at autopsy
(Fig. 44.15). The degree of steatosis is often mild, however,
even in the presence of massive hepatomegaly. Interestingly,
analysis of the lipid content of liver obtained at autopsy
documented the presence of excess lipid but showed that its
quantity was far too small to account for the increase in
weight of the liver.99 Congestion of the liver is also frequently
seen at autopsy, often with centrilobular necrosis, which may
Figure 44.13  This low-power micrograph shows a transverse mucosal fold
in the jejunum of a patient who was septic and hypotensive for several days
prior to death. The mucosal fold at the top is necrotic and shows no nuclear
staining, while the remainder of the intestinal mucosa and wall are intact
but show submucosal hemorrhage. H&E stain.
Figure 44.14  This picture shows dark green to black discoloration of
patches elevated above the surrounding mucosa in the cecum of a patient
who had intestinal distension and occult blood in the stools. This is a typical
appearance of pseudomembranous colitis. H&E stain.
Figure 44.15  This micrograph shows liver tissue in which almost every cell
contains one or several large pale vacuoles that are the sites where lipid was
stored within hepatocytes. Steatosis or fatty metamorphosis is consistently
seen in the liver at autopsy, but may not account for the increase in size
and mass of the liver. This patient was 6 years old and lived for one month
after injury. His liver was 2.2 times the normal weight. H&E stain.
Figure 44.16  This is a cross section of the pancreas obtained at autopsy.
The patient died after a long course of sepsis. The bright yellow flecks
represent fat necrosis with saponification of fatty acids liberated by
pancreatic lipases, and patchy hemorrhage is visible within and around the
gland.

Total Burn Care
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Musculoskeletal system
Lesions of skeletal muscle are uncommon in burn patients,
but are ominous when they occur. Occasionally, direct
thermal injury extends into deep muscle, and at times this
injury can be so severe that adequate debridement is not
practical. Electrical injury is not uncommonly associated
with extensive necrosis of muscle. When invasive bacterial
or fungal infection extends into muscle, again, it may not be
feasible to treat adequately by excision of the infected tissue,
and the infection may be resistant to antibiotic therapy and
likely to disseminate. Atrophy of skeletal muscle occurs as
part of the catabolic state of burn patients, and represents a
challenge for those involved in rehabilitative efforts.
Central nervous system
When the brain and spinal cord are examined carefully at
autopsy, abnormalities can be found in the great majority of
patients who die after burn injury. The commonest lesion is
degeneration or loss of neurons in the portions of the cortex
most susceptible to hypoxic and ischemic injury. These
lesions can be a result of hypovolemia during resuscitation,
shock developing as part of the syndrome of sepsis, or as
a consequence of respiratory failure. Of course, extensive
hypoxic brain injury may occur in patients who are asphyxi­
ated during the initial burn injury. Some patients, especially
those who require cardiopulmonary resuscitation at the
scene of injury, develop massive cerebral edema and brain
death several days after the initial injury, reflecting the
response to extensive hypoxic/ischemic injury in the brain.
Severe hypoxic brain injury also can occur in burn patients
who are deprived of oxygen during the progress of a house
fire, or who are poisoned by carbon monoxide at the scene
of the burn. Occasionally prolonged delay in fluid resuscita­
tion of a patient with a large burn is associated with hypoxic/
ischemic brain injury and brain death. Another special case
Lymphoid system
Depletion of lymphocytes from lymphoid tissues through­
out the body is a consistent feature seen at autopsy in
patients with burn injury. The abnormalities were well
described by Linares in 1978.102 The thymus is consistently
very small, even in young children. The lymph nodes often
lack germinal centers, and may be strikingly depleted of
lymphocytes. Sinus histiocytosis is often present, and pyron­
inophilic cells resembling plasma cells are often prominent
in the portions of the node normally occupied by B cells.
The splenic white pulp is deficient, sometimes strikingly so.
The gastrointestinal lymphoid tissue of the terminal ileum
is generally atrophic, in spite of its normal prominence in
children, and the appendix often shows a striking lack
of normal lymphoid tissue in its wall (Fig. 44.17).
These abnormalities of lymphoid tissue correlate with
the deficient immune response typical of patients with
extensive burn injury. To some extent they may represent
the effects of high levels of endogenous glucocorticoids in
burn patients.
Endocrine system
Although abnormalities of the endocrine organs are some­
times observed in autopsies of burn patients, their incidence
does not seem to differ greatly from that in the general
population. Excessive secretion of glucocorticoids and of
epinephrine by the adrenal gland is characteristic of the
prolonged hypermetabolic response to burns. Morphologic
evidence of lipid depletion of the adrenal cortex has not
been seen in our experience. In one interesting case, reactiva­
tion of neonatal infection with herpes simplex virus type II
occurred in a young child with a large burn, leading to exten­
sive skin injury and graft loss. Focal necrotic lesions were
found in the adrenal cortex that were labeled by an immu­
nostain for herpes simplex, indicating that dissemination of
the infection had occurred (Figure 44.18).
Figure 44.18  This micrograph is an immunohistochemical stain for herpes
simplex virus type II of the adrenal cortex of a child who had extensive skin
infection and injury due to reactivation of a neonatal herpes infection. The
dark brown material is reaction product that was not seen when the
antibody was omitted. Multiple small necrotic lesions were seen in the liver
and adrenal glands.
Figure 44.17  This low-magnification micrograph shows a cross-section of
the appendix. There is striking depletion of the amount of blue-staining
lymphoid tissue that normally makes up the bulk of the surface of a section
of the appendix. H&E stain.

The burn problem: a pathologist’s perspective
493
pathogenesis of the disease processes of importance in an
individual patient. When approached in this way, investiga­
tion of patient deaths becomes a valuable learning experi­
ence for all those who participate in it. Not infrequently,
unexpected lesions are found which were likely to have
been significant in the patient’s course. Of course, the
circumstances of burn injury may have legal implications,
and documentation of the patient’s injuries and careful
interpretation of the hospital course can have the beneficial
effect of providing factual evidence where only supposition
would be available otherwise. Several recent publications
have confirmed the continuing usefulness of autopsy, espe­
cially in the setting of burn trauma.103–107 We advocate a
policy of carrying out complete autopsies on all patients who
die after burn injury, whenever possible, including micro­
scopic study and consultation with specialists, in collabora­
tion with the local medical examiner or coroner.
Further reading
Barrow RE, Hawkins HK, Aarsland A, et al. Identification of factors
contributing to hepatomegaly in severely burned children. Shock.
2005 Dec;24(6):523-528.
Cox RA, Mlcak RP, Chinkes DL, et al. Upper airway mucus deposition
in lung tissue of burn trauma victims. Shock. 2008 Mar;29(3):
356-361.
Linares HA. A report of 115 consecutive autopsies in burned children:
1966–80. Burns. 1981;8:263-270.
Pereira CT, Barrow RE, Sterns AM, et al. Age-dependent differences in
survival after severe burns: a unicentric review of 1,674 patients
and 179 autopsies over 15 years. J Am Coll Surg. 2006 Mar;202(3):
536-548.
Kallinen O, Partanen TA, Maisniemi K, et al. Comparison of
premortem clinical diagnosis and autopsy findings in patients with
burns. Burns. 2008 Aug;34(5):595-602.
is the patient who has direct thermal injury to the brain.
Such lesions, which occur occasionally in young children,
can be detected by radiologic imaging studies, and are rep­
resented at autopsy by small foci of tissue necrosis on the
cortical surface, surrounded by a hyperemic reaction.
The burn autopsy
As long as patients continue to develop complications of
burn injury which are difficult to manage, and as long as the
pathogenesis of these complications remains uncertain,
careful postmortem examination of patients who do not
survive will continue to contribute to patient care. There is
a paradox here. Tissue injury occurs due to elevated tempera­
ture, a very simple physical alteration. However, there is no
disease with more complex clinical and physiopathologic
derangements than an extensive burn. Observations made at
the time of autopsy often clarify the nature of the problems
that have led to the patient’s demise. Sometimes the findings
lead to suggestions for changes in procedure that may lead
to improved patient safety. Very often a review of recent
deaths effectively reminds the staff of the importance of
measures to prevent wound infection. Often a causal
sequence of events can be reconstructed by including the
clinical evidence, including cultures with sensitivity testing
and metabolic profiling, and the autopsy findings. Infectious
processes, for example, often can be traced from their sites
of origin, in the skin or elsewhere, to the fatal conclusion.
The emergence of unusually resistant bacterial strains can be
traced. The autopsy should always be approached from the
point of view of using both clinical and autopsy evidence to
better understand the reactions of the patient to the burn
injury and to the treatments provided. In other words, the
burn autopsy can provide not only an appropriate morpho­
logic analysis, but also a dynamic interpretation of the
 
Access the complete reference list online at

The burn problem: a pathologist’s perspective
493.e1
© Copyright 2012 Elsevier, Inc. All rights reserved.
References
1. Long J. Post-mortem appearances found after burns. Lond Med
Gaz. 1840;25:743-750.
2. Harkins HN. Experimental burns. I. The rate of fluid shift and
its relation to the onset of shock in severe burns. Arch Surg.
1935;31:71-85.
3. Underhill FP, Kapsinow R, Fisk M. Studies on the mechanism
of water exchange in the animal organism. Am J Physiol.
1930;95:302-314.
4. Cope O, Moore FD. The redistribution of body water and the
fluid therapy of the burned patient. Ann Surg. 1947;126:
1010-1045.
5. Evans EI, Purnell OJ, Robinett PW, et al. Fluid and electrolyte
requirements in severe burns. Ann Surg. 1952;135:804-817.
6. Demling RH. Fluid replacement in burned patients. Surg Clin
North Am. 1987;67:15-30.
7. Justis DL, Law EJ, MacMillan BG. Tibial compartment syndromes
in burn patients. A report of four cases. Arch Surg. 1976 Sep;
111(9):1004-1008.
8. Rosen CL, Adler JN, Rabban JT, et al. Early predictors of
myoglobinuria and acute renal failure following electrical injury.
J Emerg Med. 1999 Sep;17(5):783-789.
9. Aub JC, Beecher HKCB, et al. Management of the Coconut Grove
Burns at the Massachusetts General Hospital. 1943.
10. Horton JW. Free radicals and lipid peroxidation mediated injury
in burn trauma: the role of antioxidant therapy. Toxicology. 2003
Jul 15;189(1–2):75-88.
11. Meneshian A, Bulkley GB. The physiology of endothelial
xanthine oxidase: from urate catabolism to reperfusion injury to
inflammatory signal transduction. Microcirculation. 2002
Jul;9(3):161-175.
12. Sakano T, Okerberg CV, Shippee RL, et al. A rabbit model of
inhalation injury. Journal of Trauma: Injury and Critical Care.
1993;34:411-416.
13. Clements Jr NC, Habib MP. The early pattern of conjugated
dienes in liver and lung after endotoxin exposure. Am J Respir
Crit Care Med. 1995 Mar;151(3 Pt 1):780-784.
14. Linares HA. Sepsis, disseminated intravascular coagulation and
multiorgan failure: catastrophic events in severe burns. In: Schlag
G, Redl H, Siegel JH, Traber DL, eds. Shock, Sepsis, and Organ
Failure. Berlin: Springer-Verlag; 1991:370-398.
15. Linares HA. A report of 115 consecutive autopsies in burned
children: 1966–80. Burns. 1981;8:263-270.
This classic paper describes many features of severe burn injury that
are still found when autopsies are done on young patients who die
after burns.
16. Teplitz C. The pathology of burns and the fundamentals of burn
wound sepsis. In: Atrz CL, Moncrief JA, Pruitt BA, eds. Burns.
1979;45.
17. Bone RC, Sibbald WJ, Sprung CL. The ACCP-SCCM consensus
conference on sepsis and organ failure. Chest. 1992;101:
1481-1482.
18. Fredholm B, Hagermark O. Studies on histamine release from
skin and from peritoneal mast cells of the rat induced by heat.
Acta Derm Venereol. 1970;50:273-277.
19. Horakova Z, Beaven MA. Time course of histamine release and
edema formation in the rat paw after thermal injury. Eur J
Pharmacol. 1974;27:305-312.
20. Olsson P. Clinical views on the kinin system. Scand J Clin Lab
Invest. 1969;24:123-124.
21. Effeney DJ, Blaisdell FW, McIntyre KE, et al. The relationship
between sepsis and disseminated intravascular coagulation.
Journal of Trauma: Injury and Critical Care. 1978 Oct;18(10):
689-695.
22. Cox RA, Mlcak RP, Chinkes DL, et al. Upper airway mucus
deposition in lung tissue of burn trauma victims. Shock. 2008
Mar;29(3):356-361.
This recent paper reports study of human autopsy tissue from the
viewpoint gained from extensive experience analyzing tissues from
sheep after experimental smoke inhalation injury. Airway obstruction
was found to be frequent and focally severe.
23. Wisplinghoff H, Perbix W, Seifert H. Risk factors for nosocomial
bloodstream infections due to Acinetobacter baumannii: a
case-control study of adult burn patients. Clin Infect Dis. 1999
Jan;28(1):59-66.
24. Wurtz R, Karajovic M, Dacumos E, Nosocomial infections in a
burn intensive care unit. Burns. 1995 May;21(3):181-184.
25. Depuydt PO, Blot SI, Benoit DD, et al. Antimicrobial resistance
in nosocomial bloodstream infection associated with
pneumonia and the value of systematic surveillance cultures in
an adult intensive care unit. Crit Care Med. 2006 Mar;34(3):
653-659.
26. Murray CK, Loo FL, Hospenthal DR, et al. Incidence of systemic
fungal infection and related mortality following severe burns.
Burns. 2008 Dec;34(8):1108-1112.
27. Franco DM, Aronson JF, Hawkins HK, et al. Systemic Pythium
insidiosum in a pediatric burn patient. Burns. 2010 Aug;36(5):
e68-e71.
28. Curreri PW, Kak AF, Dotin LN, et al. Coagulation abnormalities
in the thermally injured patient. In: Skinner DB, Ebert PA, eds.
Current Topics in Surgical Research. New York and London:
Academic Press; 1970.
29. McManus WF, Eurenius K, Pruitt BA. Disseminated intravascular
coagulation in burned patients. Journal of Trauma: Injury and
Critical Care. 1973;13:416-422.
30. Alkjaersig N, Fletcher AP, Peden JC, et al. Fibrinogen catabolism
in burned patients. Journal of Trauma: Injury and Critical Care.
1980;20:154-159.
31. Bick R. Disseminated intravascular coagulation and related
syndromes: a clinical review. Semin Thromb Hemost. 1988;14:
299-337.
32. Niedermayr M, Schramm W, Kamolz L, et al. Antithrombin
deficiency and its relationship to severe burns. Burns. 2007
Mar;33(2):173-178.
33. Lavrentieva A, Kontakiotis T, Bitzani M, et al. The efficacy of
antithrombin administration in the acute phase of burn injury.
Thromb Haemost. 2008 Aug;100(2):286-290.
34. Watanabe T., Imamura T, Nakagaki K, et al. Disseminated
intravascular coagulation in autopsy cases: its incidence and
clinico-pathologic significance. Pathol Res Pract. 1979;165:
311-322.
35. Papp A, Kiraly K, Harma M, et al. The progression of burn depth
in experimental burns: a histological and methodological study.
Burns. 2004 Nov;30(7):684-690.
36. Mileski WJ, Borgstrom D, Lightfoot E, et al. Inhibition of
leukocyte-endothelial adherence following thermal injury. J Surg
Res. 1992;52:334-339.
37. Schnell LG, Danks RR. Massive Marjolin’s ulcer in a burn graft
site 46 years later. J Burn Care Res. 2009 May;30(3):533-535.
38. Kowal-Vern A, Criswell BK. Burn scar neoplasms: a literature
review and statistical analysis. Burns. 2005 Jun;31(4):403-413.
39. Theopold C, Hoeller D, Velander P, et al. Graft site malignancy
following treatment of full-thickness burn with cultured
epidermal autograft. Plast Reconstr Surg. 2004 Oct;114(5):
1215-1219.
40. Linares HA. Autopsy findings in burned children. In: Carvajal
HF, Parks DH, eds. Burns in Children. Chicago: Year Book
Medical Publishers; 1988.
41. Teplitz C, Davis D, Mason AD, et al. Pseudomonas burn wound
sepsis. 1. Pathogenesis of experimental pseudomonas burn
wound sepsis. J Surg Res. 1964;4:200-222.
42. Eldridge JP, Baldridge ED, MacMillan BG. Ecthyma gangrenosum
in a burned child. Burns Incl Therm Inj. 1986 Dec;12(8):578-585.
43. Jones SG, Olver WJ, Boswell TC, et al. Ecthyma gangrenosum.
Eur J Haematol. 2002 Nov;69(5–6):324.

Total Burn Care
44
493.e2
© Copyright 2012 Elsevier, Inc. All rights reserved.
44. Demling RH, Wong C, Jin LJ, et al. Early lung dysfunction after
major burns: role of edema and vasoactive mediators. Journal of
Trauma: Injury and Critical Care. 1985;25:959-966.
45. Clowes GHA, Zuschneid W, Dragacevic S, et al. The nonspecific
pulmonary inflammatory reactions leading to respiratory failure
after shock, gangrene and sepsis. Journal of Trauma: Injury and
Critical Care. 1968;8:899-914.
46. Swank DW, Moore SB. Roles of the neutrophil and other
mediators in adult respiratory distress syndrome. Mayo Clin Proc.
1989 Sep;64(9):1118-1132.
47. Mulligan MS, Smith CW, Anderson DC, et al. Role of leukocyte
adhesion molecules in complement-induced lung injury.
J Immunol. 1993;150:2401-2406.
48. Huie RE, Padmaja S. The reaction of NO with superoxide. Free
Rad R. 1993;18:195-199.
49. Cooper JA, Solano SJ, Bizios R, et al. Pulmonary neutrophil
kinetics after thrombin-induced intravascular coagulation. J Appl
Physiol: Respirat Environ Exercise Physiol. 1984;57:826-832.
50. Lentz LA, Ziegler ST, Cox CS, et al. Cytokine response to thermal
injury, shock sepsis and organ failure, The second Wiggers
Bernard Conference. In: Schlag G, Redl H, Siegel JH, Traber DL,
eds. Shock, Sepsis, and Organ Failure. New York: Springer-Verlag;
1993:245-264.
51. Lin YS, Kou YR. Acute neurogenic airway plasma exudation and
edema induced by inhaled wood smoke in guinea pigs: role of
tachykinins and hydroxyl radical. Eur J Pharmacol. 2000 Apr
7;394(1):139-148.
52. Siney L, Brain SD. Involvement of sensory neuropeptides in the
development of plasma extravasation in rat dorsal skin following
thermal injury. Br J Pharmacol. 1996 Mar;117(6):1065-1070.
53. Fukushima M, King LS, Kang KH, et al. Lung mechanics and
airway reactivity in sheep during development of oxygen toxicity.
J Appl Physiol. 1990 Nov;69(5):1779-1785.
54. Moran JF, Robinson LA, Lowe JE, et al. Effects of oxygen toxicity
on regional ventilation and perfusion in the primate lung.
Surgery. 1981 May;89(5):575-581.
55. Barazzone C, Horowitz S, Donati YR, et al. Oxygen toxicity in
mouse lung: pathways to cell death. Am J Respir Cell Mol Biol.
1998 Oct;19(4):573-581.
56. Barrow RE, Spies M, Barrow LN, et al. Influence of demographics
and inhalation injury on burn mortality in children. Burns. 2004
Feb;30(1):72-77.
57. Kobayashi K, Ikeda H, Higuchi R, et al. Epidemiological and
outcome characteristics of major burns in Tokyo. Burns. 2005
Jan;31(suppl 1):S3-S11.
58. Muller MJ, Pegg SP, Rule MR. Determinants of death following
burn injury. Br J Surg. 2001 Apr;88(4):583-587.
59. Suzuki M, Aikawa N, Kobayashi K, et al. Prognostic implications
of inhalation injury in burn patients in Tokyo. Burns. 2005
May;31(3):331-336.
60. Tredget EE, Shankowsky HA, Taerum TV, et al. The role of
inhalation injury in burn trauma. A Canadian experience. Ann
Surg. 1990 Dec;212(6):720-727.
61. Linares HA, Herndon DN, Traber DL. Sequence of morphologic
events in experimental smoke inhalation. J Burn Care Rehab.
1989;10:27-37.
62. Herndon DN, Traber DL, Niehaus GD, et al. The
pathophysiology of smoke inhalation injury in a sheep model.
J Trauma. 1984 Dec;24(12):1044-1051.
63. Murakami K, Traber DL. Pathophysiological basis of smoke
inhalation injury. News Physiol Sci. 2003 Jun;18:125-129.
64. Soejima K, Schmalstieg FC, Sakurai H, et al. Pathophysiological
analysis of combined burn and smoke inhalation injuries in
sheep. Am J Physiol Lung Cell Mol Physiol. 2001 Jun;280(6):
L1233-L1241.
65. Abdi S, Evans MJ, Cox RA, et al. Inhalation injury to tracheal
epithelium in an ovine model of cotton smoke exposure. Early
phase (30 minutes). Am Rev Respir Dis. 1990;142:1436-1439.
66. Abdi S, Herndon DN, McGuire J, et al. Time course of
alterations in lung lymph and bronchial blood flows after
inhalation injury. J Burn Care Rehabil. 1990;11:510-515.
67. Stothert Jr JC, Ashley KD, Kramer GC, et al. Intrapulmonary
distribution of bronchial blood flow after moderate smoke
inhalation. J Appl Physiol. 1990 Nov;69(5):1734-1739.
68. Cox RA, Burke AS, Soejima K, et al. Airway obstruction in sheep
with burn and smoke inhalation injuries. Am J Respir Cell Mol
Biol. 2003 Sep;29(3 Pt 1):295-302.
69. Enkhbaatar P, Traber DL. Pathophysiology of acute lung injury
in combined burn and smoke inhalation injury. Clin Sci (Lond).
2004 Aug;107(2):137-143.
70. Veronesi B, Carter JD, Devlin RB, et al.. Neuropeptides and
capsaicin stimulate the release of inflammatory cytokines in a
human bronchial epithelial cell line. Neuropeptides. 1999
Dec;33(6):447-456.
71. Zimmerman BJ, Anderson DC, Granger DN. Neuropeptides
promote neutrophil adherence to endothelial cell monolayers.
Am J Physiol. 1992;263:G678-G682.
72. Lentz CW, Abdi S, Traber LD. The role of sensory neuropeptides
in inhalation injury. Pro Amer Burn Assoc. 1992;10:27-37.
73. Kunkel SL, Standiford TJ, Kasahara K, et al. Interleukin-8 (IL-8):
The major neutrophil chemotactic factor in the lung. Exp Lung
Res. 1991;17:17-23.
74. Enkhbaatar P, Murakami K, Shimoda K, et al. Inhibition of
neuronal nitric oxide synthase by 7-nitroindazole attenuates
acute lung injury in an ovine model. Am J Physiol Regul Integr
Comp Physiol. 2003 Aug;285(2):R366-R372.
75. Enkhbaatar P, Murakami K, Shimoda K, et al. The inducible
nitric oxide synthase inhibitor BBS-2 prevents acute lung injury
in sheep after burn and smoke inhalation injury. Am J Respir Crit
Care Med. 2003 Apr 1;167(7):1021-1026.
76. Cox RA, Soejima K, Burke AS, et al. Enhanced pulmonary
expression of endothelin-1 in an ovine model of smoke
inhalation injury. J Burn Care Rehabil. 2001 Nov;22(6):
375-383.
77. Cox RA, Enkhabaatar P, Burke AS, et al. Effects of a dual
endothelin-1 receptor antagonist on airway obstruction and
acute lung injury in sheep following smoke inhalation and burn
injury. Clin Sci (Lond). 2005 Mar;108(3):265-272.
78. Shimoda K, Murakami K, Enkhbaatar P, et al. Effect of poly
(ADP ribose) synthetase inhibition on burn and smoke
inhalation injury in sheep. Am J Physiol Lung Cell Mol Physiol.
2003 Jul;285(1):L240-L249.
79. Cox RA, Burke AS, kazutaka S, et al. Airway obstruction in sheep
with burn and smoke inhalation injuries. Am J Respir Cell Mol
Biol. 2003 29:295-302.
Ref Type: Journal (Full)
80. Murakami K, McGuire R, Cox RA, et al. Recombinant
antithrombin attenuates pulmonary inflammation following
smoke inhalation and pneumonia in sheep. Crit Care Med. 2003
Feb;31(2):577-583.
81. Murakami K, McGuire R, Cox RA, et al. Heparin nebulization
attenuates acute lung injury in sepsis following smoke
inhalation in sheep. Shock. 2002 Sep;18(3):236-241.
82. Enkhbaatar P, Traber DL. Pathophysiology of acute lung injury
in combined burn and smoke inhalation injury. Clin Sci (Lond).
2004 Aug;107(2):137-143.
83. Murakami K, Traber DL. Pathophysiological basis of smoke
inhalation injury. News Physiol Sci. 2003 Jun;18:125-129.
84. Fracasso T, Schmeling A. Delayed asphyxia due to inhalation
injury. Int J Legal Med. 2010 May;18.
85. Pereira CT, Barrow RE, Sterns AM, et al. Age-dependent
differences in survival after severe burns: a unicentric review of
1,674 patients and 179 autopsies over 15 years. J Am Coll Surg.
2006 Mar;202(3):536-548.
This recent paper thoroughly surveys the findings in autopsies of
children who died after burns, and highlights some unexpected
observations.

The burn problem: a pathologist’s perspective
493.e3
© Copyright 2012 Elsevier, Inc. All rights reserved.
86. Rona G, Boutet M, Huttner I, et al. Pathogenesis of
isoproterenol-induced myocardial alterations: functional and
morphological correlates. Recent Adv Stud Cardiac Struct Metab.
1973;3:507-525.
87. Kahn DS, Rona G, Chappel CI. Isoproterenol-induced cardiac
necrosis. Ann N Y Acad Sci. 1969 Jan 31;156(1):285-293.
88. Martineau PP, Hartman FW. The renal lesions in extensive
cutaneous burns. JAMA. 1947;134:429-436.
89. Wolf SE, Rose JK, Desai MH, et al. Mortality determinants in
massive pediatric burns. An analysis of 103 children with > or =
80% TBSA burns (> or = 70% full-thickness). Ann Surg. 1997
May;225(5):554-565.
90. Curling TB. On acute ulceration of duodenum in cases of burn.
Trans R Med Chir Soc Lond. 1842;25:260-281.
91. Fronek K, Zweifach BW. Changes of splanchnic hemodynamics
in hemorrhagic hypotension and endotoxemia. J Surg Res. 1971
May;11(5):232-237.
92. Berg RD, Garlington AW. Translocation of certain indigenous
bacteria from the gastrointestinal tract to the mesenteric lymph
nodes and other organs in a gnotobiotic mouse model. Infect
Immun. 1979;23:403-411.
93. Deitch EA, Berg R. Bacterial translocation from the gut: a
mechanism of infection. J Burn Care Rehab. 1987;8:475-482.
94. Wells CL, Maddaus MA, Simmons RL. Proposed mechanisms for
the translocation of intestinal bacteria. Rev Infect Dis.
1988;10:958-979.
95. Baker JW, Deitch EA, Berg RD, et al. Hemorrhagic shock induces
bacterial translocation from the gut. Journal of Trauma: Injury and
Critical Care. 1988;28:896-906.
96. Berg RD, Wommack E, Deitch EA. Immunosuppression and
intestinal bacterial overgrowth synergistically promote bacterial
translocation. Arch Surg. 1988;123:1359-1364.
97. Ahren C, Haglund V. Mucosal lesions in the small intestine
of the cat during low flow. Acta Physiol Scand. 1973;88:541-550.
98. Barrow RE, Mlcak R, Barrow LN, et al. Increased liver weights in
severely burned children: comparison of ultrasound and autopsy
measurements. Burns. 2004 Sep;30(6):565-568.
99. Barrow RE, Hawkins HK, Aarsland A, et al. Identification of
factors contributing to hepatomegaly in severely burned
children. Shock. 2005 Dec;24(6):523-528.
The massive hepatomegaly that is consistently found at autopsy in
patients who die weeks after their initial burn is a biological problem
still seeking an explanation.
100. Hurd T, Lysz T, Dikdan G, et al. Hepatic cellular dysfunction in
sepsis: an ischemic phenomenon? Curr Surg. 1988;45:114-119.
101. Cano N, Gerolami A. Intrahepatic cholestatsis during total
parenteral nutrition. Lancet. 1983;1:985.
102. Linares HA, Beathard GA, Larson DL. Morphological changes of
lymph nodes of children following acute thermal burns. Burns.
1978;4:165-170.
103. D’Avignon LC, Hogan BK, Murray CK, et al. Contribution of
bacterial and viral infections to attributable mortality in patients
with severe burns: an autopsy series. Burns. 2010 Sep;36(6):
773-779.
104. Gomez R, Murray CK, Hospenthal DR, et al. Causes of mortality
by autopsy findings of combat casualties and civilian patients
admitted to a burn unit. J Am Coll Surg. 2009 Mar;208(3):
348-354.
105. Kallinen O, Partanen TA, Maisniemi K, et al. Comparison of
premortem clinical diagnosis and autopsy findings in patients
with burns. Burns. 2008 Aug;34(5):595-602.
This paper from Finland compares clinical diagnoses with autopsy
findings in burn patients and emphasizes the value of a high autopsy
rate in these cases.
106. Silfvast T, Takkunen O, Kolho E, et al. Characteristics of
discrepancies between clinical and autopsy diagnoses in the
intensive care unit: a 5-year review. Intensive Care Med. 2003
Feb;29(2):321-324.
107. Bloemsma GC, Dokter J, Boxma H, Oen IM. Mortality and
causes of death in a burn centre. Burns. 2008 Dec;34(8):
1103-1107.

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©2012 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2786-9.00045-X
Molecular and cellular basis of
hypertrophic scarring
Peter Kwan, Alexis Desmoulière, Edward E. Tredget
Introduction
Clinically, post-burn hypertrophic scars (HTS) are elevated,
erythematous, pruritic, and inelastic.1 In addition to poor
cosmesis, these scars typically form contractures resulting in
dysfunction and discomfort, leading to significant morbidity
for burn patients (Fig. 45.1). Hypertrophic scar is fundamen­
tally different from normal skin and mature scar in several
key ways: 1) the extracellular matrix (ECM) of HTS is signifi­
cantly altered in both composition and architecture, 2) the
behavior of keratinocytes and fibroblasts present in hyper­
trophic scar is profibrotic compared to mature scar, and 3)
many profibrotic cytokines are upregulated and their expres­
sion prolonged. Generally, HTS undergoes some remodeling
and maturation over time and this may account for the vari­
ability in descriptions of HTS. Many features of HTS are
shared by other fibroproliferative disorders, including renal
fibrosis, pulmonary fibrosis, and scleroderma.2 Thus, under­
standing the pathophysiology of HTS applies to other areas
of medicine, and developments in treating various fibro­
proliferative diseases can directly affect scar management.
Since an exhaustive discussion of every nuance of abnormal
wound healing is impossible, we focus on aspects of HTS
formation highlighting well understood pathways or novel
developments. It is our hope that a deeper understanding of
abnormal wound healing pathophysiology and fibrosis will
lead to nonsurgical treatments that improve life not only for
burn patients, but for the many patients suffering fibrotic
diseases.
Extracellular matrix
Extracellular matrix in healing wounds is laid down by
fibroblasts and subsequently remodeled as the scar matures.
The ECM in HTS displays significant differences from mature
scar and normal skin, most notably in the arrangement and
composition of collagen bundles, and in the relative propor­
tions of several proteoglycans.3 Owing to the interaction of
fibroblasts and ECM these differences not only result from
abnormal fibroblast behavior but also contribute to it.4
Collagen
Collagen is the major constituent of ECM, providing a scaf­
fold for cells and mechanical strength to tissues. In HTS the
quantity of collagen per unit surface area is increased;5
however, the relative proportion of collagen in HTS is
decreased compared to normal skin owing to much greater
increases in proteoglycans and glycoproteins.3 In normal skin
the majority of collagen is type I (80%) with smaller amounts
of type III (10–15%) and type V (minimal) resulting in thick,
regular collagen fibril bundles running parallel to the skin
surface.6 In contrast, HTS is composed of greatly increased
amounts of type III (33%)7 and type V (10%)8 collagen, which
drastically alters collagen fibrils making them thinner6 and
disorganized.9 In normal wound healing, type III collagen
appears early then gradually disappears as the scar is remod­
eled and matures,10 but this does not occur in HTS where
persistently high levels reflect biological immaturity.11
Classic histologic descriptions of HTS highlight ‘whorls’
and ‘nodules’ of poorly organized collagen encapsulated in
more normal-appearing collagen fibrils,6 as seen in Figure
45.6. However, not only are collagen fibril composition and
morphology altered in HTS, but interfibrillar spacing is
also irregular and greatly increased.12 This space is filled
with proteoglycans and glycoproteins, whose composition is
markedly different from normal skin and mature scar.
Proteoglycans and glycoproteins
Proteoglycans are responsible for physical properties of skin
such as turgor, resilience, and resistance to compression,
resulting from their interaction with collagen. Proteoglycans
also modulate the activities of multiple growth factors and
cytokines. Glycoproteins, such as fibronectin, are generally
involved in cell–matrix adhesion and influence cell behavior
via this mechanism. Together, proteoglycans and glyco­
proteins are major constituents of skin, both physically and
functionally.
Proteoglycans are formed by a protein core, often with
repeating units such as leucine in decorin, and gly­
cosaminoglycan side chains.13 These side chains are ionized
and hydrophilic, and thus mainly responsible for tissue water
retention.14 Early studies of HTS demonstrated elevated gly­
cosaminoglycan levels,15 which are responsible for the hyper­
hydrated state of HTS leading to its classically increased
turgor. These levels of glycosaminoglycan are not uniformly
elevated. Instead, certain proteoglycans are downregulated
and others upregulated, with unique implications for HTS.
Decorin is a prototypical small, leucine-rich proteoglycan
(SLRP) produced in abundance in normal skin and mature
scar but reduced by 75% in HTS.3 Originally named for
‘decorating’ collagen fibrils, decorin affects wound healing
CHAPTER 45 
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IN THIS CHAPTER
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several cell surface receptor tyrosine kinases: EGFR,23
HGFR,24 and IGF1R,25 which reduces cellular proliferation
and migration. Decorin production increases significantly
as scars mature.26 In a mouse model of diabetes, renal fibro­
sis and nephropathy developed significantly faster in decorin
knockout than in wild-type mice.27 Similarly, upregulating
decorin production via an adenoviral vector in mouse
models of bleomycin-induced pulmonary fibrosis reduced
fibrosis.28
In contrast to decorin downregulation, two other
proteoglycans, biglycan, and versican, are significantly
via several distinct and complementary pathways. Decorin
binds to collagen fibrils, controlling their diameter, mor­
phology,16 and interfibrillar distance.17 In decorin knockout
mice collagen fibrils are irregular in morphology and have
highly variable diameters.18 Decorin binds to and inactivates
the profibrotic cytokines transforming growth factor-β (TGF-
β),19 and platelet-derived growth factor (PDGF).20 The effects
of this inactivation are most readily visible in fibroblast-
populated collagen lattices where decorin significantly
reduces contraction by normal and HTS fibroblasts.21,22
Decorin also binds to and antagonistically downregulates
Figure 45.1  Hypertrophic scarring in a 34-year-old white man, 8 months following a 60% total body surface area burn involving the face, upper extremities
and hands. (From Scott PG, Ghahary A, Chambers MM, Tredget EE. Biological basis of hypertrophic scarring. In: Malhotra SK, ed. Advances in Structural Biology, Vol. 3. Greenwich,
Connecticut: JAI Press, 1994; 157-202).
A
B
C
D

Molecular and cellular basis of hypertrophic scarring
497
process, leaving the healing wound in a hyperactive state
(Fig. 45.2).
Role of myofibroblasts in normal and
pathological situations
Myofibroblasts are cells that have acquired a phenotype
intermediate between fibroblasts and smooth muscle cells.
Presently, it is accepted that myofibroblast modulation of
fibroblastic cells begins with the appearance of precursor
proto-myofibroblasts, whose stress fibers contain only β-
and γ-cytoplasmic actins. These proto-myofibroblasts acquire
de novo contractile bundles whose stress fibers generate
sufficient forces to pull cells forward to populate tissue
spaces in a migration process and to pre-remodel the ECM.
Proto-myofibroblasts evolve, but not necessarily always, into
the differentiated myofibroblast.40 Fully differentiated myofi­
broblasts express α-smooth muscle actin (α-SMA), the actin
isoform present in typical contractile vascular smooth muscle
cells (Fig. 45.3). The presence of α-SMA is directly related to
the contractile activity of myofibroblasts. A direct correlation
has been demonstrated both in vitro and in vivo between
the level of α-SMA expression and myofibroblast contrac­
tion.41,42 Myofibroblasts also exhibit some similarities with
pericytes.43 In physiological conditions, after healing, myofi­
broblasts undergo apoptosis44 and only a few fibroblasts are
left to ensure renewal of the ECM.
Among the soluble factors, TGF-β1 is a potent inducer
of myofibroblast differentiation.45,46 TGF-β1 action on
upregulated in HTS. Biglycan is 57% similar to decorin in
amino acid sequence but with two dermatan sulfate chains,
and is believed to have originated as a gene duplication of
decorin.29 Despite these similarities, biglycan and decorin
have significantly different functions in vivo. Biglycan is
minimally present in normal skin but significantly upregu­
lated in fibrosis, yet does not compensate for the lack of
decorin.29,30 Versican is also significantly upregulated in HTS,
up to six times higher than in normal skin,3 where it is nor­
mally confined to the proliferating epidermis.31 As a large
proteoglycan with 12–30 glycosaminoglycans chains, versi­
can is most likely responsible for the increased hydration
and turgor leading to the increased volume of HTS.5
The most common glycoprotein in ECM is fibronectin,
which has effects on cell–matrix interaction via its interac­
tion with integrins. Although the role of fibronectin in HTS
is unclear, its upregulation in HTS,32 influence on the assem­
bly of other ECM proteins, and interaction with cellular
integrins33 suggest it too plays a role in fibroblast behavior
and HTS formation.
Cellular contributions to hypertrophic scar
Hypertrophic scar fibroblasts
Fibroblasts are the cells primarily responsible for ECM pro­
duction and remodeling in wound healing. Numerous
studies have demonstrated that dermal fibroblasts can be
divided into distinct subpopulations: superficial (papillary),
and deep (reticular), based on both physical location and
phenotype.34–36 When characteristics of superficial dermal,
deep dermal, and HTS fibroblasts are compared, as in Table
45.1, it becomes clear that HTS fibroblasts most closely
resemble deep dermal fibroblasts.36 These in vitro results
correlate directly with a clinically relevant dermal scratch
model developed by Dunkin and colleagues.37 In this model
a linear skin wound is created with depth that increases
along its length from no injury to full-thickness penetration.
This results in regeneration in the superficial portion (depth
≤0.56 mm) with minimal scar; whereas HTS formation
occurs in the deeper portion of the wound.37 Combining
these basic science and clinical observations with the ten­
dency of HTS to form following deep partial- to full-thickness
burns suggests two possible theories of HTS formation: 1)
selective proliferation of deep dermal fibroblasts after fibro­
genic cytokine stimulation, or 2) destruction of superficial
dermal fibroblasts by thermal injury, leaving only deep
dermal fibroblasts to repopulate the wound.38 Both theories
are consistent with an experimental model where human
skin was grafted onto the backs of nude mice and subse­
quently injured. In this model, deep dermal fibroblasts
closed wounds and superficial dermal fibroblasts then
remodeled them.39 It is possible that in deep burns superfi­
cial fibroblasts are not present to initiate this remodeling
Table 45.1  Superficial and deep dermal fibroblasts compared to
hypertrophic scar fibroblasts
Superficial
dermal
fibroblasts
Deep
dermal
fibroblasts
Hypertrophic
scar
fibroblasts
Collagen
production
↓
↑
↑
Collagenase
production
↑
↓
↓
Decorin
production
↑
↓
↓
TGF-β
production
↓
↑
↑
CTGF production
↓
↑
↑
Keratinocyte
proliferation
↑
↓
↓
Capillary
formation
↑
↓
↓
Figure 45.2  Injury below a critical depth in skin
leads to scarring. (From Kwan P, Hori K, Ding J, Tredget
EE. Scar and contracture: biological principles. Hand Clinics.
25(4): 511-28, 2009).
Scarring
Regeneration
Critical depth
Superficial
fibroblasts
Deep
fibroblasts

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been shown, in gingival fibroblasts, that α-SMA expression
induced by TGF-β1 is regulated by the compliance of col­
lagen gels on or in which they are cultured.54 The direct
effects of mechanical stress on fibroblasts can be easily
shown in culture using stressed fibroblast-populated colla­
gen lattices (Fig. 45.4). Moreover, myofibroblast differentia­
tion features, such as stress fibers, ED-A fibronectin or
α-SMA expression, appear earlier in granulation tissue sub­
jected to increased mechanical tension by splinting of the
full-thickness wound with a plastic frame than in normally
healing wounds.42 It has also been shown that fibroblasts
cultured on substrates of variable stiffness present different
phenotypes. Cultured fibroblasts do not express stress fibers
on soft surfaces, but when the stiffness of the substrate
increases a sudden change in cell morphology occurs and
stress fibers appear.55,56 Shear forces exerted by fluid flow are
also able to induce TGF-β1 production and differentiation
of fibroblasts cultured in collagen gels in the absence of
other external stimuli, such as cytokine treatment.57 Intercel­
lular mechanical coupling of stress fibers via adherens
junctions improves contraction of collagen gels by myofi­
broblasts.58 By assessing spontaneous intracellular Ca2+
oscillations, Follonier et al. have shown that intracellular
Ca2+ oscillations are coordinated between contacting myofi­
broblasts via adherens junctions, but randomly between
fibroblasts and non-contacting cells.59 They propose the fol­
lowing model of mechanical coupling for myofibroblasts:
individual cell contraction is transmitted via adherens junc­
tions and leads to opening of mechanosensitive ion chan­
nels in adjacent cells. The resulting Ca2+ influx induces a
contraction that can feed back on the first cell and/or stimu­
late other contacting cells working like a syncytium. This
mechanism could improve the remodeling of cell-dense
tissue by coordinating the activity of myofibroblasts.60
Pathological repair (hypertrophic scars
and keloids)
Pathological wound healing can result from impaired
remodeling of the granulation tissue, leading to abnormal
cutaneous repair in hypertrophic or keloid scars (Fig.
45.5). Keloid and HTS differ in their expression of α-SMA;
indeed, in keloids, no α-SMA is observed, although proto-
myofibroblasts could account for large amounts of extracel­
lular matrix but are unable to contract, whereas numerous
myofibroblasts express this protein in HTS, explaining the
fact that contracture often appears specifically in HTS.38,61
Thus, the use of α-SMA to differentiate HTS and keloids has
been proposed.62 The presence of contractile myofibroblasts
in HTS is responsible for the formation of contractures that
interfere with function and may require extensive recon­
structive surgery (Fig. 45.6). Moreover, keloids contain thick
collagen fibres, whereas HTS contain thin fibres organized
in nodules.61,63 It emphasizes that the different processes
involved in collagen maturation together with the effects
of the matrix metalloproteinase (MMP)/tissue inhibitor of
MMP(TIMP) system play an important role in excessive scar
formation. The expression of lysyl hydroxylase (LH)-2b, a
splice variant of LH-2, an enzyme involved in the cross-
linking of the collagen fibrils, has been linked to fibrotic
development occurring in pathologic situations.64 Animal
myofibroblast differentiation is only possible in the presence
of ED-A fibronectin, which underlines the fact that ECM
components play an important role in soluble factor activ­
ity.48 Granulocyte–macrophage colony-stimulating factor
stimulates macrophage proliferation and myofibroblast dif­
ferentiation, thereby promoting granulation tissue forma­
tion.49,50 Endothelin has also a positive effect on differentiation
and activation of myofibroblasts. This peptide also induces
myofibroblast contraction and migration.51 More recently, it
has been shown that granulation tissue formation is modi­
fied by chemical denervation.52 This peripheral nervous
system involvement in tissue repair has likewise been
shown in the liver; in this organ, in an experimental model
of fibrosis using carbon tetrachloride treatment, chemical
denervation significantly reduces matrix deposition and
myofibroblast differentiation.53
Role of mechanical stress and myofibroblasts
Myofibroblast cells, because of their contractile properties
and privileged relationships with ECM, can modify their
activity depending on the mechanical environment. It has
Figure 45.3  Schematic illustration showing the evolution of the (myo)
fibroblast phenotype. The myofibroblast modulation of fibroblastic cells
begins with the appearance of the proto-myofibroblast, whose stress fibers
contain only β- and γ-cytoplasmic actins and evolves, but not necessarily
always, into the appearance of the differentiated myofibroblast, the most
common variant of this cell, with stress fibers containing α-smooth muscle
actin. Myofibroblasts present a well developed rough endoplasmic
reticulum and are responsible for (excessive) deposition of extracellular
matrix (ECM); they also secrete matrix metalloproteinases (MMPs) and tissue
inhibitors of metalloproteinases (TIMPs), and are involved in granulation
tissue remodelling. Soluble factors, particularly transforming growth
factor-β1, associated with ECM components (e.g. fibronectin ED-A), play
important roles during myofibroblast differentiation. Mechanical
stress is also importantly involved in myofibroblast differentiation. The
myofibroblast can undergo apoptosis; the deactivation leading to a
quiescent phenotype has not been clearly demonstrated at least in vivo.
(From Desmoulière A, who retains copyright of the image).
Protomyofibroblast
Stress fibers expressing
β- and γ-cytoplasmic actins
Proliferation and migration
Myofibroblast
Stress fibers expressing
α-smooth muscle actin
Contraction and ECM
deposition
Fibroblast
Deactivation
Apoptosis
ECM
MMPs and
TIMPs/remodelling
Soluble factors
and ECM
components
Mechanical
stress
?

Molecular and cellular basis of hypertrophic scarring
499
Figure 45.4  Myofibroblast evolution in collagen gels. When myofibroblasts previously cultured in plastic dishes are incorporated in a floating collagen gel, a
high proportion rapidly undergo apoptosis (arrows). In contrast, when incorporated in an attached collagen gel, they show a typical elongated morphology,
express high amounts of α-smooth muscle actin, and proliferate. (From Coulomb B, Inserm U970, Université Paris Descartes, France and Desmoulière A who retains copyright of
the Images (unpublished data)).
A
B
C
D
E
F

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stress can maintain myofibroblast differentiation. It has
been shown that mechanical loading early in the prolifera­
tive phase of wound healing produces HTS by inhibiting
cellular apoptosis.69 In contrast, it is suggested that mechani­
cal challenge could be a clinically relevant strategy to improve
ischemic and chronic wound healing by supporting myo­
fibroblast formation.70 Interestingly, oncogenic-Ras-trans­
formed human fibroblasts lose growth factor selectivity and
cell matrix density-dependent inhibition of migration.71 In
the liver, and certain other organs, stiffness appears to result
from matrix cross-linking and possibly other unknown vari­
ables in addition to matrix quantity, suggesting that increased
stiffness may play an important role in initiating the early
stages of fibrosis.72 The epithelium could also be involved in
the development of excessive scarring.73 Hakvoort et al. have
shown that, in HTS, keratinocytes expressed an activated
CD36+ phenotype.74 They suggest that HTS formation is not
only due to dermal dysfunction, but is the result of a pertur­
bation affecting dermal–epidermal interactions involving
neurohormonal factors. Indeed, a ‘neurogenic inflammation
hypothesis’ has been suggested.75 Mechanical stress stimu­
lates mechanosensitive nociceptors in skin sensory fibers,
which release neuropeptides involved in vessel modifica­
tions and fibroblast activation.
Origin of (myo)fibroblasts
It is now accepted that myofibroblasts can originate from
various cell types, as illustrated in Figure 45.7. The majority
of these cells originate from local recruitment of connective
tissue fibroblasts. For example, in skin, dermal fibroblasts
located in the edges of the wound can acquire a myofibro­
blast phenotype and participate in tissue repair.76,77 In diffuse
cutaneous systemic sclerosis, microvascular pericytes consti­
tute a cellular link between microvascular damage and fibro­
sis by transdifferentiating into myofibroblasts.78 In the liver,
the role of hepatic perisinusoidal hepatic stellate cells has
been widely studied and their key role during fibrogenesis
has been clearly demonstrated.79 Recently, it has also been
shown that portal fibroblasts are involved in the formation
of portal septa.80 Vascular smooth muscle cells residing in
the walls of portal vein branches and portal arteries have
been implicated in fibrosis observed in chronic schisto­
somiasis.81 In the kidney, both mesangial cells and inter­
stitial fibroblasts of the medulla can acquire a myofibroblast
phenotype and participate in ECM deposition after
damage.82,83 Moreover, the involvement in tissue repair of
local mesenchymal stem cells is becoming better under­
stood. These progenitor cells have been described in the
dermal sheath that surrounds the outside of the hair follicle
facing the epithelial stem cells, constituting a niche of stem
cells. They are involved in the regeneration of the dermal
papilla and can also become wound healing (myo)fibro­
blasts after an injury.84 This concept of a cell association, able
to reconstitute the different organ cell populations and con­
stituting a niche of stem cells, is currently discussed in diverse
organs, notably the liver, in the periportal zone containing
Hering’s canals.85,86 Recent data have shown the implication
of circulating cells, called fibrocytes, in the tissue repair
process.90 Another type of circulating cell originating from
bone marrow participates in tissue repair. These mesenchy­
mal stem cells are bone marrow-derived non-hematopoietic
models mimicking this specific expression of LH-2b are
available and could be used to test new anti-scarring thera­
pies based on the inhibition of LH-2b.65 In these lesions, the
normal healing process cannot be achieved and granulation
tissue continues to grow, owing to an abnormal and exces­
sive secretion of growth factors and/or lack of molecules
inducing apoptosis or ECM remodeling. Interestingly, HTS
have an excess of microvessels, most of which are partially
or totally occluded due to a functional regression of endothe­
lial cells induced by (myo)fibroblast hyperactivity.66 In exces­
sive scarring a focal upregulation of p53 expression, which
probably inhibits apoptosis, has been observed. Extracellular
matrix modifications also seem to be an important factor in
induction of the apoptotic process. In vivo, covering granula­
tion tissue by a vascularized skin flap induces an upregula­
tion of MMP together with a decrease in TIMP, leading to a
rapid loss of granulation tissue cells by apoptosis.67 In vitro,
the matrix environment can modulate fibroblast apoptosis.
Furthermore, in HTS, the mechanical forces obtained by
compression of the scar are able to restore the classic organi­
zation observed in normal wounds and trigger the disap­
pearance of myofibroblasts by apoptosis.68 Thus, mechanical
Figure 45.5  Processes leading to normal repair or pathological scarring.
In normal tissue repair, myofibroblasts disappear by apoptosis during the
transition between granulation tissue and scar. In pathological situations,
myofibroblasts proliferate and participate in the excessive deposition of
extracellular matrix. In all these situations, not only interaction between
fibroblasts/myofibroblasts and extracellular matrix, but also the dialogue
between epithelial cells and mesenchymal cells play a major role. BM:
basement membrane; SMA: smooth muscle actin; ECM: extracellular matrix.
Modified from Sarrazy et al. (Wound Repair Regen. in press).
Epithelial cells
BM
Fibroblasts
Myofibroblasts
Growing and
migrating
epithelial cells
Abnormal
epithelial
cells?
Interaction
ECM
Resolution
(apoptosis and
matrix remodelling)
α-SMA
Repair
Scarring
Chronicity

Molecular and cellular basis of hypertrophic scarring
501
phenotype can be modulated by their interactions with
neighboring cells and ECM.95,96
The role of fibrocytes in hypertrophic scar
Fibrocytes are a bloodborne, CD14+ monocyte subpopula­
tion87 that mediate wound healing, first identified in 1994
by Bucala et al. in mouse wound chambers.97 Although origi­
nally defined as collagen+/vimentin+/CD34+ cells, other
accepted markers include combinations of collagen+ and
CD45+ or LSP1+ markers.88,98 Fibrocytes have been found in
normal wound healing87 and also a wide variety of fibrotic
diseases, including pulmonary fibrosis,99 renal fibrosis,100
and hypertrophic burn scars.88 Fibrocytes traffic to wounds
via a secondary lymphoid chemokine gradient, and differ­
entiate under the influence of T cells and TGF-β.87 It has been
noted that CD4+ T cells producing TGF-β are present in high
levels in burn wounds,101 where fibrocyte levels in burn
patients are also increased.102 In contrast, Pilling et al. dem­
onstrated that fibrocyte differentiation is blocked by serum
amyloid P (SAP), a constitutive plasma protein related to
C-reactive protein, by using SAP to inhibit fibrocytes in a
precursor cells91,92 which contribute to the maintenance and
regeneration of connective tissues through engraftment.
Indeed, they have the capacity to engraft into several organs
and to differentiate into wound healing myofibroblasts.
However, recently it has been suggested that fibroblasts/
myofibroblasts that participate in cutaneous wound
healing are not derived from circulating progenitor cells.93
Finally, epithelial- and endothelial-to-mesenchymal transi­
tion (EMT), a process by which differentiated (or malignant)
epithelial cells and endothelial cells undergo a phenotypic
conversion that gives rise to the matrix-producing fibroblasts
and myofibroblasts, is increasingly recognized as an integral
part of tissue fibrogenesis after injury, particularly in the
kidney94 and during stroma reaction formation. However,
the degree to which this process contributes to fibrosis and
stroma reaction in the skin remains a matter of intense
debate and is likely to be context dependent. Altogether,
mesenchymal stem cells, fibrocytes, bone marrow-derived
cells and cells derived from EMT, may represent alternative
sources of myofibroblasts when local fibroblasts are not able
to respond. These diverse cell types probably contribute
to the appearance of myofibroblast subpopulations whose
Figure 45.6  Myofibroblasts in hypertrophic scars. In hypertrophic scar nodules myofibroblasts express large amounts of α-smooth muscle actin (a and
b, immunohistochemistry for α-smooth muscle actin), and develop huge contractile activity in scars after burn injury (c, d) (From Desmoulière A, who retains
copyright of the images.) (c, d) (From Casoli P, Plastic Surgery and Burns Unit, University Hospital of Bordeaux, France, who retains copyright of the images).
A
B
C
D

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Hypertrophic scar keratinocytes
Keratinocytes are an important component of wound
healing. Classically, the remodeling phase of wound healing
begins once re-epithelialization of the wound is complete,111
and wounds taking longer than 2 weeks to re-epithelialize
are more likely to form HTS.112 Keratinocytes regulate fibro­
blast activity and vice versa,111 suggesting that they play key
roles in normal wound healing and HTS formation.113
Experiments with keratinocyte-conditioned media in skin-
equivalent models show that keratinocytes downregulate
fibroblast production of the profibrotic cytokines TGF-β and
CTGF.114 Normally, keratinocytes increase fibroblast prolif­
eration but simultaneously reduce collagen production115
and increase collagen breakdown by upregulating MMP-1
via factors such as stratifin.116 In contrast, keratinocytes from
HTS promote increased fibrosis in normal dermal fibrob­
lasts,73 display an activated phenotype similar to early wound
healing keratinocytes,117 and have higher proliferation rates
in the basal layer many months after re-epithelialization is
complete.118 This may be due, in part, to elevated PDGF
production by HTS keratinocytes.119 This suggests that normal
keratinocytes promote normal wound healing, and abnor­
mal keratinocytes promote HTS formation. It is also possible
that HTS fibroblasts alter the normal wound healing kerati­
nocyte phenotype to a HTS phenotype, and these HTS kerati­
nocytes in turn reinforce the HTS fibroblast phenotype.
Thus, therapies for HTS must address not only wound
fibroblasts but also wound keratinocytes.
The role of cytokines in hypertrophic scar
Cytokines serve as signals for communication between cells,
in paracrine signaling, and for cells to signal themselves in
autocrine signaling. While the number of cytokines, and
hence the diversity of signals, is immense there are several
key cytokines whose prototypic role in fibrosis and HTS has
been extensively studied, and whose actions account for a
wide variety of fibroses. The roles of these cytokines are
illustrated in Figure 45.8.
TGF-β
Transforming growth factor beta (TGF-β) is one of the most
studied profibrotic cytokines and belongs to a large super­
family of related proteins regulating processes as diverse as
embryonic development, chemotaxis, cell cycle, homeosta­
sis, and wound healing. When produced by cells, TGF-β is
secreted in an inactive form bound to latent TGF-β-binding
protein. This bond is subsequently cleaved by enzymes in
the milieu of healing wounds, including several matrix met­
alloproteinases (MMP-2, MMP-9) and plasmin (present in
blood). Mammals produce three known isoforms: TGF-β1,
TGF-β2, and TGF-β3.120 These are produced by many cells
involved in wound healing, including degranulating plate­
lets, macrophages, T lymphocytes, endothelial cells, fibro­
blasts, and keratinocytes.121 The actions of TGF-β1 and -β2 are
mediated by the intracellular Smad pathway and have
directly profibrotic actions on mesenchymal cells.122 TGF-β
is upregulated locally in wounds and systemically in the
blood of burn patients with HTS.123 HTS fibroblasts produce
Figure 45.7  Schematic illustrations showing the different origins of the
myofibroblast cells. Various cell types can acquire a myofibroblast
phenotype; these diverse origins lead to distinct myofibroblast
subpopulations. Circulating fibrocytes and bone marrow-derived
mesenchymal stem cells (MSC) are important sources of myofibroblasts
when the dermis, source of local fibroblasts, is destroyed (2nd and 3rd
degree burns). A local source can also be local stem cells (both epithelial
stem cells and MSC forming a niche located at the level of hair follicles). The
hypothesis suggesting that a major source of fibrosis- and tumor-associated
myofibroblasts is through transdifferentiation from non-malignant epithelial
cells, from epithelial-derived carcinoma cells or from endothelial cells
through epithelial- and endothelial-to-mesenchymal transition (EMT)
requires further studies. SMA: smooth muscle actin; ECM: extracellular
matrix. (From Desmoulière A, who retains copyright of the image.)
Epithelial cells
BM
Local
epithelial
stem cells
Local
MSC
‘Niche’
(hair follicle)
Fibroblasts
Local fibroblast
subpopulations
Endothelial
cells
Pericytes
EMT
Fibrocytes and
bone marrow-
derived MSC
Myofibroblasts
α-SMA
ECM
mouse bleomycin-induced pulmonary fibrosis model.103 It
appears that fibrocytes contribute to ECM formation and
fibrosis through two mechanisms. Exposure to profibrotic
cytokines causes fibrocytes to secrete collagen and differenti­
ate into myofibroblasts via Smad2/3 and SAPK/JNK MAPK
pathway activation.104 Fibrocytes also modulate the activity
of local fibroblasts in burn wounds via secretion of TGF-β
and connective tissue growth factor (CTGF),105 and may serve
as a crucial link between healing wounds and the immune
system. Like leukocytes, fibrocytes can act as antigen-
presenting cells to prime naïve T cells,106 and also express
Toll-like receptors allowing them to function as part of the
innate immune system.107 Fibrocytes also induce revasculari­
zation of wounds through MMP-9 secretion, which degrades
ECM and promotes endothelial invasion and the production
of vascular endothelial growth factor.108 Our understanding
of fibrocytes as profibrotic mediators of wound healing con­
tinues to evolve, with several recent descriptions of alternate
fibrocyte subpopulations109 and the ability to reprogram
fibrocytes into an antifibrotic phenotype.110 Although this
appears to complicate the fibrocyte picture, it does highlight
the importance of systemic responses to wound healing, and
suggests that the initial cytokine signals that bone marrow-
derived cells receive as they leave the circulation can have a
significant impact on their role in HTS formation.

Molecular and cellular basis of hypertrophic scarring
503
stimulation by TGF-β or CTGF alone induces only transient
fibrotic upregulation in fibroblasts, whereas co-stimulation
by both cytokines leads to prolonged fibrosis,135 and in
chronic fibrosis CTGF remains elevated after TGF-β returns
to basal levels.136 Thus, one can surmise that TGF-β serves to
initiate fibrosis and CTGF serves to continue the process as
a downstream mediator of TGF-β.126 In keeping with this
hypothesis, CTGF is upregulated in HTS, scleroderma,137 and
other fibrotic diseases.138 TGF-β induces CTGF through the
Ras/MEK/ERK pathway, and blocking this activation with
iloprost (a synthetic prostacyclin PGI2 analog) reduces fibro­
sis.139 Other methods of targeting CTGF, such as anti-CTGF
antibodies and CTGF siRNA, have also proved effective in
reducing fibrosis.140
PDGF
Platelet-derived growth factor (PDGF) is delivered to wounds
by platelets from injured capillary vessels, and is also pro­
duced by local fibroblasts.141 There are four isoforms of
PDGF: A, B, C, and D, which form dimers to activate two
structurally related tyrosine kinase receptors142 leading to
fibroblast proliferation and actin filament reorganization
that induces a transformation into myofibroblasts.45 PDGF
also increases ECM production and inhibits myofibroblast
apoptosis.143 PDGF activity contributes to pulmonary fibro­
sis, hepatic fibrosis, renal fibrosis, and scleroderma.144 PDGF
has been shown to upregulate TGF-β receptors in sclero­
derma fibroblasts,141 and its multiple effects are magnified in
HTS and keloid fibroblasts.145 Recent research into the causes
of nephrogenic systemic fibrosis, a disorder of dermal fibro­
sis occurring after gadolinium contrast administration in
patients with impaired renal function, shows that blocking
PDGF receptors using antibodies inhibits the proliferative
effects of gadolinium on fibroblasts.146 Other researchers
have shown that blocking PDGF action using tyrosine kinase
inhibitors reduces fibrosis in murine models of radiation-
induced pulmonary fibrosis147 and scleroderma.148 Thus,
although PDGF is an independently profibrotic cytokine, it
also serves to reinforce and magnify the effects of TGF-β, and
blocking its activity can reduce fibrosis.
IGF-1
Insulin-like growth factor 1 (IGF-1) was originally described
in chondrocytes, where it regulates glycosaminoglycan pro­
duction.149 IGF-1 is a mitogen for fibroblasts150 and endothe­
lial cells,151 and induces collagen production in pulmonary152
and dermal153 fibroblasts. IGF-1 upregulates TGF-β gene
transcription in fibroblasts, accounting for observed similari­
ties in their profibrotic actions.153 It has been shown that
IGF-1 also downregulates collagenase mRNA levels and
activity in dermal fibroblasts.154 This increase in collagen
production and decrease in breakdown shift the balance of
ECM remodeling towards fibrosis. IGF-1 is upregulated in a
number of fibrotic conditions, including post-burn HTS,155
scleroderma, pulmonary fibrosis, and hepatic fibrosis.5
Interestingly, in unwounded skin IGF-1 is produced exclu­
sively in epidermal sweat and sebaceous glands, and is thus
sequestered from dermal fibroblasts.155 One may hypothe­
size that when these structures are disrupted, as in burns
and other wounds, dermal fibroblasts are then directly
greater amounts of TGF-β than normal fibroblasts124 and
regenerative fetal fibroblasts.125 In fact, normally regenerative
fetal fibroblasts can be induced to form scar following TGF-β
exposure.125 TGF-β has direct effects on the ECM by upregu­
lating collagen production126 and downregulating decorin
production127 by fibroblasts. This decrease in dermal decorin
is profibrotic, as decorin binds to TGF-β in the ECM, block­
ing its activity.128 TGF-β promotes not only the trans­
formation of fibroblasts into myofibroblasts46 but also the
transdifferentiation of epithelial cells into mesenchymal
cells,129 and reduces apoptosis in the healing wound.130 In
this context, TGF-β is a highly profibrotic cytokine playing a
unique role in HTS initiation. Interestingly, it has been sug­
gested that the isoform TGF-β3 acts as an antifibrotic cytokine.
Clinical trials of TGF-β3 have shown promise in improving
wound healing,131 and it is noteworthy that TGF-β3, which is
upregulated in the remodeling phase of wound healing,
reduces ECM deposition.132 Many effects of other cytokines
in wound healing can be directly related to activation by or
interaction with TGF-β.
CTGF/CCN2
Connective tissue growth factor (CTGF or CCN2) is a
prototypic member of the CCN family of cytokines.
The CCN family motif consists of four linked regions: an
IGF-binding domain, a von Willebrand type C domain, a
thrombospondin-1 domain, and a cysteine knot heparin-
binding domain.133 This configuration and multiple studies
suggest that CTGF does not act simply as a growth factor,
but rather as an important cofactor for TGF-β, and as
an interface between cells and the ECM by binding to cel­
lular integrins and matrix proteoglycans.134 Independent
Figure 45.8  Balance of pro- and anti-fibrotic cytokines in wound healing.
The fibrogenic and antifibrogenic factors that modulate fibroblast function
during wound healing. (From Tredget EE, Nedelec B, Scott PG, Ghahary A, Hypertrophic
scars, keloids and molecular basis for therapy. Surgical Clinics of North America 1997; 77:
701-30).
Platelets
Proliferation
Proteoglycans
Fibronectin
Collagen
Macrophages
Lymphocytes
γ IFN(–)
α IFN(–)
IGF-1
Serum
Dermal keratinocytes
Glandular cells
(sweat glands)
Macrophages
TGF-β
(active)
TGF-β(+)
(latent)
PDGF(+)
+
–
+

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in cell-mediated immunity, whereas Th2 cells produce
IL-4, IL-5, and IL-10 and are involved in antibody-
mediated immunity.167 Interestingly, these cytokine profiles
are involved not only in specific immune responses, but are
also anti- or profibrotic.168 The Th2 cytokine IL-10 stimulates
activated naïve Th cells to secrete TGF-β, and this is more
pronounced in IFN-γ (Th1) knockout mice and reduced in
IL-4 (Th2) knockout mice.169 In a burn mouse model Th2
cytokines (IL-5) were upregulated and Th1 cytokines (IFN-γ
and IL-2) were coordinately downregulated.170 A similar Th2
type response is seen in human burn patients using stimu­
lated PBMC from those with burns ≥25% total body surface
area (TBSA),171 a finding confirmed by another study in burn
and major trauma patients.172 The severity of fibrosis in
animal models has also been linked to the type of Th-cell
response. In a model of liver fibrosis BALB/c mice developed
a Th2 response to chemically induced liver injury and
displayed more severe fibrosis than C57BL/6 mice, which
developed a Th1 response. This effect was abrogated by
administration of IL-4 antibodies or IFN-γ, which induced a
Th1 response in the BALB/c mice.173 A longitudinal study of
recovering burn patients demonstrated a predominant Th2
response to burn injury, as demonstrated by increased IL-4
and IL-10 levels from PBMC and in scar tissue (Fig. 45.9).
Interestingly, this response was significantly higher in
burn patients who went on to develop HTS than in those
who developed normal scars, whereas those patients devel­
oping normal scar had higher levels of IFN-γ-producing
PBMC.174 Recently, it was found that IFN-α blocks Th2 devel­
opment, and inhibits cytokine secretion by committed Th2
cells.166 This suggests that IFN-α2b has effects not only on
fibroblasts, as discussed previously, but also the Th2 cells
that modulate them.
Summary
HTS is a fibrotic disorder resulting from derangement of the
normal wound healing process and shares many common
features with other fibrotic diseases. As discussed, HTS is
markedly different from normal skin and mature scar in
terms of the structure and composition of ECM, active cel­
lular phenotypes, and cytokine messages displayed. This
results in a mass of disorganized connective tissue with thin,
irregular collagen bundles in whorls and nodules instead of
thick, organized fibers parallel to the surface. The concomi­
tant decrease in decorin and increase in other proteoglycans
not only contributes to this disorganized ECM but also
allows profibrotic signals to propagate in the dermis. The
fibrotic, hypercellular nature of HTS both contributes to and
results from elevated profibrotic (e.g. TGF-β, CTGF) and
decreased antifibrotic (IFN-γ) cytokine levels. The resulting
local HTS fibroblast is modulated by systemic fibrocytes and
Th cells, which migrate to the wound. The resulting patho­
genesis of HTS is complex, with many aspects that serve to
reinforce the fibrotic process. Although this complexity
makes elucidating the mechanisms of HTS formation diffi­
cult, it also provides multiple targets for medical therapy. It
is our hope that this will provide therapies to improve the
quality of life for both burn patients and others with fibro­
proliferative conditions.
exposed to IGF-1. Prolonged inflammation and delayed
re-epithelialization would increase the duration of fibroblast
stimulation with IGF-1 and could help explain the forma­
tion of HTS. Although IGF-1 is certainly not the only cause
of HTS, its relationship to TGF-β and its unique distribution
in skin suggest a key role in the pathogenesis of abnormal
scarring.
Interferons
HTS is not simply the result of overexpression of profibrotic
signals, but results from a disturbance in the delicate balance
between pro- and antifibrotic cytokines. The interferons
(IFN) are cytokines classically produced by immune cells to
activate the host defense system.156 IFNs can be divided into
type I (IFN-α and IFN-β produced by leukocytes and fibro­
blasts, respectively) and type II (IFN-γ produced by activated
T lymphocytes).156 Of these, the two antifibrotic cytokines
whose roles in wound healing and HTS have been best
studied are IFN-α2b and IFN-γ. Treatment of fibroblasts with
these IFNs inhibits cell proliferation and also downregulates
collagen,157 fibronectin,157 and TGF-β production.123 IFN-α2b
also upregulates collagenase production and reduces TIMP-
1,158 making it a good candidate to promote scar remod­
eling.123 IFN-α2b reduces in vitro collagen lattice contraction
rates159 and in vivo wound contraction in guinea pigs.160
IFN-α2b also reduces myofibroblast populations and increases
the numbers of apoptotic fibroblasts in later stages of wound
healing,160 a finding also demonstrated in several other cell
types.161,162 A prospective clinical trial of IFN-α2b in post-burn
HTS patients demonstrated reductions in scar volume, nor­
malized TGF-β levels, and reduced scar angiogenesis.123 It is
suggested that abnormal scar results, at least in part, from
reduced levels of endogenous IFN in burn patients. An exam­
ination of the peripheral blood mononuclear cells (PBMC)
of patients forming keloids after trauma compared to those
with normal scarring showed decreased production of IFN-α
and IFN-γ,163 which is consistent with this hypothesis. There­
fore, an understanding of IFNs highlights the important
balance between pro- and antifibrotic cytokines, and sug­
gests possible therapeutic treatments for HTS.
The immune system regulates wound healing
Mast cells, neutrophils, and macrophages have long been
recognized as playing an important role in the inflammatory
phase of wound healing.164 Macrophages produce classic
immune cytokines interleukin-1 (IL-1), IL-6, and tumor
necrosis factor-α (TNF-α) which stimulate keratinocytes and
fibroblasts,45 and classic profibrotic cytokines TGF-β, PDGF,
and IGF-1.165 Recently, the importance of the immune
response type rather than degree of inflammation in deter­
mining the risk of HTS formation has been recognized. HTS
are highly infiltrated by lymphocytes,6 of which activated
CD4+ T-helper (Th) cells are an important subgroup.101
These Th cells can be generally classified as one of at least
four groups: Th1, Th2, Th17, and T-regulatory cells, based
on cytokine production patterns.166 Of these, the Th1-Th2
axis in wound healing and burn patients is the most studied.
Th1 cells produce IFN-γ, IL-2, and TNF-β and are involved