Điều Trị Bỏng Toàn Diện (Bản Expert Consult)

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198.e6
© Copyright 2012 Elsevier, Inc. All rights reserved.
228. Borgman MA, et al. The ratio of blood products transfused
affects mortality in patients receiving massive transfusions at a
combat support hospital. J Trauma. 2007;63(4):805-813.
229. Teixeira PG, et al. Impact of plasma transfusion in massively
transfused trauma patients. J Trauma. 2009;66(3):693-697.
230. Nunez TC, et al. Creation, implementation, and maturation of a
massive transfusion protocol for the exsanguinating trauma
patient. J Trauma. 2010;68(6):1498-1505.
231. Hardy JF, De Moerloose P, Samama M. Massive transfusion and
coagulopathy: pathophysiology and implications for clinical
management. Can J Anaesth. 2004;51(4):293-310.
232. Smoot EC 3rd. Modified use of extremity tourniquets for burn
wound debridement. J Burn Care Rehabil. 1996 Jul-
Aug;17(4):334-337.
233. Missavage AE, Bush RL, Kien ND, et al. The effect of clysed
and topical epinephrine on intraoperative catecholamine levels.
J Trauma. 1998 Dec;45(6):1074-1078.
234. Barret JP, Dziewulski P, Wolf SE, et al. Effect of topical and
subcutaneous epinephrine in combination with topical
thrombin in blood loss during immediate near-total burn
wound excision in pediatric burned patients. Burns. 1999 Sep;
25(6):509-513.
235. Mzezewa S, Jonsson K, Aberg M, et al. A prospective double
blind randomized study comparing the need for blood
transfusion with terlipressin or a placebo during early excision
and grafting of burns. Burns. 2004 May;30(3):236-240.
236. Dzik WH, Kirkley SA. Citrate toxicity during massive blood
transfusion. Transfus Med Rev. 1988 Jun;2(2):76-94.
237. Kor DJ, Stubbs JR, Gajic O. Perioperative coagulation
management–fresh frozen plasma. Best Pract Res Clin
Anaesthesiol. 2010;24(1):51-64.
238. Graves TA, Cioffi WG, Mason AD Jr, et al. Relationship of
transfusion and infection in a burn population. J Trauma. 1989
Jul;29(7):948-952; discussion 952-954.
239. Rodeberg DA, Easter AJ, Washam MA, et al. Use of a helium-
oxygen mixture in the treatment of postextubation stridor in
pediatric patients with burns. J Burn Care Rehabil. 1995 Sep-Oct;
16(5):476-480.

In Memoriam
This chapter is dedicated to the memory of Ronald T.
Plessinger – friend, colleague, mentor, research scientist,
and tissue donor.
History
The first skin autograft was described by Reverdin1 in 1871
and the use of allograft skin as a clinical method for wound
coverage soon followed.2 In 1874, Thiersch published a
report about a small series of patients on whom he had used
partial-thickness skin grafts.3 This led to extensive trials of
harvesting extremely thin grafts, leaving some of the surface
epithelium behind to aid in donor site healing. Results from
the use of these small thin grafts, known as ‘Thiersch grafts,’
‘pinch grafts,’ ‘epidermis grafts,’ or ‘razor grafts’ were gener­
ally so unsatisfactory for resurfacing large areas that they
were typically limited to the treatment of small ulcerated
wounds. The first successful use of allogeneic skin for burn
wound coverage was reported by Girdner4 in 1881. Five years
later, Thiersch described the histologic anatomy of skin
engraftment which popularized the clinical use of split-
thickness skin grafts.3
Radical advances in the treatment of burn wounds brought
about three developments in skin graft recovery techniques.
First, it was noted that the dermal layer was the most impor­
tant part of a skin graft in producing a new, tough, resilient
surface. Secondly, it was demonstrated that after removing a
partial-thickness graft, the donor-site epithelium was regen­
erated from deep epithelial islands within the hair follicles
and sebaceous glands; therefore, thicker grafts could be har­
vested and transferring the upper dermis would not interfere
with donor-site healing. Finally, by allowing for the recovery
of thicker grafts, the design instruments for their harvesting
became more feasible. These thicker grafts were termed ‘split-
thickness grafts,’ and resulted in the coverage of large areas
of the body surface. These major advances in skin graft recov­
ery techniques permitted increased flexibility in the treat­
ment of burn wounds so that the Thiersch, or pinch graft,
method and the use of pedicle flaps were rarely necessary for
the treatment of cutaneous scar contractures. The use of split-
thickness grafts permitted skin grafting to become a routine
procedure.
Storage of human skin did not begin until the early 1900s,
when Wentscher5 reported his experience with the transplan­
tation of human skin that had been refrigerated for 3–14
days; however, it was not until the 1930s that blood and
tissue banking took their place in the clinical practice of
medicine. The clinical utility of allograft skin in burn wound
coverage was first described in 1938 when Bettman6 reported
his success in the treatment of children with extensive
full-thickness burn injuries. Webster7 and Matthews8 later
described the successful healing of skin autografts stored for
3 weeks at 4–7°C; however, it was not until 1949, following
the establishment of the United States Navy tissue bank, that
modern day skin banking began.
The establishment of skin banking signaled the beginning
of significant research related to the processing, preservation,
and storage of human tissues. Baxter9 explored the histologic
effects of freezing on human skin and discovered that the
formation of ice crystals caused the destruction of skin archi­
tecture. This was followed in 1952 by the pioneering research
of Billingham and Medawar10 who demonstrated that skin
could be effectively cryopreserved using glycerol. Soon after­
wards, Taylor11 was able to demonstrate that the addition of
glycerol to storage solutions decreased ice crystal formation
in frozen tissues. These advancements permitted Brown12
and Jackson13 to popularize the use of allogeneic human
skin grafts as biologic dressings for extensive burns and
denuded tissue. By 1966, Zaroff14 had reported the 10-year
experience using allograft skin in the treatment of thermally
injured patients at the Brooke Army Medical Center. In
this report, he described the mechanical and physiologic
advantages of allograft skin as a biologic dressing. In 1966,
Cochrane15 reported the first successful use of frozen autolo­
gous skin grafts following controlled-rate freezing in 15%
glycerol and rapid rewarming prior to implantation. This
was followed by Morris’16 report demonstrating the benefi­
cial effects of using allogeneic skin in the treatment of
infected ulcers and other contaminated wounds and Shuck
et al.’s17 report suggesting the potential use of allogeneic skin
in the treatment of traumatic wounds based upon their
Vietnam War experience. These increased uses of allograft
skin led to further research into the beneficial effects of allo­
graft skin on wound healing, including its association with
a reduced incidence of bacterial infections18,19 and the stimu­
lation of wound bed neovascularization.20
Bondoc and Burke21 are credited with the establishment of
the first functional skin bank in 1971. Their experience with
allograft skin led to a report of successful burn wound exci­
sion and allografting with temporary immunosuppression
in children with extensive injuries.22 Today, allograft skin
remains an ideal temporary cover for extensive or excised
©2012 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2786-9.00015-1
The skin bank
Richard J. Kagan, Robert Winter, Edward C. Robb
CHAPTER 15 
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IN THIS CHAPTER
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Total Burn Care
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200
growth and development of local and regional skin banks
throughout the world.
Fresh allograft skin represents the Gold Standard for
all biologic dressings employed for temporary wound
closure based upon a number of its distinctive properties
compared to cryopreserved skin (Box 15.3). Its availability
is critically important for the surgeon faced with the need to
provide immediate coverage of large excised burn wounds.
Allogeneic grafts are best applied unmeshed (or minimally
expanded) in order to maximize their ability to temporarily
close the wound. Fresh allografts become well vascularized,
stimulate neovascularization in the underlying wound bed,
and prepare the recipient sites for permanent coverage with
autologous skin. In addition, fresh allografts tolerate modest
wound contamination and adhere better to the freshly
excised subcutaneous fat than do cryopreserved grafts. The
allogeneic skin is usually removed once the patient’s donor
sites have healed sufficiently for reharvesting or once autolo­
gous cultured skin is available for permanent wound closure.
Figure 15.1 depicts the quantitative use of allograft skin and,
Box 15.1  Indications for allograft skin use in wound
management
•
Coverage of extensive wounds where autologous tissue is not
available
•
Coverage of widely meshed skin autografts
•
Extensive partial-thickness burns
•
Extensive epidermal slough
– Stevens–Johnson syndrome
– Toxic epidermal necrolysis
– Staphylococcal scalded skin syndrome
•
Testing the wound bed’s ability to accept autograft
•
Template for the delayed application of keratinocytes.
Box 15.2  Advantages of human allograft skin use
•
Reduce water, electrolyte, and protein loss
•
Prevent desiccation of tissue
•
Suppress bacterial proliferation
•
Reduce wound pain
•
Reduce energy requirements
•
Promote epithelialization
•
Prepare wounds for definitive closure
•
Provide dermal template for epidermal grafts.
Box 15.3  Advantages of fresh allograft skin
•
Rapidity and strength of adherence to the wound
•
Control of microbial growth
•
Rapidity of revascularization
•
Reproducible clinical results
Figure 15.1  Allograft skin usage at the Shriners
Burns Hospital, Cincinnati, Ohio.
Square feet
50
100
150
200
250
300
0
1998
Fresh
Frozen
2000
2002
2004
2006
2008
Year
cutaneous or soft tissue wounds, particularly when sufficient
autograft skin is not available or when temporary wound
coverage is desired.
Clinical uses of allograft skin
Coverage of extensive full-thickness wounds
The increasing use of allograft skin in specialized burn care
centers has been one of the driving forces behind the growth
and development of skin banks in the United States. The
general indications for its use in wound management are
listed in Box 15.1. Allograft skin possesses many of the ideal
properties of biologic dressings and plays a major role in the
surgical management of extensive wounds when autologous
tissue may not be immediately available (Box 15.2). It
reduces evaporative water loss and the exudation of protein-
rich fluids, prevents wound desiccation, and suppresses
microbial proliferation. Wound pain is lessened and is asso­
ciated with better patient compliance with occupational and
physical therapy. By restoring the physiologic barrier at the
wound surface, the allografts reduce heat loss through the
wound and mitigate the hypermetabolic response to burn
injury. The frequent and unpredictable demand for allograft
skin in specialized burn care centers has prompted the

The skin bank
201
utilizing meshed allograft25 and provides immediate, as well
as both temporary and permanent wound closure. For this
reason, most burn surgeons who currently perform overlay
allografting utilize non-meshed or non-expanded mesh allo­
grafts. This affords better protection of the underlying wound
bed from desiccation and microbial contamination as this
Figure 15.2  Appearance of cryopreserved and fresh, refrigerated allograft
skin on postoperative day 5. Note (a) poor vascularization and epidermolysis
in the cryopreserved skin compared to the (b) pink revascularized
refrigerated allograft.
A
B
Figure 15.3  Diagrammatic illustration of meshed
allograft overlay technique (as described by
Alexander et al.). The allograft is generally meshed
1.5 : 1 or 2 : 1 while the underlying autograft may
be meshed 3 : 1 or greater. (Reproduced with
permission from Alexander JW, MacMillan BG, Law E, et al.
Treatment of severe burns with widely meshed skin autograft
and widely meshed skin allograft overlay. J Trauma 1981;
21:433–438).25
1:1.5 Allograft
3:1 Autograft
Excised wound
in particular, the increased use of fresh refrigerated allograft
skin, in thermally-injured children treated at the Shriners
Hospital for Children in Cincinnati, Ohio since 1998.
When fresh allograft is not available, cryopreserved skin is
an excellent alternative for temporary wound coverage.
Although frozen cryopreserved skin generally has less meas­
urable viability than fresh skin, it is currently difficult to
maintain continuous and ample stores of fresh skin beyond
14 days. It has therefore been standard skin banking practice
to cryopreserve allograft skin within 7–10 days of recovery if
it is not going to be utilized within the time period that
viability can be maintained. Regardless of whether the allo­
grafts are fresh or cryopreserved, wide (mesh) expansion of
allograft skin is rarely performed because reepithelialization
of the interstices by allogeneic epidermis is uncommon.
Figure 15.2 demonstrates the difference in appearance and
vascularization of cryopreserved and fresh, refrigerated skin.
The emergence of Integra® dermal regeneration template
for the treatment of excised burn wounds has been signifi­
cant and in some burn centers has replaced or decreased the
use of allograft skin in patients with extensive full-thickness
burn injuries. Heimbach et al. reported the results of a ran­
domized multicenter clinical trial comparing Integra® and
other grafting materials.23 When the artificial dermis was
compared to allograft, there was no difference in the ‘take’
rates; however, ‘take’ was not defined in the manuscript and
it is unclear whether there were equivalent rates of adherence
and/or vascularization. Furthermore, it is unclear if the allo­
grafts applied were fresh or cryopreserved, although it is
most likely that the allografts were frozen as the refrigeration
of allograft skin was not common skin banking practice at
the time of the study. A subsequent retrospective study per­
formed at our burn center and skin bank 10 years later
indicated that fresh, refrigerated allograft had a better rate of
engraftment than the dermal regeneration template.24
Coverage of widely meshed skin autografts
Another use of allograft skin has been its application as an
overlay on top of widely expanded, meshed autologous skin
grafts (Fig. 15.3). This technique was originally described

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for patients with extensive full-thickness burn injuries. This
methodology has not been without problems, however, with
many authors describing variable take rates and instability
of the grafts. Cuono first advocated the use of allogeneic skin
with CEA, allowing the allograft skin to vascularize before
removing the antigenic epidermal layer by dermabrasion.28
Hickerson et al. reported results on five burn patients dem­
onstrating over 90% CEA take on the allogeneic dermis and
supple, durable grafts up to 4 years postoperatively.29
The past decade or so has also witnessed the development
of an acellular allogeneic dermal matrix (AlloDerm®) as a
template for the simultaneous application of thin split-
thickness autografts.30 The potential advantage of the dermal
template is reasoned to be the use of a thinner autologous
skin graft resulting in more rapid donor site healing and
reduced morbidity. A recently completed multicenter clinical
trial demonstrated equivalence of this technique with a
standard split-thickness meshed autograft; however, autograft
take rates were somewhat lower than that for controls and
varied from center to center.31 In addition, the allogeneic
dermal grafts measured only 36–116 cm2 and were only
evaluated up to 180 days post-grafting. AlloDerm® has also
been used as a template for CEA; however, there have been
only a few anecdotal reports related to this potential
application.
Micrografting techniques
Chinese surgeons have proposed the use of micrografts using
both autologous and allogeneic skin.32 This technique
involves the mincing of autologous skin into pieces less than
1 mm in diameter. These micrografts are then used to seed
the dermal surface of large sheets of allogeneic skin prior to
transplantation onto the excised burn wound. As the autolo­
gous epidermal cells propagate on the wound surface, the
allograft skin gradually separates in a manner similar to that
observed with the overlay technique. This method, while
resulting in an effective skin expansion ratio approaching
1 : 18, has been shown to be associated with severe wound
contraction that is often worse than that noted following the
application of meshed skin autografts.
Potential disadvantages of allograft use
Infection
Allograft skin has been reported to cause bacterial infec­
tion.33 It is therefore imperative that skin banks perform
microbial cultures prior to releasing the tissue for transplan­
tation. In fact, the American Association of Tissue Banks
(AATB) Standards34 require that skin be discarded if patho­
genic bacteria or fungi are present. This is particularly impor­
tant given the immunocompromised status of the potential
recipient and the potential for developing wound sepsis
following such contamination.
There have also been reports of viral disease transmission
by skin allografts. In 1987, Clarke reported what was thought
to be the transmission of HIV-1 to a burn patient from an
HIV-positive donor;35 however, the results of donor testing
were not known prior to skin use. Moreover, the recipient,
who had a number of risk factors for HIV, had not been
tissue is potentially exposed by the interstices of the widely
meshed autograft until autologous epithelialization is com­
plete. While this technique may play a role in the manage­
ment of massive excised full-thickness injuries, it should be
used with discretion since many surgeons have expressed
concern that the overlying allograft may induce an inflam­
matory rejection response that can retard the rate of
re­epithelialization of the underlying autografts. Some have
therefore advocated the use of lyophilized allograft for this
purpose as it is less viable and less antigenic.26
Healing of partial-thickness wounds
Frozen allograft skin is an excellent wound cover when vas­
cularization is not desired. Because it is usually less viable
than fresh skin, it functions more as a biologic dressing than
as a temporary skin replacement. Its adherence to the under­
lying wound bed results in the relief of pain and the limita­
tion of exudative and water losses, and reduces the need for
frequent dressing changes. As the partial-thickness wound
reepithelializes, the allograft slowly separates without dis­
turbing the delicate underlying epithelium. Although this
application is probably not cost-effective in the management
of small second-degree burns or skin graft donor sites, it is
often beneficial in the treatment of extensive partial-thickness
burns where its ability to prevent desiccation and promote
epithelialization may reduce hospital stay and/or the need
for autografting. In addition, cryopreserved allograft is an
excellent biologic dressing for the management of patients
with extensive cutaneous wounds resulting from drug
reactions or superficial skin disorders (e.g. toxic epidermal
necrolysis,
Stevens–Johnson
syndrome,
staphylococcal
scalded skin syndrome). When used for the coverage of these
superficial wounds, allograft skin should be applied prior to
exposing the wound to topical antibiotics since the applica­
tion of these agents results in decreased allograft adherence
to the wound surface.
Testing for later acceptance of autograft
Both cryopreserved and fresh allografts have been used for
the care of a variety of cutaneous and soft tissue wounds. In
these instances, allograft is used to provide a temporary
biologic cover and to help predict the likelihood of autolo­
gous graft-take later in the course of treatment. Allograft
usage for this indication has been quite common in the
management of deep electrical burns, infected or necrotic
wounds, and purpura fulminans. Allograft has also been
used to cover the soft tissues exposed by escharotomies and
fasciotomies as well as extensive open abdominal and soft
tissue wounds. Adherence or vascularization of the allograft
is a reliable indication that the wound bed has sufficient
blood supply to accept an autologous graft or flap.
Template for delayed application
of keratinocytes
The clinical use of cultured epidermal autografts (CEA) in
the care of burn patients was first described by O’Connor
et al.27 in 1981. Since that time, there have been numerous
reports supporting its use as a permanent skin replacement

The skin bank
203
after the completion of therapy. Further studies of these and
newer immunosuppressive agents may be warranted.
The growth of skin banking
The widespread use of allograft skin in the management of
patients with extensive burn, traumatic and soft tissue inju­
ries has had a major impact on the number of skin banking
facilities over the past two decades or so. Consequently, the
majority of skin banks have been founded in close proximity
to regional burn centers or within the burn center hospitals
themselves. Skin banks must therefore maintain a close
working relationship with regional burn centers not only to
meet the specific needs of the burn surgeon but also to help
generate community support for skin donation through
combined educational outreach programs.
From 1969 to 1988, there was a steady growth in the
number of skin banks; however, this number declined,
reaching its nadir in 2002. Since that time, however, there
has been a steady increase in the number of skin banking
facilities to its current total of 54 AATB-accredited tissue
banks that recover, process, store, and/or distribute skin for
transplantation (Fig. 15.4). In 1983, DeClement and May
estimated that as much as 32 000 square feet of skin might
be needed in burn and wound care centers.44 This figure,
however, was only a crude estimate and, over the past 10
years, there has been a substantial increase in the amount of
skin recovered and distributed for transplantation within
North America (Fig. 15.5), as indicated in the AATB’s 2007
Annual Survey of both accredited and non-accredited tissue
banks. In that calendar year, skin was recovered from 19 854
donors with nearly 30 000 square feet of skin distributed for
human transplantation.
Role of the American Association
of Tissue Banks
As skin banking facilities grew in number, it became appar­
ent that policies and procedures required standardization.
This was quite difficult initially as there was insufficient data
to develop a consensus regarding standards of practice. As
early as 1976, the AATB had begun to address this issue by
the formation of a Skin Council. This provided a forum for
the discussion of skin banking practices and was comple­
mented by the activities of the American Burn Association’s
Skin Banking Special Interest Group. The Standards and Pro­
cedures Committees were created in 1977 and produced the
first ‘Guidelines’ for tissue banking in 1979. The first Stand­
ards for Tissue Banking were published in 1984 and tissue-
specific technical manuals (including skin) were developed
in 1987. Since that time, the Standards have been modified
and refined based upon consensus and, where available,
supportive scientific research. In addition, shortly after the
development and promulgation of its Standards for Tissue
Banking, the AATB created an inspection and accreditation
committee in 1982 and began conducting voluntary inspec­
tions in 1986. This program continues today and is impor­
tant in ensuring that tissue banks adhere not only to AATB
Standards but also the Food and Drug Administration (FDA)
regulations governing all aspects of human tissue banking.
tested prior to receiving the allograft. To date, there have
been no other reported cases of HIV or hepatitis transmis­
sion from skin allografts.
Kealey et al. have reported the transmission of cytomega­
lovirus (CMV) from cadaver skin allografts.36 Because nearly
23% of the CMV-negative patients seroconverted, they
recommended the use of CMV-negative allograft skin for
seronegative burn patients. Plessinger et al. reviewed 479
consecutive skin donors and found 63% of this predomi­
nantly adult donor pool to be CMV-positive.37 They reasoned
that while tissue from seronegative donors would be ideal
for use in seronegative patients, such a practice would sig­
nificantly limit the availability of fresh allograft skin for most
thermally-injured patients. In addition, while there is good
evidence to support the transmission of CMV by allograft in
burn patients, there is little evidence that CMV seroconver­
sion is clinically significant or affects outcome in thermally-
injured patients.38,39 Furthermore, Herndon and Rose38
reiterated that the benefits of using cadaver allograft skin for
the treatment of burn patients clearly outweigh the small
risks associated with CMV seroconversion. At present, most
burn surgeons and skin banks recommend that the decision
regarding the use of allograft skin from CMV-positive donors
should be made by the burn/transplanting surgeon.
Rejection
While demonstrating many characteristics of an ideal wound
covering, allograft skin contains Langerhans cells which
express class II antigens on their surface. These cells reside
in the epidermis of the skin and are ultimately rejected as
the result of an immunologic rejection response. This typi­
cally results in an acute inflammatory reaction and can lead
to wound infection. Vascularized allogeneic skin grafts typi­
cally remain intact on the wound of a burn patient for 2–3
weeks although there have been reports of allograft skin
survival for up to 67 days due to the inherent immuno­
suppression of extensive burn injury.40 Recent improvements
in immunonutrition, critical care management, and a more
aggressive surgical approach to definitive wound closure,
however, have made the persistence of allografts less
predictable.
Efforts to prevent rejection have included methods that
might reduce antigen expression by controlling the activity
of the Langerhans cells in the allograft skin. Treatment of the
allografts with ultraviolet light irradiation and incubation of
the skin in glucocorticoids has been reported to result in a
modest prolongation of allograft survival compared to non-
treated skin; however, the utility of this methodology has not
been substantiated. Other investigators have studied the
effects of pharmacologic agents to induce immunosuppres­
sion in patients with major burn injuries. Initial clinical
trials reported an improvement in both allograft and patient
survival when children were treated with azathioprine and
antithymocyte globulin;41 however, this regimen was associ­
ated with azathioprine-induced neutropenia and the clinical
outcomes were not corroborated by others. More recently,
the use of cyclosporin A was demonstrated to prolong skin
allograft survival in patients with extensive full-thickness
burns.42,43 In these studies, allograft rejection was generally
observed within a few days of discontinuing treatment;
however, there were instances where engraftment persisted

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Technical aspects of skin banking
Donor screening
It is vitally important that complete and accurate medical
information about the potential donor be obtained to
ensure the safety of the tissue for transplantation. The AATB
and the FDA require a comprehensive medical and social
history of the donor. In this regard, the AATB developed a
Donor Medical History and Behavioral Risk Assessment
Questionnaire with the cooperation and assistance of other
organ and tissue procurement organizations and the FDA.
A thorough physical examination is also necessary to deter­
mine if the donor should be deferred for other medical
reasons as well as to determine the quality of the skin and
the technical feasibility of skin retrieval by evaluating the
donor’s size and skin condition. Box 15.4 lists disease states
which are commonly associated with deferral of a potential
skin donor.
Figure 15.5  Allograft skin donation and
distribution from 1992–2007. (Data collected from
AATB sources (various), with permission).
Number
5000
10000
15000
20000
25000
30000
0
1992
1996
2000
2003
1994
1999
12001
2007
Year
Donors
Square feet distributed
Box 15.4  Disease states commonly associated with potential
skin donor deferral
•
Extensive dermatitis
•
Acute burn injuries
•
Cutaneous malignancy
•
Poor skin quality
•
Extensive tattoos
•
Collagen vascular disease
•
Toxic chemical exposure
•
Skin infections
•
Extensive skin lesions
•
Extensive skin or soft tissue trauma.
Figure 15.4  Growth in the number of skin
banks in the United States and Canada.
(Data collected from AATB sources (various), with
permission).
Number
10
20
30
40
50
60
70
80
0
1967
1977
1987
1997
2007
1972
1982
1992
2002
Year
Total
AATB-accredited

The skin bank
205
or intraventricular puncture. Following this, a thin layer of
sterile mineral oil (or other sterile lubricant) is applied to
the surfaces from which skin is to be removed. Split-thickness
skin grafts are then removed using a dermatome at a thick­
ness of 0.012–0.018 inches. The width of the grafts generally
should range from 3 to 4 inches but ideally should be deter­
mined by the preference of the transplanting surgeon(s).
Skin retrieval sites are usually limited to the torso, hips,
thighs, and upper calves. The amount of skin obtained may
vary depending on body habitus, skin defects or lesions, and
body geometry; however, an average of 4–6 square feet per
donor is not unusual. After tissue is obtained from the pos­
terior surfaces, the donor is turned to expose the anterior
surface, reprepped, and draped prior to completing the
retrieval process. The skin is then placed in tissue culture
medium and maintained at 1–10°C during transport to the
skin bank for processing.47
Skin processing
Processing environment
Skin should be processed under aseptic conditions in a bac­
teriologically and climate-controlled environment. While
current AATB Standards mandate the processing of cardio­
vascular tissues in a class 100 laminar flow environment, no
such requirement exists for human skin banking. In fact, a
study performed by Plessinger et al. failed to demonstrate
any statistically significant quantitative or qualitative differ­
ence in microbial growth whether the skin was processed
and packaged in a class 100 laminar flow hood or a class
10 000 clean room.48
Microbiologic testing
After returning to the skin bank, the procurement team
should obtain cultures for aerobic and anaerobic bacteria,
yeast, and fungi. Incubation of allograft skin in antibiotics
remains somewhat controversial since many of these antimi­
crobial agents are unable to effectively kill microorganisms
at 4°C and there is the potential for exposing the recipient
to resistant organisms. In addition, there has been little
research to determine which antibiotics are effective against
most skin contaminants yet nontoxic to the cellular compo­
nents of the skin. It is therefore recommended that samples
be obtained prior to exposure of the skin to antibiotics49
using a 1 cm2 biopsy sample for each 10% of the body
surface area from which the skin has been recovered.47,50
Testing should be conducted in accordance with the National
Committee on Clinical Laboratory Standards and the skin
should not be used for transplantation if it contains any of
the following microorganisms:
•
Staphylococcus aureus
•
Group A, beta-hemolytic Streptococci
•
Enterococcus sp.
•
Gram-negative bacilli
•
Clostridium sp.
•
Fungi (yeasts or molds).
While AATB Standards require that microbiology culture
results should not be reported before 7 days of incubation
before releasing the tissues for transplantation, when fresh,
non-cryopreserved allograft skin is to be exceptionally
While it is also necessary for the tissue bank medical direc­
tor to review the results of an autopsy (if one was performed),
a review of over 2200 consecutive donors recovered by our
tissue bank from January 1994 through May 1998 indicated
that only 11 donors (0.5%) required discard as a result of the
autopsy findings.45 Furthermore, a 10-month follow-up study
of 264 donors recovered following the 1998 changes in the
AATB Standards revealed that none of the donors required
deferral based upon the autopsy findings alone.45
A panel of serologic screening tests for transmissible dis­
eases is required.34 These include:
•
Antibodies to human immunodeficiency virus, types 1
and 2 (anti-HIV-1 and anti-HIV-2)
•
Nucleic acid amplification test (NAT) for HIV-1
•
Hepatitis B surface antigen
•
Total antibodies to hepatitis core antigen (including
both IgG and IgM)
•
Antibodies to hepatitis C virus (anti-HCV)
•
Nucleic acid amplification test (NAT) for HCV
•
Syphilis (a non-treponemal or treponemal-specific
assay may be performed)
Test kits should be FDA-licensed, approved, or cleared for
donor screening, and ideally, should be approved for cadav­
eric specimens. Barnett et al. reported their 2-year experience
with cadaveric skin donor discards due to positive serologic
tests. In that report, they noted that 61 of 813 donors (7.5%)
required tissue discard due to positive serologic tests. A posi­
tive hepatitis B core antibody test accounted for 52.3% of
the serology-based discards while hepatitis B surface antigen
testing accounted for 18.1%, and hepatitis C, HIV-1/2,
HTLV-1, and syphilis tests accounted for 14.3%, 4.9%, 4.9%,
and 5.5%, respectively.46 This finding was substantiated by
Plessinger et al. in their 5-year review of 1235 donors, of
whom 93 (7.5%) were deferred based upon positive sero­
logic tests.45
Skin recovery
Once donor screening is complete and proper consents have
been obtained, the recovery team must arrange the time and
location for skin removal in an appropriate facility (i.e. hos­
pital morgue or operating room, medical examiner’s office,
or the tissue bank). It is extremely important that the time
of death and body storage conditions be accurately docu­
mented as these have a significant bearing upon skin viabil­
ity and microbial contamination. Current AATB Standards
require that skin retrieval begin within 24 h of asystole if the
donor was cooled or refrigerated within 12 h of asystole or
within 15 h of death if refrigeration did not occur within the
prescribed time limits.34
In brief, the skin is removed under aseptic conditions. The
areas from which the skin is taken are shaved of hair and
cleansed with detergent solutions approved for use in opera­
tive procedures (i.e. povidone-iodine, chlorhexidine). The
retrieval technician puts on a cap and mask, performs a
surgical scrub, and dons a sterile gown and gloves while the
circulating technician prepares tissue and transport contain­
ers. This is usually followed by a chlorhexidine prep and
rinsing with 70% isopropyl alcohol, and allowing the skin
surface to dry. The donor is then draped with sterile sheets
and a blood sample is obtained by either a central venous

Total Burn Care
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206
weeks at 4°C if the nutrient medium is changed every 3
days.57,58 The major shortcoming of this storage method is
the limited time that viability can be maintained.
It has been common practice to cryopreserve the skin
within 5–7 days of refrigeration. This has been based on the
work of May et al., who demonstrated that glucose metabo­
lism declined at a rate of 10–15% each day during refriger­
ated storage.55 Recently, we have demonstrated the benefit of
a two-layer storage method utilizing 95% oxygen-enriched
perfluorocarbon (O2PFC) combined with changing the
nutrient medium every 3 days in an effort to prolong the
viability of refrigerated skin. This method results in mainte­
nance of skin viability for up to 41–63 days as well as
maintenance of normal skin anatomy.59 Further research in
allograft skin cryopreservation techniques will be essential
in order to maintain an ample supply of viable fresh tissue
for clinical use.
Cryopreservation
When skin is frozen for long-term storage, it is important
that the methods utilized maintain cell viability and struc­
tural integrity. AATB Standards dictate that refrigerated skin
should not be stored for longer than 14 days; however, if the
skin is not to be used ‘fresh,’ it should be cryopreserved
within 10 days of procurement if the nutrient medium is
changed every 72 h. If the medium is not utilized or changed
in this manner, AATB Standards dictate that the skin must
be frozen within 96 h of recovery.34 The skin is generally
incubated in cryoprotectant solution for 30 min at 4°C. Skin
that is to be frozen should be folded with fine mesh gauze
or bridal veil covering the dermal surface prior to placement
in a flat packet to ensure uniformity of the cooling process.60
This is followed by slow-rate cooling at a rate of approxi­
mately −1°C per minute. Although computer-assisted,
control-rate freezing is thought to be optimal, studies have
demonstrated that cooling in a heat sink box at less than
−2°C per minute is equally effective and does not compro­
mise the metabolic activity of the skin.61 The skin is frozen
to a temperature of −70 to −100°C prior to placement in
either a mechanical freezer or liquid nitrogen. Skin stored
in a mechanical freezer (−70 to −100°C) can be maintained
for 3–6 months, whereas storage in liquid nitrogen (−150
to −196°C) has been shown to maintain viability for up
to 10 years. Although this methodology has been reported
to result in 85% retention of viability, there remains a need
for research to determine the optimal technology for skin
preservation.62
Lyophilization
Skin can also be lyophilized by freeze drying or incubation
in glycerol.63 This process has been reported to decrease
biologic degradation and antigenicity; however, this also
results in epidermal cell destruction and the loss of barrier
function. Moreover, lyophilized allograft skin has poor
adherence to the excised wound bed and is far less effective
than ‘fresh’ skin or cryopreserved skin in controlling micro­
bial growth. Its clinical use has been further limited by
its high cost of production compared to conventional
allograft.
released for transplantation within days of tissue recovery,
the results of the microbial cultures are frequently unavaila­
ble. Plessinger et al. reviewed the results of the microbiologic
skin cultures from 219 consecutive skin donors whose tissues
were released for transplantation prior to the availability of
culture results. While 14.3% of the cultures were positive for
microbial growth, only 1.8% of the cultures identified organ­
isms that required subsequent notification of the transplant­
ing surgeon. In each of these instances, there were no adverse
outcomes in any of the patients who received the skin trans­
plants.51 These findings were substantiated by and Britton-
Byrd et al.52 in their review of tissue donors whose skin was
authorized for exceptional release after only 3 days of incuba­
tion. They reported three cases resulting in tissue recall due
to positive microbiological cultures and concluded that 3-day
culture results do not result in significant microbiologic con­
tamination of allograft skin. Lastly, White et al.53 have
suggested that cadaver allograft containing <103 organisms/g
of tissue can be safely used for temporary wound coverage.
Despite the results of these studies, it is strongly recom­
mended that the tissue bank communicate all available
information regarding donor and tissue suitability to the
transplanting surgeon so that he/she can adequately assess
the potential risks and benefits for the recipient.
Maintenance of viability
Maintenance of cell viability and structural integrity are vital
for the engraftment and neovascularization of allograft skin,
yet there have been no studies that have quantified the
degree of viability necessary to ensure allograft ‘take.’ Post­
mortem time lapse appears to have the single greatest effect
on skin viability as May demonstrated that the functional
metabolic activity of the skin rapidly declined if the donor
was not refrigerated within 18 h of death.54,55 The ideal nutri­
ent tissue culture medium has also not yet been identified.
Eagle’s MEM and RPMI-1640 continue to be generally
accepted; however, Cuono demonstrated the potential ben­
efits of University of Wisconsin (UW) solution.56 To date, it
remains unclear which cryoprotectants offer the greatest
preservation of cell viability and structural integrity. Glycerol
(10–20%) and dimethylsulfoxide (10–15%) have been
reported to maintain skin viability following incubation
times ranging from 30 min to 2 h; however, the optimal
concentrations of these cryoprotectants have not been iden­
tified nor have these agents been compared for efficacy.
Lastly, factors such as age and gender do not appear to influ­
ence skin viability.
Refrigeration
‘Fresh’ allograft skin is the preferred biologic dressing for the
temporary coverage of excised extensive full-thickness burn
wounds due to its more rapid adherence and rapid vascu­
larization. The skin is typically stored at 4°C in tissue culture
medium with or without antibiotics. Refrigeration slows the
metabolic rate of the viable cells and nutrient tissue culture
medium supports cellular metabolic activity. The skin should
be free-floating in an aseptic container with approximately
300 mL of medium per square foot of skin. Recent studies
suggest that skin viability can be maintained for up to 2

The skin bank
207
The future of skin banking
Skin banking must continue to evolve as engineered skin
substitutes enter the clinical arena for the temporary and
permanent coverage of partial- and full-thickness wounds. A
number of skin substitutes have received FDA approval for
use in the United States and have become part of the sur­
geon’s armamentarium. Although they are generally more
costly than allograft skin, some of these products have been
demonstrated to possess a number of attributes, including:
•
non-antigenicity
•
ready availability
•
sterility
•
the ability to provide a dermal equivalent as a template
for the later application of ultrathin (0.006 inch) skin
autografts.
Allograft skin has the potential to play a major role
in permanent skin reconstruction after extensive thermal
injury; however, this will require interactive research with the
burn centers caring for these patients. This point is well
illustrated by the studies of Rose74 and Naoum75 who dem­
onstrated more rapid healing times and shorter hospital
stays for children with extensive indeterminate depth scald
burns when treated with early wound debridement and allo­
grafting compared to conventional topical antimicrobial
therapy. Homografts acted as the best protection for damaged
dermis, thus providing an environment for spontaneous
epithelialization.
Skin banks must also identify ways of increasing cadaveric
skin donation, ensuring recipient safety from potential
disease transmission, and reducing procurement and pro­
cessing costs while optimizing allograft viability. This will
become increasingly difficult as it becomes necessary to
perform additional and newer microbiological testing pro­
cedures to ensure recipient safety. To accomplish these goals,
it may become necessary for skin banking operations to
become regionalized. Such an undertaking could enhance
tissue supplies and availability and result in increased clini­
cal use by surgeons.
Allograft-based skin products
There is tremendous potential for human allograft-based
skin products to be developed in the upcoming years;
however, it will become increasingly important for skin
banks to perform basic science and clinical research (in con­
junction with burn and wound healing centers) to demon­
strate the clinical indications and efficacy of allograft skin
products in various clinical applications. Technological
advances may include modifications to reduce immuno­
genicity and/or the potential for disease transmission. Newer
processing techniques could sterilize the skin without
injuring the viable cellular elements or the structural inte­
grity of the tissue. In addition, with continued research,
deepidermized allograft dermis could become:
•
A source of growth factors and antimicrobial agents
•
A permanent full-thickness wound cover seeded with
the patient’s autologous keratinocytes and fibroblasts
Irradiation
Human allograft skin can also be treated with gamma irra­
diation to significantly reduce and possibly eliminate the
risk for viral disease transmission. The preservative and steri­
lizing effects of this treatment allow it to be stored at room
temperature for up to 2 years. One such product, Gamma­
Graft®, has been successfully utilized to treat partial thick­
ness burn injuries and skin graft donor sites; however it is
not often utilized to provide temporary coverage for excised
full-thickness burn wounds. Its most common indications,
however, are for the management of chronic wounds/ulcers
and exposed soft tissues.64
Transport
Refrigerated skin should be transported in tissue culture
medium at wet ice temperatures (1–10°C) in an insulated
container. Frozen allograft skin is transported on dry ice in
an insulated container to prevent the skin temperature from
rising to greater than −50°C. If the frozen skin is thawed
at the tissue bank, it should be transported at wet ice
temperatures.
Rewarming
Rewarming of frozen cryopreserved allograft skin must be
performed in such a manner as to minimize cryodamage and
preserve the structural integrity and viability of the skin.
Early studies demonstrated that warming rates of 50–70°C/
min resulted in 80–95% graft survival. Subsequent research60
has revealed that warming should be performed in 2–4 min
or less at a temperature of 10–37°C (127–470°C/min).
Rewarming in a microwave oven is not recommended due
to uneven heating and excessive intracellular temperatures.
FDA regulation of human skin banking
Concerns related to the potential transmission of disease
from tissue donors triggered concern within Congress and
the US Food and Drug Administration (FDA), which resulted
in the FDA’s publication of an interim rule for the regulation
of human tissues intended for transplantation in 1993.65 The
interim rule required that all donors have an accurately
recorded medical and social history to assure freedom from
risk factors for or clinical evidence of hepatitis B, hepatitis
C, and HIV infection. From December 2003 to July 1997,
the FDA developed its approach to the regulation of cellular
and tissue-based products.66,67 From 1998 to 2007, FDA
has published its proposed and final rules related to estab­
lishment registration,68,69 donor suitability determina­
tion,70–72 and good tissue practices.73 FDA has also published
a number of guidance documents that are available on
its website (
TissueTissueProducts/default.htm). Burn centers should
only obtain allograft skin from tissue banks that comply
with these regulations and preferably those facilities which
are accredited by the AATB. This is required for burn center
verification by the American Burn Association.

Total Burn Care
15
208
This document represents the current requirements for the recovery,
processing, storage, and distribution of human tissues for transplantation.
The contributors (members of the Association’s Standards Committee)
have many years of experience in tissue banking. Recent updates to this
publication are available on the AATB website ()
Bondoc CC, Burke JF. Clinical experience with viable frozen human
skin and a frozen skin bank. Ann Surg. 1971;174:371-382.
This landmark publication outlines the key aspects of maintaining a skin
bank as well as the authors’ early experience with the use of
cryopreserved allograft skin in burn care.
Department of Health and Human Services, Food and Drug
Administration. Human Tissue Intended for Transplantation; final
rule. Federal Register. 1997;62:40429-40447.
This publication by the Food and Drug Administration presents the scope of
government regulation of tissue banking activities in the United States.
Greater detail related to regulatory requirements (e.g. establishment
registration, donor suitability, and good tissue practices) are provided in
subsequent citations as well as FDA-issued guidance documents, all of
which are available on the FDA website.
Holder IA, Robb E, Kagan RJ. Antimicrobial mixtures used to store
harvested skin: antimicrobial activities tested at refrigerator (4°C)
temperatures. J Burn Care Rehabil. 1999;20:501-504.
This publication provides important information regarding the use of
antimicrobials used in the storage of skin grafts, their sensitivities to
organisms that commonly colonize burn wounds, and the importance
testing the effectiveness of these agents at the temperature to be utilized
for skin storage.
May SR, DeClement FA. Skin banking. Part III. Cadaveric allograft
skin viability. J Burn Care Rehabil. 1981;19:362-371.
This publication is one of a series published by the authors, describing
various aspects of skin banking. This particular publication addresses the
decay in viability of human skin allografts after skin recovery and the
impact of storage media and conditions on the functional metabolic
activity of allograft skin.
•
A bilayer membrane system for epidermal autografting,
and/or
•
A readily-available permanent wound cover pre-seeded
with non-antigenic allogeneic keratinocytes, fibroblasts,
and melanocytes.
Allogeneic skin provides a source of skin cells, including
keratinocytes, fibroblasts, melanocytes, and endothelial
cells. These cells may be grown into large populations
>1 × 1012 cells), cryopreserved in liquid nitrogen, recovered
into culture, and combined with degradable biopolymers to
form cultured skin substitutes.76 Preclinical studies have
shown organization of the epidermal keratinocytes to form
a skin barrier,77,78 expression of pigment by melanocytes,79
and organization of endothelial cells into vascular analogs.80
Clinical studies have demonstrated improved healing of
chronic wounds with allogeneic skin substitutes,81 and per­
manent closure of excised burns with cultured autologous
grafts;82 however, cryopreservation of multilayered grafts
with keratinized epithelium remains an unachieved goal in
tissue transplantation. It therefore appears likely that the
principles and practices of skin banking may contribute to
eventual availability of unlimited supplies of skin grown in
laboratories for the treatment of a wide variety of skin-loss
conditions. Collaborative research efforts will be necessary
to achieve these goals in a timely and cost-effective manner
as skin banks find themselves competing and/or collaborat­
ing with the tissue bioengineering industry.
Further reading
AATB Standards for Tissue Banking, 12th ed. McLean, VA: American
Association of Tissue Banks; 2008.
Access the complete reference list online at

The skin bank
208.e1
© Copyright 2012 Elsevier, Inc. All rights reserved.
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71. Department of Health and Human Services, Food and Drug
Administration. Eligibility Determination for Donors of Human
Cells, Tissues, and Cellular and Tissue-Based Products; final rule.
Federal Register. 2004;69:29786-29834.
72. Department of Health and Human Services, Food and Drug
Administration. Human Cells, Tissues, and Cellular and Tissue-
Based Products; Donor Screening and Testing, and Related
Labeling; final rule. Federal Register. 2007;72:33667-33669.
73. Department of Health and Human Services, Food and Drug
Administration. Current Good Tissue Practice for Human Cells,
Tissues, and Cellular and Tissue-Based Product Establishments;
Inspection and enforcement; final rule. Federal Register.
2004;69:68612-68688.
74. Rose JK, Desai MH, Mlakar JM, et al. Allograft is superior to
topical antimicrobial therapy in the treatment of partial-thickness
scald burns in children. J Burn Care Rehabil. 1997;4:338-341.
75. Naoum JJ, Roehl KR, Wolf SE, et al. The use of homograft
compared to topical antimicrobial therapy in the treatment of
second-degree burns of more than 40% total body surface area.
Burns. 2004;30:548-551.
76. Boyce ST, Warden GD. Principles and practices for treatment of
cutaneous wounds with cultured skin substitutes. Am J Surg.
2002;183:445-456.
77. Boyce ST, Supp AP, Harriger MD, et al. Surface electrical
capacitance as a noninvasive index of epidermal barrier in
cultured skin substitutes in athymic mice. J Invest Dermatol.
1996;107(1):82-87.
78. Boyce ST, Supp AP, Swope VB, et al. Vitamin C regulates
keratinocyte viability, epidermal barrier, and basement membrane
formation in vitro, and reduces wound contraction after grafting
of cultured skin substitutes. J Invest Dermatol. 2002;118:565-572.
79. Swope VB, Supp AP, Boyce ST. Regulation of cutaneous
pigmentation by titration of human melanocytes in cultured
skin substitutes grafted to athymic mice. Wound Rep Reg.
2002;10:378-386.
80. Supp DM, Wilson-Landy K, Boyce ST. Human dermal
microvascular endothelial cells form vascular analogs in cultured
skin substitutes after grafting to athymic mice. FASEB J. 2002;16:
797-804.
81. Boyce ST, Glatter R, Kitzmiller WJ. Treatment of chronic wounds
with cultured cells and biopolymers: a pilot study. Wounds.
1995;7(1):24-29.
82. Boyce ST, Kagan RJ, Yakuboff KP, et al. Cultured skin substitutes
reduce donor skin harvesting for closure of excised, full-thickness
burns. Ann Surg. 2002;235:269-279.

Introduction
The skin envelope evolved to maintain a tightly controlled
internal environment. When severely damaged, preservation
of this critical milieu becomes impossible, leading to major
physiologic derangements. The central component of burn
care is to expeditiously replace damaged areas of the skin to
restore physiologic homeostasis. An increasingly effective
group of temporary and permanent alternative wound cover­
ings are available to the burn team to help in this regard.
Although these membranes are becoming increasingly
capable, the definitive replacement material of choice
remains the patient’s own skin (Fig. 16.1).
Physiologic considerations
Skin is a truly amazing organ, rarely properly appreciated
until it is missing. To date, all attempts to replace it, either
temporarily or permanently, have been highly imperfect. As
those with serious burns survive in greater numbers, the
absence of effective skin replacements is increasingly a hind­
rance to progress in burn care.
Structure and function of the skin
Skin, the body’s largest organ, is incredibly complex. Func­
tionally there are two layers with a highly specialized and
effective bonding mechanism. Numerous appendages
traverse the skin and a rich and reactive capillary network
provides nutrient flow while controlling temperature. The
epidermis, consisting of the strata basale, spinosum, granu­
losum, and corneum, provides a vapor and bacterial barrier.
The dermis provides strength and elasticity. The thin epider­
mal layer is constantly refreshing itself from its basal layer,
with new keratinocytes undergoing terminal differentiation
over approximately 4 weeks to anuclear keratin-filled cells
that make up the stratum corneum, which provides much of
the barrier function of the epidermis. The basal layer of the
epidermis is firmly attached to the dermis by a complex
bonding mechanism containing collagen types IV and VII.
When this bond fails, serious morbidity results, as demon­
strated by the disease processes of toxic epidermal necrolysis1
and epidermolysis bullosa (Fig. 16.2).2
Consequences of loss of barrier function
Loss of the epidermal barrier has serious adverse physiologic
effects. Direct and evaporative fluid losses are immediately
seen. If wounds are large, this quickly leads to dehydration
and shock. Protein losses are also substantial, leading to loss
of colloid oncotic pressure and secondary edema. Microor­
ganisms have unimpeded access to the microcirculation with
resulting systemic infection. Deep tissues become desiccated
with secondary cell death and progression of wound depth.
Dry wounds will not epithelialize as readily. It is clearly
important for the burn surgeon to have prompt biologic
closure of wounds as an important early objective.
Although it is an imperfect replacement, autologous split-
thickness skin is closest to being the ideal skin substitute
(Box 16.1). Because of the paucity of autologous donor skin
available in patients with massive burn injuries, both the
short-term and long-term problems of skin loss must be
solved by alternative wound closure materials. Alternative
materials can be used for either wound coverage which will
be temporary or for permanent wound closure. Allogenic
(cadaver) skin has been the most widely used alternative
wound closure material. However, there are other choices.
This is an exciting and fast-moving area which may pro­
foundly change the care of patients with serious burns. The
objective of this chapter is to review the currently available
alternative skin closure materials, both temporary and
permanent.
Temporary skin substitutes
Temporary skin substitutes provide transient physiologic
wound closure, thereby helping to control pain, absorb
wound exudate, and prevent wound desiccation. They are
clinically useful in several settings in burn care:
•
as a dressing on donor sites to facilitate pain control
and epithelialization from skin appendages;
•
as a dressing on clean superficial wounds for the same
reasons;
•
to provide temporary physiologic closure of deep
dermal and full-thickness wounds after excision while
awaiting autografting or healing of underlying widely
meshed autografts; and
•
as a ‘test’ graft in questionable wound beds.
©2012 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2786-9.00016-3
Alternative wound coverings
Robert L. Sheridan, Ronald G. Tompkins
CHAPTER 16 
Access the complete reference list online at

IN THIS CHAPTER
PowerPoint Presentation Online

Total Burn Care
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210
Their principal utility is provision of temporary physio­
logic closure of wounds, which implies protection from
mechanical trauma, vapor transmission characteristics
similar to skin, and a physical barrier to bacteria. These
membranes create a moist wound environment with a low
bacterial density.
Human allograft
Human allograft is generally used as a split-thickness graft
after being procured from organ donors. When used in a
viable fresh or cryopreserved state, it vascularizes and remains
the ‘gold standard’ of temporary wound closures.3–5 It can be
refrigerated for up to 7 days, but can be stored for extended
periods when cryopreserved. It is also used in a nonviable
state after preservation in glycerol or after lyophilization;
however, most existing data describe results when it is used
in a viable state. Viable split-thickness allograft provides
durable biologic cover until it is rejected by the host, usually
within 3 or 4 weeks. Prolongation of allograft survival,
through the use of antirejection drugs, has been advocated,6
but is not generally practiced for fear that antirejection drugs
will increase the risk of infection.7
Human skin allografts are generally placed into frozen
storage awaiting the return of numerous laboratory tests
allowing one to safely exclude the possibility of viral disease
transmission. When modern screening techniques are fol­
lowed, the risk of viral disease transmission is exceedingly
small. Allograft is also effectively used in combination with
meshed autograft in patients with large burns, the interstices
of the meshed graft being immediately closed by the overly­
ing unexpanded allograft, possibly reducing metabolic stress
and local wound inflammation (Fig. 16.3).
Human amnion
Human amniotic membrane is used in many parts of the
world as a temporary dressing for clean superficial wounds
such as partial-thickness burns, donor sites, and freshly
excised burns awaiting donor site availability.8,9 Amniotic
membrane is generally procured fresh and used after brief
Figure 16.1  The replacement material of choice remains the patient’s own
(autologous) skin.
Figure 16.2  The basal layer of the epidermis is firmly attached to the
dermis by a complex bonding mechanism containing collagen types IV and
VII. When this bond fails, serious morbidity results, as demonstrated here by
the disease processes of dystrophic epidermolysis bullosa.
Box 16.1  The perfect skin substitute – autologous
split-thickness skin
•
Prevents water loss
•
Barrier to bacteria
•
Inexpensive
•
Long shelf-life
•
Can be applied in one operation
•
Does not become hypertrophic
•
Flexible
•
Conforms to irregular wound surfaces
•
Can be used ‘off the shelf’
•
Does not require refrigeration
•
Cannot transmit viral diseases
•
Does not incite inflammatory response
•
Durable
•
Easy to secure
•
Grows with a child.
Figure 16.3  Allograft is also effectively used in combination with meshed
autograft in patients with large burns, the interstices of the meshed graft
being immediately closed by the overlying unexpanded allograft, possibly
reducing metabolic stress and local wound inflammation.

Alternative wound coverings
211
dermal regeneration efforts.18 Porcine xenograft is com­
monly distributed as a reconstituted product consisting of
homogenized porcine dermis which is fashioned into sheets
and meshed.19 Split-thickness porcine skin is also used fresh,
after brief refrigeration, after cryopreservation, or after glyc­
erol preservation. It effectively provides temporary coverage
of clean wounds such as superficial second-degree burns and
donor sites20 and has been used in patients with toxic epi­
dermal necrolysis.1,21 Porcine xenograft has been combined
with silver to suppress wound colonization.22,23 Porcine
xenograft does not vascularize, but it will adhere to a clean
superficial wound and can provide excellent pain control
while the underlying wound heals.
Synthetic membranes
A number of semipermeable membrane dressings can
provide a vapor and bacterial barrier and control pain
while the underlying superficial wound or donor sites heal.
These typically consist of a single semipermeable layer
that provides a mechanical barrier to bacteria and has
physiologic vapor transmission characteristics.24 Biobrane™
(Dow-Hickham, Sugarland, TX) is a two-layer membrane
constructed of an inner layer of nylon mesh that allows
fibrovascular ingrowth and an outer layer of silastic that
serves as a vapor and bacterial barrier.25 It is widely used to
provide temporary closure of superficial burns and donor
sites.26 All synthetic membranes are occlusive and can foster
infection if placed over contaminated wounds, especially in
the presence of necrotic tissue.27 Appropriate monitoring is
essential to their proper use.
Hydrocolloid dressings are generally designed with a
three-layer structure: a porous, gently adherent inner layer; a
methyl cellulose absorbent middle layer; and a semiper­
meable outer layer. They foster a moist wound environment
while absorbing exudate. A moist wound environment has
been found to favor wound healing.28 A variety of pastes and
powders made from hydrocolloid materials are also widely
available. These can be applied to superficial or deeper
chronic wounds to absorb wound exudate while maintain­
ing a moist wound environment.
Hydrofiber mats absorb wound exudate and have been
used as temporary wound membranes. When combined
with ionic silver (Aquacel-Ag, ConvaTec, Chester, UK), addi­
tional antimicrobial activity is seen. This membrane has
been used successfully in some burn programs as an
adjunct in the management of partial-thickness burns and
donor sites.29
Combined allogenic and synthetic membranes
Epidermal growth factor, transforming growth factor-β,
insulin-like growth factor (IGF), platelet-derived growth
factors (PDGF), fibroblast growth factors, and other media­
tors play an important role in wound healing.30 To provide
some of these substances topically to wounds, investigators
have placed both viable and nonviable allogenic cell types
into temporary wound dressings.31 These cells persist for no
more than 14 days, but it is hoped that factors secreted by
the allogeneic cells, or released upon their death and dissolu­
tion, will enhance wound healing. These membranes are
generally regulated as both devices and biologics.
refrigerated storage.10,11 It can also be used in a nonviable
state after preservation with glycerol. It has been treated with
silver to facilitate control of bacterial overgrowth.12 Amnion
does not vascularize but still can provide effective temporary
wound closure.13 The principal concern with amnion is the
difficulty in screening the material for viral diseases unless
preservation methods can eliminate potential viral contami­
nation. Without the ability to screen the material in this way,
the risks of disease transmission must be balanced against
the clinical need and the known characteristics of the donor.
Allogenic epithelial sheets
In many centers, particularly in Europe, sheets of allogenic
and autogenous epithelium are used to dress partial-thickness
wounds or to cover the interstices of meshed split-thickness
autografts.14,15 These are generally applied as thin sheets
placed on a gauze carrier for ease of handling. Cell suspen­
sions in fibrin sealant have also been trailed. The concept is
that the sheets will both prevent desiccation of underlying
wounds and that the release of unknown growth-stimulating
substances by the cells as they die will stimulate native
wound healing.16 The concept is attractive, but controlled
data are not available, particularly as regards any impact on
long-term outcomes.
Xenografts
Although various animal skins have been used for many
years to provide temporary coverage of wounds,17 only
porcine xenograft is widely used today (Fig. 16.4). It has
been used as primary temporary cover and as a scaffold for
Figure 16.4  Although various animal skins have been used for many years
to provide temporary coverage of wounds, only porcine xenograft is widely
used today.

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212
When epithelial cultures were first used in patients
with large burns it was hoped that they would provide the
definitive answer to the clinical problem of the massive
wound.49–51 With more frequent use of epithelial grafts, spe­
cific liabilities have become apparent including suboptimal
engraftment rates and long-term durability.52,53 However,
when faced with a very large wound and minimal donor
sites, epithelial cell wound closure is a useful adjunct to
split-thickness autograft, their liabilities and expense becom­
ing more acceptable as wound size increases.
Many of the imperfections associated with epithelial cell
wound closure may be attributed to the absence of a dermal
element. Epithelial grafts are now commercially available.
Application is generally most successful in wounds from
which vascularized allograft has been removed. Despite scat­
tered cases, application of cultured epithelial grafts onto
synthetic dermal analogs has not been shown effective.
Dermal analogs
Virtually all of the characteristics of normal skin that are not
related to barrier function are provided by the dermis. These
characteristics include flexibility, strength, heat dissipation
and conservation, lubrication, and sensation. The first
dermal substitute used clinically was ‘artificial skin’, also
called Integra™ (Integra LifeSciences Corporation, Plains­
boro, NJ, USA); it has been recently approved by the US
Food and Drug Administration for use in life-threatening
burns. This material was developed in the early 1980s by a
biomaterials research team from the Massachusetts General
Hospital and Massachusetts Institute of Technology.54 The
research team, lead by surgeon John Burke from the Mas­
sachusetts General Hospital and materials scientist Ionnas
Yannas from the Massachusetts Institute of Technology, had
the goal of developing a wound covering that would both
provide a temporary vapor and bacterial barrier while pro­
viding a scaffold for later dermal regeneration. The material
was intended to be placed on excised burn wounds and is
now approved for clinical use. Its use for other indications
is being explored. The inner layer of this material is a 2 mm
thick combination of fibers of collagen isolated from bovine
tissue and the glycosaminoglycan chondroitin-6-sulfate.
This 2 mm thick inner layer has a 70–200 µm pore size
that allows fibrovascular ingrowth, after which it is designed
to slowly biodegrade.55,56 To manufacture the device, gly­
cosaminoglycan and collagen fibers are precipitated and
then freeze-dried and cross-linked by glutaraldehyde. The
outer layer of the membrane is 0.009-inch (0.23 mm) thick
polysiloxane polymer with vapor transmission characteris­
tics similar to normal epithelium. This membrane is intended
to be placed on freshly excised full-thickness burns and the
outer silicone membrane replaced with an ultra-thin epithe­
lial autograft 2–3 weeks later (Fig. 16.5).57 Clinical reports
in patients with large burns have been generally favora­
ble,58,59 although submembrane infection must be watched
for. Integra™ has also been found to be useful in selected
burn reconstruction operations.60
Another currently available device designed as a dermal
replacement is cryopreserved allogenic dermis. This material
is intended to be combined with a thin epithelial autograft
at the time of initial wound closure. It is marketed as Allo­
Derm® (LifeCell Corporation, The Woodlands, TX, USA).61,62
An allogeneic dermal–epidermal device that used a colla­
gen lattice to culture both cell types was shown effective in
an athymic mouse model32–34 and then went into clinical
trials. Although it has not been demonstrated to have a clini­
cal role in burn patients, the device is being explored for
utility in chronic ulcers of the lower extremity.35–39 Dow-
Hickam’s Biobrane™ has been used as a scaffold to support
the growth of allogenic fibroblasts. This device is now mar­
keted as Transcyte® (Smith and Nephew, La Jolla, CA) and
has been successful in some burn programs as an adjunct to
the management of dermal burns.40–44 Viral transfection can
be employed to modify keratinocytes so that they overex­
press PDGF, human growth hormone, IGF-1, and other
growth factors,45 and it is possible that such cells might be
employed as components of wound membranes over the
next few years.46 Although stimulation of wound healing by
topical application of mixed growth factors in this fashion
is an intriguing concept, convincing evidence of the con­
cept’s general validity is awaited.
Permanent skin substitutes
A Swiss surgeon, Jaques Louis Reverdin, has been credited as
performing the first skin autograft, in 1869, using a ‘pinch-
graft’ technique. Although procurement methods have
evolved, the split-thickness autograft remains the standard
of care. Although reliable in experienced hands, this defini­
tive solution to the open wound has substantial drawbacks,
particularly donor site morbidity and availability. Unfortu­
nately, despite decades of work, currently available alterna­
tives are even more imperfect. A reliable permanent skin
substitute will revolutionize the care of patients with burns
and other difficult wounds. The perfect substitute is described
in Box 16.1, but has yet to be approached by any currently
available device. However, there are a number of imperfect
or partial-skin substitutes available at the present time that
are valuable in particular clinical settings and may be the
forerunners of this hypothetical ideal.
Epidermal cells
For over 20 years it has been possible to culture vast numbers
of epithelial cells from a small skin biopsy,47,48 and this has
led to the widespread clinical use of cultured epithelial grafts
to cover burn wounds. Epithelial cells are procured from a
full-thickness skin biopsy, the cells being separated with
trypsin. The resulting epithelial cell suspension is cultured
in medium containing fetal calf serum, insulin, transferrin,
hydrocortisone, epidermal growth factor, and cholera toxin,
overlying a layer of murine fibroblasts that have been treated
with a nonlethal dose of radiation that prevents them from
multiplying. Colonies of epithelial cells expand into broad
sheets of undifferentiated epithelial cells. These cells are
separated from the culture vessel with trypsin and taken to
secondary culture using the same techniques until confluent
thin sheets of undifferentiated cells are obtained. The result­
ing sheets are removed from the dishes after treatment with
dipase, which digests the proteins attaching the epithelial
cells to the dish. The sheets of epithelial cells are attached to
a petrolatum gauze carrier to ease handling.

Alternative wound coverings
213
wounds closed initially with vascularized allograft. Once
allograft has vascularized, the allogeneic epithelial cells are
removed by dermabrasion or tangential excision, purpose­
fully leaving behind a vascularized but theoretically non­
antigenic allogenic dermal layer.65–67 The method has been
favorably reported,68,69 but has not been universally adopted.
Perhaps the epithelial excision either leaves behind nests of
antigenic epithelial cells if too superficial or removes the
epidermal–dermal attachment structures if too deep.
Composite substitutes
Ideally, a skin replacement technique would provide imme­
diate replacement of both dermal and epidermal layers.
Combining epithelial cells with a dermal analog in the
laboratory seems logical. A completely biologic composite
skin substitute, culturing human fibroblasts in a collagen–
glycosaminoglycan membrane, and then growing keratino­
cytes upon this, has been under development for some
years.70,71 This composite membrane has been successful in
both a nude mouse model and in initial clinical series.72,73
There is even potential to control pigment expression.74
This exciting technology continues to be refined in labora­
tory and clinical investigations and may have a major impact
on the field. A similar project, in which autogenic epithelial
cells are cultured onto allogenic dermis, shows some
promise as well.75 It remains to be seen if either technique
will lead to a reliable and durable permanent skin
replacement.
The future of alternative wound coverings
We are likely to see significant improvements in skin substi­
tute technologies, both temporary and permanent, over the
next few years. In temporary wound coverings, not only are
improved synthetics and improved skin banking techniques
probable but we may see temporary dressings containing
growth factor-secreting allogenic tissues that stimulate native
wound healing. Genetic modification of keratinocytes is
now possible. These cells have been engineered to over­
express PDGF, human growth hormone, IGF-1, and other
growth factors.45 It is likely that they will be trialled in animal
models and human wounds over the next few years.46 If they
prove efficacious, their application to healing burns and
donor sites, through incorporation in temporary dressings,
may become possible. It might be further possible to combine
autogenous cells with modified allogenic cells such that the
resulting chimeric graft benefits from transient overexpres­
sion of critical growth factors during the early stages of
engraftment.
As we become increasingly successful at salvaging the lives
of those with large burns, our need for a durable and reliable
permanent skin substitute becomes increasingly acute. This
material is needed both to truncate the acute illness through
earlier wound closure and to facilitate timely and effective
burn reconstruction. Just what form that substitute will take
is not clear. Most likely, it would seem to be an in vitro com­
bination of autologous keratinocytes and possibly fibro­
blasts and/or endothelial cells with a dermal analog.
Whatever form the successful replacement takes, it is certain
to profoundly impact the field of burn care.
Split-thickness allograft skin is obtained from cadaver donors
through tissue banks after proper screening for transmissible
diseases. Using hypertonic saline, the epithelial elements of
the grafts are removed and the remaining dermis is treated
in a detergent to inactivate any viruses and the device is
freeze-dried. The process is intended to provide a non­
antigenic dermal scaffold, leaving basement membrane pro­
teins (particularly laminin and type IV and VII collagen)
intact. The material is rehydrated immediately prior to
placement on wounds with overlying ultra-thin epithelial
autograft (Fig. 16.6). Clinical experience with this material
in burn surgery is limited, but early experiences have been
favorable.63,64
Generating a dermal replacement through the prior use of
human split-thickness allograft is another strategy with sig­
nificant clinical support. This has been done on occasion for
many years by surgeons who ‘leave behind’ remnants of
vascularized allograft dermis when replacing allograft with
thin split-thickness autografts in patients with large injuries.
This has been modified for use with cultured epithelial
grafts, such that the cultured epithelial cells are placed on
Figure 16.5  Integra™ is intended to be placed on freshly excised
full-thickness burns and the outer silicone membrane replaced with an
ultra-thin epithelial autograft 2–3 weeks later.
Figure 16.6  AlloDerm® is rehydrated immediately prior to placement on
wounds with overlying ultra-thin epithelial autograft.

Total Burn Care
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A review of the practical and regulatory aspects of skin banking.
Nguyen DQ, Potokar TS, Price P. An objective long-term evaluation of
Integra (a dermal skin substitute) and split thickness skin grafts, in
acute burns and reconstructive surgery. Burns. 2010;36(1):23-28.
Demonstration of efficacy of Integra as an adjunct in burn reconstruction.
Sheridan R. Closure of the excised burn wound: autografts,
semipermanent skin substitutes, and permanent skin substitutes.
Clin Plast Surg. 2009;36(4):643-651.
Practical review of clinical use of various permanent and temporary skin
substitutes in burns.
Supp DM, Boyce ST. Engineered skin substitutes: practices and
potentials. Clin Dermatol. 2005;23(4):403-412.
A review of the current state of the art and future possibilities in composite
skin substitute manufacture.
Further reading
Callcut RA, Schurr MJ, Sloan M, et al. Clinical experience with
Alloderm: a one-staged composite dermal/epidermal replacement
utilizing processed cadaver dermis and thin autografts. Burns.
2006;32(5):583-588.
A review of the practical use of AlloDerm in burn reconstruction,
demonstrating techniques and efficacy.
Chen FM, Zhang M, Wu ZF. Toward delivery of multiple growth
factors in tissue engineering. Biomaterials. 2010;31(24):6279-6308.
A review of the concept of growth factor delivery in wounds, including use
of membranes as delivery vehicles.
Kagan RJ, Robb EC, Plessinger RT. Human skin banking. Clin Lab
Med. 2005;25(3):587-605.
 
Access the complete reference list online at

Alternative wound coverings
214.e1
© Copyright 2012 Elsevier, Inc. All rights reserved.
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for treatment of meshed autografts. Ann Plast Surg. 1984;13:
482-487.
24. Salisbury RE, Wilmore DW, Silverstein P, et al. Biological
dressings for skin graft donor sites. Arch Surg. 1973;106:705-706.
25. Lou RB, Hickerson WL. The use of skin substitutes in hand burns.
Hand Clin. 2009;25(4):497-509.
26. Lazic T, Falanga V. Bioengineered skin constructs and their use in
wound healing. Plast Reconstr Surg. 2011;127(Suppl 1):75S-90S.
27. Bacha EA, Sheridan RL, Donohue GA, et al. Staphylococcal toxic
shock syndrome in a paediatric burn unit. Burns. 1994;20:499-
502.
28. Vanstraelen P. Comparison of calcium sodium alginate
(KALTOSTAT) and porcine xenograft (E-Z DERM) in the healing
of split-thickness skin graft donor sites. Burns. 1992;18:145-148.
29. Blome-Eberwein S, Johnson RM, Miller SF, et al. Hydrofiber
dressing with silver for the management of split-thickness donor
sites: a randomized evaluation of two protocols of care. Burns.
2010;36(5):665-672.
30. Chen FM, Zhang M, Wu ZF. Toward delivery of multiple growth
factors in tissue engineering. Biomaterials. 2010;31(24):6279-6308.
31. Yanaga H, Udoh Y, Yamauchi T, et al. Cryopreserved cultured
epidermal allografts achieved early closure of wounds and
reduced scar formation in deep partial-thickness burn wounds
(DDB) and split-thickness skin donor sites of pediatric patients.
Burns. 2001;27(7):689-698.
32. Bell E, Ehrlich HP, Buttle DJ, et al. Living tissue formed in vitro
and accepted as skin-equivalent tissue of full thickness. Science.
1981;211:1052-1054.
33. Plotner AN, Mostow EN. A review of bioactive materials and
chronic wounds. Cutis. 2010;85(5):259-266.
34. Hansbrough JF, Morgan J, Greenleaf G, et al. Evaluation of
graftskin composite grafts on full-thickness wounds on athymic
mice. J Burn Care Rehabil. 1994;15:346-353.
35. Gentzkow GD, Iwasaki SD, Hershon KS, et al. Use of dermagraft,
a cultured human dermis, to treat diabetic foot ulcers. Diabetes
Care. 1996;19:350-354.
36. Sacks MS, Chuong CJ, Petroll WM, et al. Collagen fiber
architecture of a cultured dermal tissue. J Biomechan Engin.
1997;119:124-127.
37. Economou TP, Rosenquist MD, Lewis RW II, et al. An
experimental study to determine the effects of Dermagraft on skin
graft viability in the presence of bacterial wound contamination.
J Burn Care Rehabil. 1995;16:27-30.
38. DeCarbo WT. Special segment: soft tissue matrices. Bilayered
bioengineered skin substitute to augment wound healing. Foot
Ankle Spec. 2009;2(6):303-305.
39. Yannas IV, Orgill DP, Burke JF. Template for skin regeneration.
Plast Reconstr Surg. 2011;127(Suppl 1):60S-70S.
40. Hansbrough JF, Morgan J, Greenleaf G, et al. Development of a
temporary living skin replacement composed of human neonatal
fibroblasts cultured in Biobrane, a synthetic dressing material.
Surgery. 1994;115:633-644.
41. Hansbrough J. Dermagraft-TC for partial-thickness burns: a
clinical evaluation. J Burn Care Rehabil. 1997;18:S25-S28.
42. Junkins-Hopkins JM. Biologic dressings. J Am Acad Dermatol.
2011;64(1):e5-e7.
43. Purdue GF. Dermagraft-TC pivotal efficacy and safety study. J Burn
Care Rehabil. 1997;18:S13-S14.
44. Lukish JR, Eichelberger MR, Newman KD, et al. The use of a
bioactive skin substitute decreases length of stay for pediatric
burn patients. J Pediatr Surg. 2001;36(8):1118-1121.
45. Pham C, Greenwood J, Cleland H, et al. Bioengineered skin
substitutes for the management of burns: a systematic review.
Burns. 2007;33(8):946-957.
46. Morgan JR, Yarmush ML. Bioengineered skin substitutes. Sci Med.
1997;4:6-15.
47. Rheinwald JG, Green H. Serial cultivation of strains of human
epidermal keratinocytes: the formation of keratinizing colonies
from single cells. Cell. 1975;6:331-343.
48. Green H, Kehinde O, Thomas J. Growth of cultured human
epidermal cells into multiple epithelia suitable for grafting.
Proc Natl Acad Sci USA. 1979;76:5665-5668.

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214.e2
© Copyright 2012 Elsevier, Inc. All rights reserved.
49. Green H. Cultured cells for the treatment of disease. Sci Am.
1991;265:96-102.
50. Gallico GG III, O’Connor NE, Compton CC, et al. Permanent
coverage of large burn wounds with autologous cultured human
epithelium. N Engl J Med. 1984;311:448-451.
51. Sheridan RL, Tompkins RG. Cultured autologous epithelium in
patients with burns of ninety percent or more of the body surface.
J Trauma. 1995;38:48-50.
52. Rue LW III, Cioffi WG, McManus WF, et al. Wound closure and
outcome in extensively burned patients treated with cultured
autologous keratinocytes. J Trauma. 1993;34:662-667.
53. Barret JP, Wolf SE, Desai MH, et al. Cost-efficacy of cultured
epidermal autografts in massive pediatric burns. Ann Surg.
2000;231(6):869-876.
54. Tompkins RG, Burke JF. Progress in burn treatment and the use of
artificial skin. World J Surg. 1990;14:819-824.
55. Yannas IV, Burke JF, Warpehoski M, et al. Prompt, long-term
functional replacement of skin. Trans Am Soc Artif Intern Organs.
1981;27:19-23.
56. Yannas IV, Burke JF, Orgill DP, et al. Wound tissue can utilize a
polymeric template to synthesize a functional extension of skin.
Science. 1982;215:174-176.
57. Tompkins RG, Hilton JF, Burke JF, et al. Increased survival after
massive thermal injuries in adults: preliminary report using
artificial skin. Crit Care Med. 1989;17:734-740.
58. Sheridan RL, Heggerty M, Tompkins RG, et al. Artificial skin
in massive burns – results at ten years. Eur J Plast Surg. 1994;17:
91-93.
59. Heimbach DM, Warden GD, Luterman A, et al. Multicenter
postapproval clinical trial of Integra dermal regeneration
template for burn treatment. J Burn Care Rehabil. 2003;24(1):
42-48.
60. Nguyen DQ, Potokar TS, Price P. An objective long-term
evaluation of Integra (a dermal skin substitute) and split
thickness skin grafts, in acute burns and reconstructive surgery.
Burns. 2010;36(1):23-28.
61. Callcut RA, Schurr MJ, Sloan M, et al. Clinical experience with
Alloderm: a one-staged composite dermal/epidermal replacement
utilizing processed cadaver dermis and thin autografts. Burns.
2006;32(5):583-588.
62. Yim H, Cho YS, Seo CH, et al. The use of AlloDerm on major
burn patients: AlloDerm prevents post-burn joint contracture.
Burns. 2010;36(3):322-328.
63. Sheridan RL, Choucair RJ. Acellular allograft dermis does not
hinder initial engraftment in burn resurfacing and reconstruction.
J Burn Care Rehabil. 1997;18:496-499.
64. Sheridan RL, Choucair RJ. Acellular allodermis in burn surgery:
1-year results of a pilot trial. J Burn Care Rehabil. 1998;19:
528-530.
65. Langdon RC, Cuono CB, Birchall N, et al. Reconstitution of
structure and cell function in human skin grafts derived from
cryopreserved allogeneic dermis and autologous cultured
keratinocytes. J Invest Dermatol. 1988;91:478-485.
66. Cuono CB, Langdon R, Birchall N, et al. Composite autologous-
allogeneic skin replacement: development and clinical
application. Plast Reconstr Surg. 1987;80:626-637.
67. Cuono C, Langdon R, McGuire J. Use of cultured epidermal
autografts and dermal allografts as skin replacement after burn
injury. Lancet. 1986;1:1123-1124.
68. Hickerson WL, Compton C, Fletchall S, et al. Cultured epidermal
autografts and allodermis combination for permanent burn
wound coverage. Burns. 1994;20(Suppl 1):S52-S55; discussion
S55-S56.
69. Compton CC, Hickerson W, Nadire K, et al. Acceleration
of skin regeneration from cultured epithelial autografts by
transplantation to homograft dermis. J Burn Care Rehabil.
1993;14:653-662.
70. Boyce ST, Hansbrough JF. Biologic attachment, growth, and
differentiation of cultured human epidermal keratinocytes on a
graftable collagen and chondroitin-6-sulfate substrate. Surgery.
1988;103:421-431.
71. Supp DM, Boyce ST. Engineered skin substitutes: practices and
potentials. Clin Dermatol. 2005;23(4):403-412.
72. Cooper ML, Hansbrough JF. Use of a composite skin graft
composed of cultured human keratinocytes and fibroblasts and a
collagen-GAG matrix to cover full-thickness wounds on athymic
mice. Surgery. 1991;109:198-207.
73. Boyce ST, Kagan RJ, Yakuboff KP, et al. Cultured skin substitutes
reduce donor skin harvesting for closure of excised, full-thickness
burns. Ann Surg. 2002;235(2):269-279.
74. Swope VB, Supp AP, Boyce ST. Regulation of cutaneous
pigmentation by titration of human melanocytes in cultured
skin substitutes grafted to athymic mice. Wound Repair Regen.
2002;10(6):378-386.
75. Sheridan RL, Morgan JR. Initial clinical experience with an
autologous composite skin substitute. J Burn Care Rehabil.
2000;21:S214.

Introduction
The loss of the cutaneous barrier creates an important
problem for the injured organism. The skin barrier is
damaged, homeostasis altered, and part, if not all, of the
immunological function of the skin is lost. Following a burn
injury many issues must be addressed. Trauma guidelines,
resuscitation, maintenance of the internal milieu by critical
care techniques, and protection of the victim against infec­
tion, among others, are therapies directed towards a common
goal: survival and complete functional rehabilitation.
However, the main focus of the reconstructive surgeon is
the complete and permanent closure of the burn wound.
Two main factors are involved in this scenario. A clean, vital,
graftable wound bed has to be obtained in order to be ready
for the engraftment and survival of any skin coverage that
has been selected. Following this process, a permanent
wound cover has to be obtained that protects the recipient,
provides all skin properties and functions, and allows for
complete recovery and rehabilitation of the victim.
The treatment of severe burn sequelae follows similar
sound surgical principles. Alternative wound coverings are
reserved for those situations encountered in burn reconstruc­
tion as well as in acute setting: either a paucity of skin donor
site availability or a failure of previous surgeries to provide
good, pliable skin coverage.
The ideal wound coverage
A permanent, durable, nature-like wound coverage is the
gold standard for any disease process that requires the
replacement of damaged and destroyed skin. The provision
of large and infinite quantities of such wound coverage is
also desirable. The wound cover that most resembles normal
skin is autologous skin graft. However, even though it is
durable and permanent, it relies on wound healing cascades
to produce the desired vitality, vascularization and matura­
tion. This is accomplished by connective tissue deposition,
leaving permanent sequelae ranging from minimal scarring
to florid hypertrophic scarring and keloid formation.1
Current attempts to obtain a better quality of skin graft
and a more profound control of scar formation between the
interface of the wound bed and the transplanted autologous
skin include single-layer dermal substitutes: Integra single-
layer dermal template (Integra life Sciences) and Matriderm
(Dr Sawelacs Skin). These are similar but differ in their com­
position and width. Capillary ingrowth in these templates
precedes final ingrowth into super-thin applied skin grafts
(18/1000 inch); therefore careful wound manipulation is
necessary. These templates are applied on the wound bed
with similar goals as delineated for Integra double-layer.
Optimization of graft take can be obtained by using a
negative-pressure dressing, but in general, guidelines for
wound care as applied in all burn centers worldwide render
excellent graft take. The use of both dermal templates follows
the same philosophy as that involved in the application of
Alloderm and super-thin skin grafts. Future clinical research
focusing on similar biologic dermal templates, such as
glycerol-preserved dermis, Strattice and Veritas, will deter­
mine their role in this type of surgery.
Alternative wound covers
This broad definition refers to any materials used as an alter­
native to the gold standard: the autologous skin graft. Ideally,
they should carry the same characteristics (durability, perma­
nency, good vascularization, defense against infection, and
provision of excellent quality of life). Their relevant role in
the improvement of the quality of wound cover in major
burns and other large wounds should not be underesti­
mated, although their final outcomes are still far from
perfect. The emergence in the clinical scenario of alternative
wound coverage allowed swift burn reconstruction in either
the acute or the rehabilitation phase. The possibility to
obtain large amounts of tissue (dermal templates, etc.) off
the shelf has made possible immediate coverage of large
open wounds in one operation. It has allowed the develop­
ment of controlled surgical protocols for critical burns and
for the resection of large areas of hypertrophic scar.
The health industry is constantly providing burn surgeons
with new alternative wound covers (either temporary or
©2012 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2786-9.00017-5
The role of alternative wound
substitutes in major burn wounds
and burn scar resurfacing
Juan P. Barret
CHAPTER 17 
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IN THIS CHAPTER
PowerPoint Presentation Online

Total Burn Care
17
216
surgery, the purpose of the technique is to remove all
damaged and scarred tissue and to replace it with an even,
flat surface that will accommodate a laminar thin split-
thickness skin autograft.
The preparation of the wound bed and the application of
the dermal regeneration template are similar in acute and
reconstructive surgeries.
Preparation of the wound bed
Following a few simple clinical principles is the recipe for
success. A clean, vital, non-infected, non-hemorrhagic
wound bed must be obtained. All eschar and burn wound
necrosis is surgically removed until clean vital tissue is
revealed (Figs 17.1 and 17.2). All scar tissue is removed to
normal tissue. Hemostasis should be carefully obtained. The
excised area is kept moist with warm compresses (adrenaline
soaks are very helpful to obtain a dry surface) until the alter­
native coverage is ready for application.
permanent).2 Some remain in the past, others are current
standard practice, and a few require prospective testing. A list
of the most relevant alternative wound covers is given in
Table 17.1. It is mandatory to develop programs of clinical
prospective research to produce evidence-based data in order
to make a rational and cost-effective way of use. For an
extensive and more in-depth analysis of these covers the
reader is referred to Chapter 16.
The role of alternative wound coverage
in large wounds
Either in the acute setting or in the reconstructive phase,
alternative wound covers provide surgeons with an indefinite
source of material. Surgery can then be performed disregard­
ing the most important limiting factor: the availability of
donor sites. Planning of surgery can be organized focusing
on the best alternative for the patient, such as complete
removal of necrotic tissue or total scar resection. These two
scenarios are the real indication for the use of this costly
technology.
Patients who have suffered major burns with extensive
zones of full-thickness burn are the best candidates for tem­
porary and permanent wound covers. The goal is to extirpate
all necrotic tissue at once while preserving the homeostasis.
Leaving behind large open wounds challenges patient sur­
vival and triggers the development of multiple organ dys­
function. Closure of the wound is mandatory and maintaining
an infection free environment necessary. The purpose is to
obtain a clean surface, free of any necrotic tissue, that can
accept coverage by skin substitutes without postoperative
hematoma or infection.
Patients who survive burn injuries frequently develop
hypertrophic scar formation. Complete resection of these
areas and immediate coverage with dermal templates is now
possible. This is one of the most relevant recent changes in
burn reconstruction. Similar to their use in acute burn
Table 17.1  Alternative wound covers used in the past, present,
and future developments
1. TEMPORARY WOUND COVERS
– Human allograft
– Pig skin xenograft
– Human amnion
– Oasis (small intestine submucosa xenograft)
– Biobrane (outer silicone inner nylon mesh with added collagen)
– Transcyte (outer silicone inner nylon mesh with neonatal
allofibroblasts)
– Suprathel (absorbable microporous membrane)
– Unite (equine pericardium)
2. PERMANENT WOUND COVERS
– Apligraf (allogenic composite, human neonatal keratinocytes and
fibroblasts)
– OrCel (collagen sponge seeded with human neonatal keratinocytes
and fibroblasts)
– Epicel (cultured autologous keratinocytes)
– Alloderm (allogenic dermis)
– Matriderm (synthetic dermal template)
– Integra (synthetic dermal template)
– Renoskin (synthetic dermal template)
Figure 17.1  Hypertrophic scars and burn scar contractures are indications
for scar resection and resurfacing with alternative wound covers.
Figure 17.2  Total resection of the scar contracture leaves a clean, even,
graftable wound bed.

The role of alternative wound substitutes in major burn wounds and burn scar resurfacing
217
Wound coverage
During the preoperative visit all areas that need burn wound
excision or burn scar resurfacing are delineated and an
inventory of potential donor sites is developed. A decision
is made on whether a temporary, permanent single or
bi­laminar template will be used.3 A complete informed
consent for the treatment proposed, which includes alterna­
tives to the technique and the potential hazards of the
product, should be obtained.
Indications for single-layer templates include small, highly
functional areas acutely or in burn reconstruction and those
patients that will benefit from a single-step operation (limit
of ages, etc.).4 All other wounds are best treated with a
bi­laminar dermal substitute (Fig. 17.3).
Temporary skin substitutes may serve as temporary cover
until good haemostasis is achieved, improving the survival
of the dermal substitute. Furthermore, their use is helpful in
determining the vitality of the wound bed by allowing a
second look 48 hours after the initial surgery. Any small
areas of dubious or clear necrosis are then re-excised and the
skin substitute then applied Small areas of necrosis are foci
for infection and subsequent dislodgement of the substitute;
Figure 17.3  A bilaminar dermal regeneration template has been used to
improve the quality of the scar. A second surgical stage will be necessary to
graft the template with a super-thin skin graft.
when not controlled, the whole area becomes infected and
debridement is necessary, challenging the final outcome of
the intervention. Other temporary substitutes serve as non-
permanent covers that allow the wound to regenerate, either
by absorption or by spontaneous peeling.
Biological actions of alternative
wound coverage
Skin substitutes improve the quality of the closed
burn wound, control infection and pain, and avoid poor-
quality scars. Alternative wound covers allow early and
complete closure of wounds, even in major burns, which
helps to reduce the metabolic rate, systemic inflammatory
response, muscle wasting, infections, and overall mortality.
Effective pain control is achieved with both temporary and
permanent wound covers. The biological activity of skin
equivalents improves the healing process, reduces scarring
and disorganized collagen deposition, and enhances clone
differentiation of parenchymal cells.
Summary
Dermal templates have become an alternative for those
patients that present with large open wounds. They provide
a durable, permanent, and reliable source of coverage
ma­terial that is readily available off the shelf. A sound surgi­
cal protocol is necessary to produce reproducible results. The
application of these alternative wound covers in burn recon­
struction follows similar principles, and, as in the acute
setting, they have revolutionized reconstruction.
Further reading
Atiyeh BS, Hayek SN, Gunn SW. New technologies for burn wound
closure and healing—review of the literature. Burns. 2005;31:944-
956.
Brusselaers N, Pirayesh A, Hoeksema H, et al. Skin replacement in
burns. J Trauma. 2010;68:490-501.
Pham C, Greenwood J, Cleland H, et al. Bioengineered skin
substitutes for the management of burns: asystematic review.
Burns. 2007;33:946-957.
Saffle JP. Closure of the excised burn wound: temporary skin
substitutes. Clin Plast Surg. 2009;36:627-641.
 
Access the complete reference list online at

The role of alternative wound substitutes in major burn wounds and burn scar resurfacing
217.e1
© Copyright 2012 Elsevier, Inc. All rights reserved.
References
1. Badylak S. The extracellular matrix as a scaffold for tissue
reconstruction. Cell Develop Biol. 2001;13:377-383.
2. Jones L, Currie L, Martin R. A guide to biological skin substitutes.
Br J Plast Surg. 2002;55:185-193.
3. Wisser D, Rennekampff HD, Schaller HE. Skin assessment of burn
wounds covered with a collagen based dermal substance in a
2-year-follow up. Burns. 2004;113:978-981.
4. Gore DC. Utility of acellular allograft dermis in the care of elderly
burn patients. J Surg Res. 2005;125:37-41.

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The pathophysiology of
inhalation injury
Daniel L. Traber, David N. Herndon, Perenlei Enkhbaatar,
Marc O. Maybauer, Dirk M. Maybauer
Introduction and epidemiology
It has been over two decades since the authors published
their first manuscript on inhalation injury.1 In the review
article published the next year, it was reported that inhala­
tion injury was a main factor responsible for mortality in
thermally injured patients.2 Inhalation injury is still a major
problem.3 Although sepsis may be the major cause of death
among burned children, two-thirds of the patients who have
died in our own hospital have had an inhalation injury.4
Smoke inhalation causes 5000–10 000 deaths annually in
the United States and more than 23 000 injuries, including
approximately 5000 firefighter injuries.5 In fact, the United
States has one of the highest fire death rates among indus­
trialized countries. Inhalation injury is a serious medical
problem. More than 30% of thermally injured patients
admitted to burn centers in the United States have a con­
comitant smoke inhalation injury.6 Similar percentages of
fire victims who have sustained smoke inhalation appear in
several other countries.7–10 Despite effective management of
fluid resuscitation, early surgical excision of burned tissue
and improved ventilation techniques, the mortality rate of
patients who have combined burn and smoke inhalation
injury is still high.6,11–13 In patients with combined injury, the
lung is a critical organ and the progressive respiratory failure
associated with pulmonary edema is a pivotal determinant
of mortality.14–16 Albeit not as lethal, smoke inhalation alone
is a serious problem. It is estimated by the World Health
Organization that over one billion people develop airway
and pulmonary inflammation as a result of inhaling smoke
from indoor cooking fires, forest fires and burning of crops
(Fig. 18.1).17,18
The inhalation of toxic materials has been of interest for
a number of years, especially as the result of their use in gas
warfare. In the 1940s two very large fires focused interest on
the inhalation of smoke in fire victims. The first was a fire at
a nightclub in Boston called the Cocoanut Grove, where a
large number of people were trapped in a burning building
and consequently sustained severe inhalation injury.19,20 It is
interesting that in recent times a similar fire occurred in a
nightclub near Boston in Rhode Island.21 The second disaster
occurred in 1947 in Texas City, Texas.22 Here, a ship loaded
with ammonium nitrate fertilizer exploded in the harbor
and set off a chain of explosions and fires among some 50
refineries and chemical plants, resulting in over 2000 hospi­
tal admissions of patients with burn injury, many of whom
who had simultaneously inhaled smoke, as well as victims
with smoke inhalation alone. In many ways the burn victims
of the 9/11 disaster at the Pentagon were similar to these
individuals, as the burns and inhalation involved combus­
tion of petroleum products. Among the 790 injured survi­
vors of the terrorist attack on the Word Trade Center in New
York on 11 September 2001, 49% suffered from inhalation
injury. The situation was the same as the attack on the Pen­
tagon, and in both situations inhalation injury was also seen
in some patients who were not burned.21–23 Disasters like
those in Boston and Texas led to the establishment of centers
for the care of burn victims and to research into the patho­
physiology of burn injury.
Inhalation injury can be classified as 1) upper airway
injury, 2) lower airway injury, 3) pulmonary parenchyma
injury, and 4) systemic toxicity. The extent of inhalation
damage depends on the fire environment: the ignition
source, temperature, concentration, and solubility of the
toxic gases generated. For instance, thermal and chemical
compounds usually cause upper airway injury. The water-
soluble materials such as acrolein and the other aldehydes
damage the proximal airways and set off reactions that are
inflammatory to the bronchi and parenchyma, whereas
agents with lower water solubility, such as chlorine, phos­
gene, and nitrogen oxide, nitrogen dioxide or N2O3 or even
N2O4, are more likely to cause insidious injury.24
Pathophysiology
Injury to the oropharynx
Much of the pathophysiology that occurs with inhalation
injury is related to edema formation in the oropharynx,
bronchial areas and parenchyma, and results from an
increased transvascular fluid flux from these respective vas­
cular beds. Before a discussion of the changes that occur in
©2012 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2786-9.00018-7
CHAPTER 18 
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Total Burn Care
18
220
neutrophils then amplify the release of oxygen radicals, pro­
teases and other materials into burned areas (Fig. 18.2).
The massive edema occurring in the soft tissue of the
oropharynx following burns involves most of the variables in
the Starling equation. There is a large increase in microvascu­
lar hydrostatic pressure,38 a decrease in interstitial hydrostatic
pressure,39 a fall in the reflection coefficient,38 and an increase
in interstitial oncotic pressure.39,40 The usual treatment for
burn resuscitation calls for the administration of large
amounts of crystalloid solutions, which has the effect of
reducing the plasma oncotic pressure.41,42 This reduction not
only affects the oncotic pressure gradient in the microcircula­
tion but also has been reported to increase the filtration coef­
ficient.43,44 The result of this almost complete breakdown in
control of the microvascular function and the insult of fluid
administration is massive edema. This is probably nowhere
more apparent than in soft tissues of the face and oro­
pharynx. The danger to the patient is extreme. The edema
may obstruct the airway, not only making it laborious or
impossible to breathe but also making it difficult for the
anesthesiologist to intubate the patient (Fig. 18.3A). To avoid
this problem, many units prophylactically perform tracheos­
tomies on those patients who have evidence of thermal injury
to the upper airway on admission. However, tracheostomy
itself may present problems. The tube may further damage
injured areas, especially the larynx.45 It may be time to recon­
sider some of these practices. Perhaps some consideration
should be given to fluid resuscitation with colloids, which
can prevent some of this soft tissue edema and reduce the
volume of fluids required for resuscitation.46,47
Injury to the tracheobronchial area
With rare exceptions such as inhalation of steam, the injury
to the airway is usually due to the chemicals in smoke. The
heat capacity of air is low and the bronchial circulation very
these structures following inhalation injury, a review of the
forces responsible for the variables of the Starling–Landis
equation should be reviewed:25,26
J
k
P
P
COP
COP
v
f
c
if
p
if
=
−
−
−
[(
)
(
)]
σ
This equation describes the physical forces and physiologic
mechanisms that govern fluid transfer between vascular and
extravascular compartments. Jv, the transvascular fluid flux,
is equal to lymph flow during equilibrium states. As trans­
vascular fluid flux increases, interstitial volume also increases
(edema formation) until a new equilibrium with lymph flow
occurs. Kf is the filtration coefficient, an index of the total
number of pores that are filtering. The number of pores
could increase if a larger area of the microcirculation were
perfused, or if there were more pores per given area of the
microcirculation. These pores are the same size as those of
water and electrolytes, as opposed to the larger pores associ­
ated with permeability to protein. Pc and Pif are the hydro­
static pressures in the microcirculation and the interstitial
space, respectively. The reflection coefficient, σ, is an index
of microvascular permeability to protein. If σ is 1, the mem­
brane is impermeable to protein; when σ is 0, the membrane
is completely permeable to protein. COPp and COPif are the
oncotic or colloid osmotic pressures in the plasma and inter­
stitial spaces, respectively.
The major pathophysiology seen in the oropharynx follow­
ing inhalation injury is induced by microvascular changes
similar to those seen with thermal injury in other areas of the
body. The heat denatures protein, which in turn activates
complement. Complement activation causes the release of
histamine.27,28 Histamine then causes the formation of xan­
thine oxidase, an enzyme involved in the breakdown of
purines to uric acid.29 During this conversion, reactive oxygen
species (ROS) are released.30,31 Reactive oxygen species
combine with NO, constitutively formed in the endothelium,
to form reactive nitrogen species (RNS).32 The latter produce
edema in the burned area by increasing the microvascular
pressure and permeability to protein.33,34 Eicosanoids are
also released35,36 which, along with oxygen free radicals and
IL-8, attract polymorphonuclear cells to the area.37 These
Figure 18.1  An example of direct exposure to smoke as a result of open
fire using various materials as a fuel.
Figure 18.2  Mechanism of edema formation in the oropharynx.
Burn/smoke
Heat denaturization of protein
Complement activation
Histamine release
Conversion of xanthine oxidase
Release of superoxide ion
Permeability changes
Neutrophil adherence

The pathophysiology of inhalation injury
221
Figure 18.3  Facial and airway injury in the patient after burn and smoke inhalation. (a) A facial burn often associated with thermal injury to the upper
airway.153 (b) Hyperemia of airway epithelium. (c) Formation of airway obstructive cast. (A, from Cancio LC. Airway management and smoke inhalation injury in the burn
patient. Clin Plast Surg. 2009; 36(4): 555–67.)
aA
bB
cC
efficient in warming or cooling the airway gases, so that most
gases are at body temperature as they pass the glottis.48
Flames must be in almost direct contact with the airway to
induce thermal injury.49 The chemicals in smoke are depend­
ent on the materials that are being burned; however, for the
most part the host response is similar. In most instances
biological materials such as cotton fabric, wood, grass, or
products of these such as cattle feces (commonly used as fuel
in Third World countries) are the fuel for the fire. These
contain caustic materials such as ROS and RNS, organic
acids and aldehydes.50 These chemicals interact with the
airway to induce an initial response to trigger an inflamma­
tory response.
Many of the studies that have been reported relative to the
bronchial circulation following smoke inhalation injury
have been performed in sheep, because these animals have
a single bronchial artery51 and have a single lymphatic drain­
ing the lung that allows the measure of pulmonary transvas­
cular fluid flux.52 There was a 10-fold increase in bronchial
blood flow within 20 minutes of smoke inhalation.53
These same animals demonstrate a sixfold increase in
pulmonary transvascular fluid flux and a fall in PaO2/FiO2 ≤
200, but these were delayed to 24 hours. Similar findings
have been reported in patients with smoke inhalation alone
or the combination of a large cutaneous thermal injury and
smoke inhalation.54
Hyperemia of the airway is such a consistent finding in
smoke inhalation that it is used to diagnose the injury.55,56
Other variables that are used include injury in an enclosed
space, singed nasal hair and soot in sputum. However,
these latter injuries may be present but the subject may
still not develop the signs of low Pa and pulmonary edema
characteristic of inhalation injury. Airway inflammation
plays a major role in the overall response to inhalation injury
(Fig. 18.3B and 3C).
As we have noted, there is a large sustained increase in
blood flow in the airway following smoke inhalation.57
These changes in blood flow were associated with increased
bronchial microvascular permeability to protein and small
particles58 and pressure.59 Simultaneously with the changes
in the function of the bronchial microvasculature, there is a
loss or shedding of the bronchial columnar epithelium.60,61

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These changes result in a perfuse transudate with a protein
content similar to an ultrafiltrate of the plasma.62 There are
also copious secretions from the goblet cells.63 Early in
the response these secretions are fluid and form a foamy
material in the airway that many have mistaken for severe
pulmonary edema in humans.64 After several hours this
transudate/exudate solidifies or clots, forming obstructive
material in the airways65 (Table 18.1). These obstructive
materials formed in the upper airway may appear in the
lower airway and alveoli.63 This is problematic in several
respects. In some rare instances of severe airway injury these
materials can induce total obstruction (Fig. 18.4). Occlusion
of some of the bronchi or bronchioles in the setting of high
production of NO can lead to a loss of hypoxic pulmonary
vasoconstriction and hence increased shunt fraction. Loss of
hypoxic pulmonary vasoconstriction with inhalation injury
has been reported. Lastly, if single bronchi are occluded
while the patient is on a volume-limited ventilator there
could be overstretch, and barotrauma to the alveoli of the
non-occluded portion of the lung can occur.
Table 18.1  Mean levels of airway obstruction in uninjured sheep
and 48h after burn, smoke inhalation, and combined smoke
inhalation and burn injury
Injury
Bronchi
Airway level
Bronchiole
Terminal
Bronchiole
Uninjured (n = 5)
2.7 ± 2.4%
1.6 ± 0.9%
0.0 ± 0.0%
Burn alone (n = 6)
4.4 ± 3.5%
2.5 ± 1.5 %
0.4 ± 0.1%
Smoke alone (n = 5)
18.1 ± 10.1%*†
8.1 ± 3.0%*†
0.3 ± 0.4%*
Smoke + Burn (n = 7)
29.3 ± 15.1%*†
11.5 ± 6.7%*†
1.2 ± 1.9%*
Data are presented as mean percent ± SD (n number of animals in each group).
*Significantly different from uninjured animals’ means, Wilcoxon rank sum test,
p < 0.05.
†Significantly different from burn injury, Wilcoxon rank sum test, p < 0.05.
Cox R et al. Am J Respir Cell Mol Biol 9: 295, 2003
Figure 18.4  Airway obstructive cast. (A) Macroscopic pictures of airway obstructive cast in sheep 48 hours after burn and smoke inhalation injury.
(B) Macroscopic picture of airway cast taken from patient with burn and smoke inhalation injury by bronchoscope.154 (C and D) Microscopic pictures of
bronchi in sheep and bronchioles in a patient, totally blocked by obstructive cast after burn and smoke inhalation injury. (A & B from Nakae H, Tanaka H, Inaba H.
Failure to clear casts and secretions following inhalation injury can be dangerous: report of a case. Burns. 2001; 27(2): 189–91.)
A
B
C
D

The pathophysiology of inhalation injury
223
particles), and an increase in pulmonary microvascular pres­
sure.87,88 Animals that had been exposed to smoke inhalation
injury were also noted to have reduced PaO2/FiO2. These
variables are more severely affected when the inhalation is
combined with burn injury.89 The change in this variable
showed a good relationship with the histology injury scores
and the changes in transvascular fluid flux.79 In addition,
there was a loss of hypoxic pulmonary vasoconstriction in
the injured animals that would help to explain the loss of
oxygenation.90
As in the oropharynx the injury is associated with activa­
tion of PARP and 3-nitrotyrosine and is markedly reduced
by the administration of an iNOS or PARP inhibitors.78
The venous outflow of the bronchial circulation drains
into the pulmonary microcirculation at the pre-capillary
level.91 Considering the fact that initial damage to the airway
appeared to drive the pathophysiology of the parenchyma,
investigators hypothesized that the bronchial blood might
deliver cytotoxic materials or cells into the pulmonary
microcirculation. To test this hypothesis, several investiga­
tors have tied off the bronchial artery of sheep and then
exposed the animals to smoke.58,82,92 In these studies the
hypothesis was confirmed and the lung parenchymal changes
were reduced.
What could be the linkage between the airway, the bron­
chial venous drainage and parenchymal injury to the lung?
Neutrophils activated in the bronchial circulation flow out
into the bronchial venous drainage. Activated polymorpho­
nuclear cells (PMN), especially neutrophils, are stiff. The
diameter of neutrophils that have been fixed is approxi­
mately 7 µm.93 Because these cells have been dehydrated in
alcohol as part of the fixation process, unfixed cells are much
larger, of the order of 12 µm. The pulmonary capillary is
small, with an average diameter of 6 µm.93 Normally, the
large neutrophil can traverse the pulmonary capillary by
changing shape. However, many of the neutrophils have
been activated in the bronchial areas, their F-actin is acti­
vated, and the cells are stiff and cannot deform. These stiff
cells are carried to the pulmonary microvasculature where
they are impaled by the narrow pulmonary capillaries. The
activated neutrophils release reactive oxygen species and
proteases that damage the parenchyma. The following evi­
dence supports this concept of neutrophil cytotoxicity. Oxi­
dative processes are well known following inhalation injury.
There is lipid peroxidation and release of proteolytic enzymes
following injury.94–96 Administration of protease inhibitors
or scavengers of reactive oxygen species will reduce the
response to smoke inhalation95,97–99 when activated PMNs
lose the L-selectin on their surface. This L-selectin shedding
is prevented by the treatment with an L-selectin antibody.100
Treatment of the cells with an antibody to L-selectin will
prevent the changes in transvascular fluid flux and other
aspects of parenchymal damage.101 The final proof of this
hypothesis was to deplete the animals of their neutrophils
and determine how this affected their response to inhalation
injury. In these studies of sheep depleted of their leukocytes,
a high percentage of the response to smoke inhalation was
blocked.102 The pathophysiology of acute lung injury second­
ary to burn and smoke inhalation injury is summarized in
Figure 18.5.
In addition to the depletion of antioxidants discussed
above, it has also been reported that burned patients are
The airway is richly innervated with vasomotor and sensory
nerve endings.66 It is also known that these fibers release
neuropeptides that can produce inflammatory responses.67
Neuroinflammation is responsible for pathophysiology in a
number of clinical situations, including tissue injury induced
by chemicals.68,69 Lange et al. reported that antagonists
to substance P and calcitonin gene-related peptide had a
marked effect on the response when administered to sheep
and mice that were injured with both burn and smoke inha­
lation.70,71 In the ovine model the combination of burn and
smoke inhalation injury caused a 10-fold increase in pulmo­
nary transvascular fluid flux and a reduction of PaO2/FiO2 to
≤200. These changes were reversed by neuropeptide recep­
tors blocking agents.70 Neuropeptide release can cause activa­
tion of nitric oxide synthase, have chemokine activity, and
alter microvascular permeability.72 The resultant activities
lead to the formation of reactive oxygen and nitrogen
species.73 Some of the latter are very potent oxidants that can
damage DNA.32 Damage to DNA causes the activation of a
repair enzyme poly-(ADP-ribose) polymerase (PARP).74 This
enzyme depletes the cell of high-energy phosphates and
causes the activation of nuclear factor-κB (NF-κB).75,76 Acti­
vation of the nuclear factor causes the upregulation of iNOS
and IL-8, thereby accelerating the production of reactive
oxygen and nitrogen species.77 NO and 3-nitrotyrosine, an
index of reactive nitrogen species, iNOS mRNA and protein,
have been reported to be in the airway after smoke inhala­
tion.73,78 Compounds that catalyze the breakdown of peroxy­
nitrite reduce the response to smoke inhalation. Poly-(ADP
ribose) (PAR), the product of the constitutive enzyme poly-
(ADP ribose) polymerase, has been identified in airway
tissues following smoke inhalation.73 Inhibition of PARP
prevented the formation of PAR, the upregulation of NF-κB
and the formation of 3-nitrotyrosine.79 Similarly, Lange et al.
have reported that compounds that inhibit peroxynitrite by
catalyzing its rapid breakdown likewise prevented the forma­
tion of these materials.80 It is interesting to note that mice
lacking the PARP genes or given a PARP inhibitor will not
show the typical inflammatory changes usually observed
with asthma.81 Thus in many ways inhalation of smoke may
be similar to forms of airway injury. The fact that the response
to inhalation injury is driven by neuroinflammation suggests
that the response to smoke from wood or cotton should be
similar.
Injury to the lung parenchyma
As noted above, the lung parenchyma changes produced by
burn and smoke inhalation, as reflected by reduced PaO2/
FiO2 and reduced compliance, and increased edema forma­
tion, are delayed.82 This delay is dependent on the severity
of the airway injury.50,83 Lung injury is associated with an
increased pulmonary transvascular fluid flux.84 The degree of
transvascular fluid is proportional to the duration of smoke
exposure50 and is not caused by CO in the inhalant gas.85
However, the degree of arterial CO is related to severity of
inhalation injury.86 The factors responsible for fluid leak
are codified in the Starling–Landis equation.25,26 The varia­
bles of this equation relate fluid movement to pressure and
permeability variations. With inhalation of smoke there is a
reduction in refection coefficient (permeability to protein),
an increase in filtration coefficient (permeability to small

Total Burn Care
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224
deposition of collagen in their lungs in a similar fashion to
other forms of acute lung injury.105,109 As stated above, two
enzymes compete for arginine, nitric oxide synthase and
arginase.110 NOS forms NO and RNS. Arginase forms orni­
thine, which is converted into polyamines and proline,
leading to the formation of collagen.111 When NOS is active
it forms N-(ω)-hydroxy-nor-L-arginine (NOHA). NOHA
breaks down into NO and citrulline. NOHA is a potent
inhibitor of arginase.112,113 Thus as long as the activity of NOS
is elevated, arginase is inhibited. It has recently been reported
that the endogenous inhibitor of NOS, asymmetric dimethy­
larginine (ADMA), begins to increase in the lung of sheep
following combined burn and smoke inhalation injury.105 As
ADMA increases, NO production falls and tissue levels of
collagen increase. The increase in collagen results in hyaline
membrane formation, thickening the alveolar septum and
interfering with the diffusion of oxygen into the lung. ADMA
is formed in the lung on a regular basis but is rapidly
catabolized by dimethylarginine dimethylaminohydrolase
(DDAH).114,115 DDAH is inactivated by oxidation. Following
burn and inhalation injury lung levels of DDAH fall as
makers of oxidation increase, and as these events occur
depleted of arginine.103 When arginine levels are low the
nitric oxide synthase produces superoxide rather than nitric
oxide.104 Following smoke inhalation, arginase activity is
also elevated.105 This enzyme also depletes arginine by con­
verting it to ornithine.106 The administration of arginine may
assist in reducing the oxidation that occurs with inhalation
injury.107 However, the necessity of administering the arginine
as arginine hydrochloride (because of solubility) limits the
amount that may be given intravenously without producing
acidosis.
Long-term effects of inhalation injury
When earlier editions of this book were published mortality
from inhalation injury was high and the acute inflammatory
aspects of the injury were considered a major vector of mor­
tality. Now 85% of patients survive inhalation injury4 and
so the long-term aspects of the injury have increased. When
our patients are examined years after burn injury they dem­
onstrate restrictive lung disease and reduced diffusion capac­
ity, signs of fibrotic lung disease.108 At autopsy patients
and animals both reportedly show hyaline membrane and
Figure 18.5  Pathophysiology of burn and smoke inhalation-induced acute lung injury. iNOS, inducible nitric oxide synthase; PARP, poly-(ADP-ribose)
polymerase.
Burn/smoke
Irritants in smoke
(acrolein, aldehydes, free radicals)
Stimulation of sensory nerves of airway
Release of neuropeptides
Release of inflammatory
mediators into pulmonary circulation
Up-regulation of adherence
molecules on pulmonary
microvascular endothelial cells
Adherence of neutrophils
to endothelium
iNOS
Superoxide
Nitric oxide
Vascular
hyperpermeability
Peroxynitrite
DNA single-strand break
PARP activation
NF-κB
NF-κB
ATP depletion
Cellular dysfunction
Pulmonary dysfunction
Pulmonary edema
Pulmonary edema
Poor gas exchange
Pulmonary shunt
fraction
Loss of
hypoxic
vasoconstriction
Airway
obstruction
Increased airway
exudate containing
procoagulants
Increased
bronchovascular
permeability
Increased bronchial
venous drainage into
pulmonary circulation
Increased bronchial
blood flow
Bronchial vasodilatation
Increased pulmonary
transvascular fluid flux

The pathophysiology of inhalation injury
225
natural biological materials. Consequently, firefighters have
less time to gain control of a fire, and victims are more likely
to be incapacitated by breathing toxic gases and more likely
to sustain smoke inhalation because they have less time to
escape from the burning area.5 Inhalation injury is caused
by steam or toxic inhalants such as fumes, gases, and mists.
Fumes consist of small particles dispersed in air with various
irritants or cytotoxic chemicals adherent to the particles.
Mists consist of aerosolized irritant or cytotoxic liquids.
Smoke consists of a combination of fumes, gases, mists, and
hot air. Heat, toxic gases, and low oxygen levels are most
common causes of death in fires. A large variety of toxic gases
and chemicals can be generated depending on the fire envi­
ronment (Table 18.2).
Many of these compounds may act together to increase
mortality, especially carbon monoxide and hydrogen cya­
nide,123,124 where a synergy has been found to increase tissue
hypoxia and acidosis124 and may also decrease cerebral
oxygen consumption and metabolism.24,125 Hydrogen sulfide
would also be predicted to synergize with carbon monoxide
as both cyanide and hydrogen sulfide are inhibitors of mito­
chondrial cytochrome oxidase. Victims may be incapacitated
by the blinding and irritating effects of smoke, as well the
decreasing oxygen concentration that occurs with combus­
tion and results in progressive hypoxia.
Toxic gases such as carbon monoxide and cyanide rarely
damage the airway but affect gas exchange, producing more
systemic effects. It is thus important to obtain information
ADMA, arginase and collagen increase.105 We have previously
determined that oxidation was such a serious problem that
survival was dependent on the degree of oxidation.98 It was
also recently reported that levels of γ and α tocopherol were
markedly depleted in thermally injured children.116 Using an
ovine model it was reported that combined burn and smoke
inhalation depleted the animals of γ and α tocopherol, and
that administration of tocopherol, especially γ tocopherol,
orally (but most effectively by nebulization into the airway)
was effective in restoring lung levels of tocopherol, normal
oxidation status, and pulmonary function during the acute
phase of injury.116–122 Preliminary experiments using the
long-term model reported by Sousse et al. indicate that the
nebulization of γ tocopherol will also reverse the deposition
of collagen, elevated arginase, proline and ADMA, and
restore DDAH levels.
The fire environment and toxic
smoke compounds
Smoke toxicity is an increasing concern because industrial
products used today are changing from woods and natural
materials towards lighter construction materials, synthetics,
and petrochemical-based materials, which ignite and burn
two to three times hotter and faster than conventional
ma­terials and, when heated, emit a gas or smoke that will
also ignite two or three times faster and burn hotter than
Table 18.2  Origin of selected toxic compounds123
Gases and chemicals
Material
Source
Carbon monoxide
Polyvinyl chloride
Cellulose
Upholstery, wire/pipe coating, wall, floor, furniture coverings.
Clothing, fabric
Wood, paper, cotton
Cyanide
Wool, silk, cotton, paper, plastic, polymers
Polyurethane
Polyacrylonitrile
Polyamide
Melamine resins
Clothing, fabric, blankets, furniture
Insulation, upholstery material
Appliances, engineering, plastics
Carpeting, clothing
Household and kitchen goods
Hydrogen chloride
Polyvinyl chloride
Polyester
Upholstery, wire/pipe coating, wall, floor, furniture coverings
Clothing, fabric
Phosgene
Polyvinyl chloride
Upholstery, wire/pipe coating, wall, floor, furniture coverings
Ammonia
Wool, silk
Polyurethane
Polyamide
Melamine resins
Clothing, fabric, blankets, furniture
Insulation, upholstery material
Carpeting, clothing
Household and kitchen goods
Sulfur dioxide
Rubber
Tires
Hydrogen sulfide
Wool, silk
Clothing, fabric, blankets, furniture
Acrolein
Cellulose
Polypropylene
Acrylics
Wood, paper, cotton, jute
Upholstery, carpeting
Aircraft windows, textiles, wall coverings
Formaldehyde
Melamine resins
Household and kitchen goods
Isocyanates
Polyurethane
Insulation, upholstery material
Acrylonitriles
Polyurethane
Insulation, upholstery material
(From Prient, Traber DL. Toxic smoke compounds and inhalation injury – a review. (Burns. 1988; 14: 451–60.)

Total Burn Care
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symptoms such as headache, confusion, and collapse may
occur when the blood COHb level is 40–50%. Symptoms
such as unconsciousness, intermittent convulsions, and
respiratory failure may occur if the COHb level exceeds
60%, leading eventually to death if exposure continues.
The cardiovascular manifestations may result in tachycardia,
increased cardiac output, dysrhythmias, myocardial ischemia,
and hypotension, depending on the severity of poisoning.
The correlation of clinical manifestation and severity of CO
poisoning is summarized in Table 18.3.
Diagnosis should be based on direct measurement of
COHb levels in arterial or venous blood by CO oximetry; it
must be taken into account that venous blood underesti­
mates the arterial COHb content.136 Diagnosis may be facili­
tated by use of on-site portable breath analyzers. The inability
to differentiate oxyhemoglobin from COHb limits the use
of a pulse oximeter. The use of blood gas analyzers that
estimate SO2 based on measurement of dissolved PO2 should
also be avoided. The measurement of acid–base balance,
plasma lactate levels and bicarbonate is helpful in the man­
agement of CO poisoning with accompanying lactic or meta­
bolic acidosis. It is important to note that high oxygen
concentrations are usually administered to the victim in
transit to hospital, and some delay from cessation of expo­
sure to measurement of CO may limit evaluation of the true
extent of exposure.137 A nomogram has been developed
which can relate the carboxyhemoglobin levels of a patient
to the values that may have been present at the time of
smoke inhalation, and this can be used to estimate the true
degree of inhalation injury.86
relative to the source of the fire and the combustion products
generated when treating a fire victim (see Table 18.2). It is
also important to know the duration of exposure and the
extent to which the fire victim was in an enclosed area, as
this affects the dose of toxic materials presented to them.
Carbon monoxide
Carbon monoxide (CO) is an odorless, colorless gas that is
produced by incomplete combustion of many fuels, espe­
cially cellulolytics (cellulose products) such as wood, paper,
and cotton.126 Carbon monoxide toxicity remains one of the
most frequent immediate causes of death following smoke-
induced inhalation injury. The predominant toxic effect of
CO is its binding to hemoglobin to form carboxyhemo­
globin (COHb). The affinity of CO for hemoglobin is ~200–
250 times higher than that of oxygen.127 Inhalation of a 0.1%
CO mixture may result in the generation of a carboxyhemo­
globin level as high as 50% of the total hemoglobin. The
competitive binding of CO to hemoglobin reduces delivery
of oxygen to tissues, leading to severe hypoxia, especially of
the most vulnerable organs such as brain and heart, where
oxygen extraction is considerably higher than in most other
organs. The oxygen–hemoglobin dissociation curve loses its
sigmoid shape and is shifted to the left, thereby further
impairing tissue oxygen availability.123,128 In addition, the
ability of CO to bind to intracellular cytochromes and to
other metalloproteins contributes to CO toxicity. This com­
petitive inhibition with cytochrome oxidase enzyme systems
(most notably cytochromes-a and P-450) results in an ina­
bility of cellular systems to use oxygen.128,129 Shimazu and
his colleagues have shown that extravascular binding of CO
to cytochromes and other structures accounts for 10–15% of
total body CO stores. This intracellular binding of CO
explains the two-compartment elimination of CO from the
circulation.130 Miro and colleagues reported that CO inhibits
cytochrome-c oxidase activity in lymphocytes.131 The elec­
tron chain dysfunction caused by CO may lead to electron
leakage, superoxide production and mitochondrial oxidative
stress.132
Although smoke inhalation commonly affects the respira­
tory system, central nervous system (CNS) disturbance can
also develop. The CNS signs can be divided into acute and
delayed toxicity. The veterinary literature contains few reports
regarding the neurological consequences of smoke inhala­
tion. In dogs subjected to smoke inhalation, lesions were
identified that were compatible with acute carbon monoxide
(CO) toxicity. Lesions were confined to the caudate nucleus,
the globus pallidus, and the substantia nigra bilaterally, as
well as the cerebellum, cerebral cortex, and dorsal thalamus.
This case report describes the clinicopathological sequelae
in acute CO toxicity.133
Symptoms and diagnosis of carbon
monoxide poisoning
The symptoms of CO poisoning may manifest predomi­
nantly in organ systems with high oxygen utilization. The
severity of clinical manifestations is varied depending on the
concentration of CO. For instance, the central nervous system
Table 18.3  Symptoms and signs at various concentrations of
carboxyhemoglobin134,135
COHb (%)
Symptoms
0–10
None
10–20
Tightness over forehead, slight headache, dilation of
cutaneous blood vessels
20–30
Headache and throbbing in the temples
30–40
Severe headache, weakness, dizziness, dimness of vision,
nausea, vomiting, collapse
40–50
As above; greater possibility of collapse, syncope,
increased pulse and respiratory rate
50–60
Syncope, increased pulse and respiratory rate, coma,
intermittent convulsions, Cheyne–Stokes respirations
60–70
Coma, intermittent convulsions, depressed cardiac and
respiratory function, possible death
70–80
Weak pulse, slow respirations, death within hours
80–90
Death in <1 hour
90–100
Death within minutes
(From Einhorn IN. Physiological and toxicological aspects of smoke produced
during the combustion of polymeric materials. Environ Health Perspect. 1975; 11:
163–89 and Shulte JH. Effects of mild carbon monoxide intoxication. Arch Environ
Health. 1963; 7: 524–30.)

The pathophysiology of inhalation injury
227
depending on the concentration of cyanide inhalation
(Table 18.4).
Electrocardiographic changes such as ST segment elevation
that mimic an acute myocardial infarction143 may be sugges­
tive. Laboratory findings of anion gap metabolic acidosis
and lactic acidemia aid in confirming the diagnosis.144 Lactic
acidosis that is not rapidly responsive to oxygen therapy may
be a good indicator of cyanide poisoning.86,139 Also, an ele­
vated mixed venous saturation is suggestive for cyanide tox­
icity. Cyanide increases ventilation through carotid body and
peripheral chemoreceptor stimulation. Increasing ventila­
tion may augment toxicity in the early stages. Low levels of
hydrogen cyanide are routinely found in the blood of healthy
individuals at levels of 0.02 µg/mL in non-smokers and
0.04 µg/mL in smokers. Toxicity occurs at a level of 0.1 µg/
mL, and at 1.0 µg/ml death is likely.145 Correlation of blood
cyanide concentrations with clinical symptoms is summa­
rized in Table 18.5.
Other toxic chemicals
Other toxic chemicals may also contribute substantially to
morbidity and mortality in a burn victim. Hydrogen chloride
is produced by polyvinyl chloride degradation and causes
severe respiratory tract damage and pulmonary edema.
Nitrogen oxides may also cause pulmonary edema and a
chemical pneumonitis and may contribute to cardiovascular
depression and acidosis. Aldehydes such as acrolein and
acetaldehyde, which are found in wood and kerosene, may
further contribute to pulmonary edema and respiratory
irritability. Toxic industrial chemicals such as chlorine,
phosgene, hydrogen sulfide and ammonia are of central
importance. Because of their widespread availability and
high toxicity, there is certain concern that these chemicals
may be used as a weapon by terrorists.147,148
Phosgene gas is colorless, non-flammable, heavier than air
at room temperature, and has an odor of newly mown hay.
Hydrogen cyanide
Hydrogen cyanide (CN), the gaseous form of cyanide, is
generated by the combustion of nitrogen- and carbon-
containing substances such as wool, silk, cotton, and paper
as well as synthetic substances such as plastic and other
polymers. Combustion of these materials may rapidly and
lethally incapacitate a victim at the fire source.138 CN is a
colorless gas with the odor of bitter almonds, but it is dif­
ficult to detect at the site of fire. The cytotoxicity of cyanide
is produced by inhibition of cellular oxygenation with result­
ant tissue anoxia, which is caused by reversible inhibition of
cytochrome-c oxidase.137 CN is toxic to a number of enzyme
systems. The exact chemical mechanism by which cyanide
induces its toxicity includes combination with essential
metal ions, formation of cyanohydrins with carbonyl com­
pounds and the sequestration with sulfur as a thiocyanate.
However, the principal target enzyme of CN is cytochrome-c
oxidase, the terminal oxidase of the respiratory chain, and
involves interaction with the ferric ion of cytochrome-a3.
The importance of cyanide in smoke inhalation injuries is
reflected by a study performed in Paris, France, which showed
that mean blood cyanide concentrations in both fire victims
who survived (21.6 mol/L) and those who died (116.4 mol/L)
were significantly higher than those in control subjects
(5.0 mol/L), and levels in fire victims who died were signifi­
cantly higher than those in victims who survived.139 A report
of 144 fire victims in Dallas County, Texas, showed consist­
ent results with the Paris study.140 Elevated cyanide concen­
trations showed a direct relationship to the probability of
death, suggesting that cyanide poisoning may predominate
over carbon monoxide poisoning as a cause of death in some
fire victims. Cyanide also played a greater role in mortality
in the aircraft fire at Manchester International Airport, Man­
chester, UK, in 1985. These patients were not severely burned.
The large majority (87%) of the 54 individuals who died
had potentially lethal levels of cyanide in their blood,
whereas only 21% had COHb levels exceeding 50%. This
indicates the high possibility that under certain conditions
cyanide can be a more important determinant of morbidity
and mortality following smoke inhalation than CO, which
is usually regarded as the primary toxic threat.5 Smoke is also
an often overlooked source of CN exposure in terrorist
bombings. Following the first World Trade Center bombing
in 1993, traces of cyanide were found in the vans where the
explosion was originated. The US Centers for Disease Control
and the Department of Homeland Security consider CN
among the most likely agents of chemical terrorism.141
Cyanide possesses all the attributes of an ideal terrorist
weapon: it is plentiful, readily available, and easily obtain­
able because of its widespread use in industry and laborato­
ries. In addition, the use of cyanide does not require any
special knowledge. Cyanide is capable of causing mass inca­
pacitation and casualties, and can cause mass confusion,
panic, and social disruption.142
Symptoms and diagnosis of cyanide poisoning
Diagnosis at the fire scene may be difficult. Poisoning may
result in central nervous, respiratory, and cardiovascular
dysfunction due to inhibition of oxidative phosphorylation,
Table 18.4  Symptoms of cyanide toxicity
Symptoms in low or
moderate Inhaled cyanide
concentrations
Symptoms in moderate or
high Inhaled cyanide
concentrations
Faintness
Prostration
Flushing
Hypotension
Anxiety
Tremors
Excitement
Cardiac arrhythmia
Perspiration
Convulsions
Vertigo
Stupor
Headache
Paralysis
Drowsiness
Coma
Tachypnea
Respiratory depression
Dyspnea
Respiratory arrest
Tachycardia
Cardiovascular collapse

Total Burn Care
18
228
Chlorine is a greenish-yellow gas, an oxidizing agent, and
very reactive with water. It has a pungent odor. Upon contact
with water chlorine liberates hypochlorous acid, hydrochlo­
ric acid, and oxygen free radicals. It causes irritant effects
throughout the respiratory tree but mostly the nasal mucosa
and upper airways. Cell damage is caused by its strong oxi­
dizing capability.152 Both phosgene and chlorine were used
extensively during World War I.
Ammonia is a colorless gas at room temperature, with a
very pungent odor. Ammonia readily dissolves in water to
form ammonium hydroxide, a very caustic alkaline solution.
It causes cutaneous, ocular, and pulmonary injuries. Inhaled
ammonia can rapidly produce laryngeal injury and obstruc­
tion. It also causes upper tracheobronchial mucosal necrosis
with sloughing and severe pulmonary edema.152
There are no specific antidotes against toxicity from irritant
gases (phosgene, chlorine, and ammonia). Depending on
the severity of exposure, supportive therapy such as airway
management and ventilation should be provided. Early intu­
bation is required if any significant upper airway symptoms
such as stridor are present.
Further reading
Cancio LC. Airway management and smoke inhalation injury in the
burn patient. Clin Plast Surg. 2009;36(4):555-567.
Herndon DN, Barrow RE, Traber DL, et al. Extravascular lung water
changes following smoke inhalation and massive burn injury.
Surgery. 1987;102:341-349.
Herndon DN, Traber DL, Niehaus GD, et al. The pathophysiology of
smoke inhalation injury in a sheep model. J Trauma. 1984;24:
1044-1051.
Lange M, Szabo C, Enkhbaatar P, et al. Beneficial pulmonary effects of
a metalloporphyrinic peroxynitrite decomposition catalyst in burn
and smoke inhalation injury. Am J Physiol Lung Cell Mol Physiol.
2010; In press.
Traber DL, Schlag G, Redl H, et al. Pulmonary edema and compliance
changes following smoke inhalation. J Burn Care Rehabil.
1985;6:490-494.
Traber DL, Traber MG, Enkhbaatar P, et al. Tocopherol as treatment
for lung injury associated with burn and smoke inhalation.
J Burn Care Res. 2009;30(1):164-165.
Under 8°C phosgene is an odorless and fuming liquid.
Phosgene’s inadequate warning properties and delayed
symptoms make it a potential terrorist weapon.149,150 Phos­
gene is only slightly soluble in water, hence its deeper pen­
etration in the pulmonary system. On contact with water it
hydrolyzes into carbon dioxide and hydrochloric acid, result­
ing in direct caustic damage. It also undergoes acylation
reactions with amino, hydroxyl, and sulfhydryl groups of
cellular macromolecules, resulting in cell damage and apop­
tosis.149,151 As mentioned above, phosgene has delayed effects
from 20 minutes up to 48 hours, depending on the intensity
of exposure. Phosgene inhalation produces severe pulmo­
nary edema. Initially victims develop upper airway irritant
symptoms (eye irritation, rhinorrhea, cough) and then will
develop lower respiratory symptoms such as shortness of
breath, substernal burning, and chest tightness. The develop­
ment of overt pulmonary edema within 4 hours of exposure
portends a poor prognosis.
Table 18.5  Hydrogen cyanide concentrations in air and associated
symptoms in humans134,146
HCN concentration
(ppm)
Symptoms
0.2–5.0
Threshold of odor
10
(TLV-MAC)
18–36
Slight symptoms (headache) after several
hours
45–54
Tolerated for 0.5–1 hour without difficulty
100
Death in 1 hour
110–135
Fatal in 0.5–1 hour
181
Fatal in 10 minutes
280
Immediately fatal
(From Einhorn IN. Physiological and toxicological aspects of smoke produced
during the combustion of polymeric materials. Environ Health Perspect. 1975; 11:
163–89 and Kimmerle G. Aspects and methodology for the evaluation of
toxicological parameters during fire exposure. Polymer Conference Series:
Flammability Characteristics of Materials. Salt Lake City: University of Utah; 1973.)
 
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129. Goldbaum LR, Orellano T, Dergal E. Mechanism of the toxic
action of carbon monoxide. Ann Clin Lab Sci. 1976;6:372-376.
130. Shimazu T, Ikeuchi H, Sugimoto H, et al. Half-life of blood
carboxyhemoglobin after short-term and long-term exposure to
carbon monoxide. J Trauma. 2000;49(1):126-131.
131. Alonso JR, Cardellach F, Casademont J, et al. Reversible
inhibition of mitochondrial complex IV activity in PBMC
following acute smoking. Eur Respir J. 2004;23(2):214-218.
132. Miro O, Alonso JR, Casademont J, et al. Oxidative damage on
lymphocyte membranes is increased in patients suffering from
acute carbon monoxide poisoning. Toxicol Lett. 1999;110(3):
219-223.
133. Kent M, Creevy KE, Delahunta A. Clinical and neuropathological
findings of acute carbon monoxide toxicity in chihuahuas
following smoke inhalation. J Am Anim Hosp Assoc. 2010;46(4):
259-264.
134. Einhorn IN. Physiological and toxicological aspects of smoke
produced during the combustion of polymeric materials. Environ
Health Perspect. 1975;11:163-189.
135. Schulte JH. Effects of mild carbon monoxide intoxication. Arch
Environ Health. 1963;7:524-530.

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136. Westphal M, Morita N, Enkhbaatar P, et al. Carboxyhemoglobin
formation following smoke inhalation injury in sheep is
interrelated with pulmonary shunt fraction. Biochem Biophys Res
Commun. 2003;311(3):754-758.
137. Charnock EL, Meehan JJ. Postburn respiratory injuries in
children. Pediatr Clin North Am. 1980;27:661-676.
138. Purser DA, Grimshaw P, Berrill KR. Intoxication by cyanide in
fires: a study in monkeys using polyacrylonitrile. Arch Environ
Health. 1984;39:394-400.
139. Baud FJ, Barriot P, Toffis V, et al. Elevated blood cyanide
concentrations in victims of smoke inhalation. N Engl J Med.
1991;325:1761-1766.
140. Silverman SH, Purdue GF, Hunt JL, et al. Cyanide toxicity in
burned patients. Journal of Trauma. 1988;28:171-176.
141. Biological and chemical terrorism: strategic plan for
preparedness and response. Recommendations of the CDC
Strategic Planning Workgroup. MMWR Recomm Rep. 2000;
49(RR-4):1-14.
142. Eckstein M. Cyanide as a chemical terrorism weapon. Jems.
2004;29(8): suppl 22-31.
143. Smith PW, Crane R, Sanders DC, et al. Effects of exposure to
carbon monoxide and hydrogen cyanide. Physiological and toxological
aspects of combustion products. Washington D.C.: National
Academy of Science; 1976:75-78.
144. Morocco AP. Cyanides. Crit Care Clin. 2005;21(4):691-705.
145. Becker CE. The role of cyanide in fires. Vet Human Toxicol.
1985;27:487-490.
146. Kimmerle G. Aspects and methodology for the evaluation of
toxicological parameters during fire exposure. Polymer Conference
Series: Flammability Characteristics of Materials. Salt Lake City:
University of Utah; 1973.
147. Hughart JL: BMM. Industrial chemicals and terrorism: Human
health threat analysis, mitigation prevention. In: Registry Aftsad,
editor.: US Public Health Service; n.d.
148. Anonymous. Combating terrorism: observations on the threat
of chemical and biological terrorism. In: Office UGA, ed.
Statement of Henry L. Hinton Jr, Assistant Comptroller General.
Washington, DC: National Security and International Affairs
Division; 1999.
149. Author N. Pulmonary agent. US Army Medical Research Institute
of Chemical Defence, Medical Management of Chemical
Casualties Handbook. Aberdeen, MA: USAMRICD; 2000:18-34.
150. Author N. Medical management for phosgene. Managing hazardous
material incidents. Atlanta, GA: US Department of Health and
Human Services; 2001.
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and treatment strategies. J Occup Environ Med. 2001;43(2):110-
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152. Burns TR, Mace ML, Greenberg SD, Jachimczyk JA. Ultrastructure
of acute ammonia toxicity in the human lung. Am J Forensic Med
Pathol. 1985;6(3):204-210.
153. Cancio LC. Airway management and smoke inhalation injury in
the burn patient. Clin Plast Surg. 2009;36(4):555-567.
154. Nakae H, Tanaka H, Inaba H. Failure to clear casts and
secretions following inhalation injury can be dangerous: report
of a case. Burns. 2001;27(2):189-191.

©2012 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2786-9.00019-9
Diagnosis and treatment of
inhalation injury
Lee C. Woodson, Mark Talon, Daniel L. Traber, David N. Herndon
Introduction
Inhalation injury is a non-specific term that refers to damage
to the respiratory tract or pulmonary parenchyma by heat or
chemical irritants carried into the airways during respiration.
Inhalation injury remains one of the most critical injuries
following thermal insult. It may occur in conjunction with
cutaneous burns or in isolation. The severity of injury varies,
depending on the chemical composition of the agent(s)
inhaled, the intensity of exposure, temperatures reached
during combustion and pre-existing comorbidities. There are
three basic classes of inhalation injury: direct thermal injury,
tissue damage due to inhalation of chemical irritants, and
systemic effects of inhaled toxins. Direct thermal injury is
generally restricted to the upper airway and rarely involves
subglottic structures.1 The upper airway serves as an efficient
heat exchanger that protects lower structures from extremes
of heat or cold. Laryngeal closure also protects subglottic
areas. Exceptions are the inhalation of steam due to the
much higher specific heat of water vapor, and blast injuries
that can force hot gases past the glottic opening. Inhaled
irritants are generally present in smoke as a mixture of gases,
fumes, and mists, and the chemical composition of smoke
produced from various fuels has been described.2 Fumes
consist of particles of various size dispersed in inhaled gases.
Mists are aerosolized liquids. The intensity of exposure along
with the size and chemical composition of these particles
and droplets determines how far distally they will migrate
in the respiratory tract and the nature of the tissue injury.2
Large particles and droplets of lipid-soluble liquids are more
likely to adhere to airway surfaces and do not reach as far
distally as smaller particles and more water-soluble droplets.
Systemic toxicity occurs when toxins such as carbon mono­
xide or cyanide are present in the inhaled gases.
The reported incidence of inhalation injuries has varied
greatly over time and from region to region. Smith3 and
others reported 19.6% incidence among burn patients in the
USA, in Israel Haik4 and colleagues found as few as 1.5%,
while Luo5 and others found 8.01% in China. Regional dif­
ferences are to be expected as a result of differences in local
customs, building materials, and other factors.
The presence of inhalation injury is clinically significant
for a variety of reasons, as listed in Table 19.1. Inhalation
injury has been found to be an independent risk factor for
mortality.6,7 It is also associated with hemodynamic inst­
ability, as volume requirements for resuscitation may be
increased by as much as 50% when cutaneous burns are
accompanied by inhalation injury.8 Parenchymal injury can
lead to impaired gas exchange, pneumonia, and ARDS.
When severe, these changes increase the risk of multiorgan
failure and mortality. After recovery from inhalation injury
pulmonary function disorders may persist due to pulmonary
fibrosis or bronchiectasis. Improvements in the survival of
patients with inhalation injury have been attributed to better
overall burn outcomes, improved ventilatory management,
and improved management of pneumonias.5
Improvements in the care of cutaneous burns have out­
paced advancements in the treatment of inhalation injuries.
There are several reasons for this disparity. The treatment of
pulmonary parenchymal injury is inherently more complex
than treatment for cutaneous burns. Necrotic skin can be
excised and replaced with substitute materials or autografted
skin, and healing can be observed directly. In contrast, treat­
ment of injured lung involves measures to prevent further
injury to allow host mechanisms to repair injured tissues.
Healing of pulmonary injury is followed more indirectly by
observations of blood gas analysis and radiographs. Inhala­
tion injury results both from direct effects of heat and chemi­
cal irritants as well as indirect effects from an inflammatory
response to the initial insult. Despite extensive studies, these
processes are incompletely understood and no specific thera­
pies have been identified.
Because inhalation injury has such broad clinical implica­
tions it is important that it be diagnosed as early as possible.
Early diagnosis can be accomplished by recognition of risk
factors revealed by the history and physical examination,
and confirmed by diagnostic procedures.
Diagnosis
As stated above, inhalation injury is a non-specific term used
to describe injury to the airways and/or lungs due to the
inhalation of gases that are either hot or contain chemical
irritants, or both. There is no consensus on the diagnostic
criteria for inhalation injury. In the clinical setting the
CHAPTER 19 
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Total Burn Care
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230
The physical examination reveals additional risk factors for
inhalation injury. We guard our face vigorously, and the
presence of burns to the face or singed eyebrows or nasal
hair implies a very intense exposure. When gases hot enough
to burn tissue are near the airway it suggests that oropharyn­
geal or nasopharyngeal structures may also suffer thermal
injury. Soot deposits on the face and carbonaceous sputum
suggests intense exposure to and inhalation of smoke. Physi­
cal examination may reveal signs and symptoms such as
stridor, hoarseness, drooling, and dysphagia that are consid­
ered classic evidence of inhalation injury. These findings,
however, do not always indicate that tracheal intubation is
necessary.14 However, as described below, when patients
are considered at risk for upper airway thermal injury and
occlusion, a priority is to evaluate the upper airway for
impending occlusion that may be prevented by early tracheal
intubation.
In addition to the history and physical examination, there
are diagnostic tools that may be used to confirm a diagnosis
of inhalation or to follow the progression of injury. As stated
above, manifestations of respiratory dysfunction may be
delayed after inhalation injury. As a result, pulse oximetry
and arterial blood gas analysis are insensitive indicators of
lung injury during the initial stages. Despite this, it is impor­
tant to employ these tools as soon as possible. Early impair­
ment of gas exchange is a sign of severe injury and requires
early intervention. Diagnosis of CO or cyanide toxicity may
be facilitated by blood gas analysis. It is also important to
have baseline values to judge progress.
The chest radiograph is also considered an insensitive indi­
cator of parenchymal injury after smoke inhalation. Although
an admission chest radiograph should be obtained in all
patients suspected of inhalation injury, it has been recog­
nized that a normal study does not rule out the possibility
of significant pulmonary injury.12
Flexible fiberoptic bronchoscopy was early recognized as
a powerful tool in the diagnosis of inhalation injury.15
Fiberoptic bronchoscopy allows direct visualization of tissue
damage to the upper airway and bronchi by heat and chemi­
cal irritants. This procedure can quickly and reliably identify
patients with upper airway compromise who will benefit
from intubation.16 Bronchoscopic evidence of inhalation
injury includes soot deposits, erythema, edema (as indistinct
tracheal rings or blunting of the carina), mucosal blisters and
erosions, hemorrhages, and bronchorrhea (Fig. 19.1).
Flexible fiberoptic bronchoscopy has been considered the
‘gold standard’ and is often used to confirm the diagnosis of
inhalation injury.17 However, Hunt noted that in some cases
bronchoscopy performed soon after injury may not show
mucosal injury.15 In addition, because acute lung injury and
tracheobronchitis can be a result of systemic inflammation
due to cutaneous burns,10,11 endoscopic changes after 36–48
hours may be caused by mechanisms other than inhalation
of chemical irritants. Moreover, although fiberoptic bron­
choscopy can definitively identify tissue damage from inhala­
tion injury, it has been recognized that the observed changes
are relatively proximal and may be more severe than more
peripheral, parenchymal injuries.18 As a result, a broncho­
scopic diagnosis of inhalation does not always identify which
patients will experience progressive respiratory dysfunction.
Radionuclide studies have been used to provide evidence
of pulmonary injury distal to the more proximal views
diagnosis is a relatively subjective judgment based on history
and physical examinationination, and often confirmed by
additional diagnostic procedures such as bronchoscopy. One
of the reasons for the lack of consensus is that impaired
pulmonary function due to inhalation injury often results
from an inflammatory response to the initial injury, and
manifestations may be delayed for a day or two. In addition,
it is our clinical impression that progressive respiratory
failure is not necessarily proportional to the intensity of
smoke exposure.9 It is also possible for thermally injured
patients to experience acute lung injury from the systemic
effects of the inflammatory response to severe cutaneous
burns.10 Thus, it is not uncommon to see acute lung injury
in patients with large scald burns.11 This makes it difficult to
determine what component of respiratory failure is due to
inhalation injury in patients with large burns.
On initial presentation, patients with inhalation injury
may have relatively normal gas exchange as evaluated by
arterial blood gas analysis, and the chest radiograph is
usually normal.12 In the absence of evidence of respiratory
distress it is important to recognize features from the history
and physical examination that reveal risk factors for inhala­
tion injury. Early diagnosis is important to recognize the
potential for airway compromise, manage fluid resuscita­
tion, and to recognize systemic toxicity that may lead to
permanent neurological deficits if not promptly treated.
History pertinent to the diagnosis of inhalation injury
includes information regarding the mechanism of injury and
the intensity of exposure. Mechanisms of injury that carry
significant risk of inhalation injury include not only expo­
sure to smoke from a fire, but blast injury that can force hot
gases past the larynx, steam burns that can not only burn the
upper airway but carry heat to structures below the larynx,
and exposure to caustic fumes as in some industrial acci­
dents. Information regarding the mechanism of injury also
includes the source of combustion, which could identify
specific chemical irritants. The history can also provide infor­
mation regarding the intensity of exposure. Duration of
exposure is an important determinant of intensity of expo­
sure. When a victim’s avoidance behavior is impaired, as
when trapped in an enclosed space, intoxicated or uncon­
scious, or in the extremes of age, exposure to injurious inha­
lants is increased.
History of the mechanism of injury is especially important
in the case of scalds due to ingestion of hot liquids. Although
patients may appear asymptomatic initially, oropharyngeal
scalds have led to fatal airway occlusion. Intraoral scalds can
present in a manner similar to epiglottitis.13 The larynx
should be examined for evidence of compromise in all
patients who present with significant risk of intraoral scald.
Table 19.1  Clinical significance of inhalation injuries
• Mortality: immediate/late
• Airway closure secondary to edema
• Hemodynamic instability/increased resuscitation fluid requirements
• Impaired pulmonary gas exchange
• Pneumonia/ARDS
• Systemic inflammatory syndrome and multiorgan system failure
• Laryngeal damage
• Chronic pulmonary dysfunction

Diagnosis and treatment of inhalation injury
231
caused by the initial insult causes local accumulation of
inflammatory cells and initiation of a cascade of inflamma­
tory mediators that exacerbate and sustain tissue damage
(see below).
Airways become blocked by edema, bronchoconstriction,
fibrin casts, necrotic debris, and inflammatory infiltrate (Fig.
19.2). Degraded surfactant causes alveolar instability and
collapse. These changes result in impaired hypoxic pulmo­
nary vasoconstriction and areas of atelectasis, and postob­
structive sequestration of material that provide a medium for
bacterial growth and risk of pneumonia. Impaired function
of alveolar macrophages slows the removal of these materials
and facilitates the development of infection. Pulmonary
compliance is reduced, which can greatly increase the work
of breathing.
As a result of these changes pulmonary gas exchange is
impaired. Atelectasis due to airway obstruction increases
dead space and shunt to an extent, but the impaired gas
exchange due to smoke inhalation appears to be primarily a
ventilation–perfusion imbalance.22 It has been suggested
that this mechanism of pulmonary dysfunction is funda­
mentally different from other types of ARDS.17,23 Other
etiologies of ARDS, such as sepsis, involve disruption of the
pulmonary capillary membrane and alveolar flooding,
resulting primarily in true shunt. This distinction can influ­
ence the ventilator strategies employed. Patients with respi­
ratory failure due to smoke inhalation injury have small
airway obstruction, and care should focus on pulmonary
toilet together with recruiting and stabilizing alveoli, which
tend to collapse, whereas in ARDS due to other etiologies
the strategy is to concentrate on avoiding ventilator-induced
lung injury. In some burn centers this is a rationale for the
use of high-frequency percussive ventilation.17
Just as the bronchi are the focus of the diagnosis of inhala­
tion injury, it is also the focus of its pathology.24 The hyper­
emia and edema that are seen in the airway and which are so
important for the diagnosis of inhalation injury are the result
of an almost 20-fold increase in bronchial blood flow.25,26
Following the airway injury, there are changes in the lung
parenchyma. There is a release of the chemokine interleukin
(IL)-8 and an influx of neutrophils into the airway and
alveoli. Reactive oxygen (ROS) and nitrogen species (RNS)
are formed.27 One of the latter, peroxynitrite, damages DNA.
DNA damage results in activation of poly-(ADP ribose)
polymerase.28 Poly-(ADP ribose) protects the damaged DNA
but also activates the nuclear factor NF-κB.29 This causes the
formation of the inducible form of nitric oxide synthase and
additional release of IL-8, attracting and activating additional
neutrophils and forming more reactive nitrogen and oxygen
species.30 The oxidation, nitration, and nitrosation of lung
tissues results in membrane damage, edema formation and
impaired oxygen diffusion.31,32 Alveoli that are not ventilated
are not perfused with blood because alveolar hypoxia causes
pulmonary vasoconstriction. NO released by nitric oxide
synthase causes a loss of hypoxic pulmonary vasoconstric­
tion, leading to perfusion of unventilated alveoli and thus a
fall in arterial oxygen saturation.33
Ablation of the bronchial blood flow will prevent most of
the pathophysiology involved in inhalation injury to the
pulmonary parenchyma.24,34,35 These changes in bronchial
blood flow are not associated with heat. They can be pro­
duced in experimental animals by smoke that has been
permitted by flexible bronchoscopy. Intravenously adminis­
tered xenon-133 is excreted by the lungs and exhaled.
Delayed clearance of xenon-133 is a sensitive indicator of
inhalation injury.19 More recently, lung scintigraphy using
technetium-99 aerosol inhalation has been used to identify
areas of pulmonary dysfunction in patients with respiratory
dysfunction after smoke inhalation. Delayed clearance and
inhomogeneous lung distribution of radioactivity are evi­
dence of injury.20 These studies are sensitive indicators of
inhalation injury, but interpretation can be confounded by
pre-existing lung disease and it may be difficult to perform
these studies in critically ill burn patients.
Pathophysiology of pulmonary insufficiency
with inhalation injury
As stated above, except in special cases such as inhalation of
steam, injury to airways below the larynx and pulmonary
parenchyma nearly always results from chemical irritation.
A number of reviews are available to describe the patho­
physiology of pulmonary failure associated with smoke
inhalation.2,21 Chemicals inhaled with smoke as well as
carbon particles coated with irritants are deposited in the
airways. Aqueous secretions of the mucosa dissolve these
irritants and the respiratory mucosa is bathed in relatively
concentrated caustic solutions. The initial response to this
insult is injury to the respiratory epithelium, resulting in
hyperemia, edema, increased mucous secretions, impaired
ciliary clearance, and bronchoconstriction. Work in experi­
mental animals has also demonstrated an early separation
of ciliated respiratory epithelial cells from the basement
membrane. This results in denuded areas of the airways and
explains the copious formation of protein-rich exudate.
Fibrin casts tenaciously adherent to the airway surfaces are
formed from this exudate.
Much of the morbidity associated with smoke inhalation
is the result of the inflammatory response to the early direct
effect of chemical irritants. The inflammatory response to
smoke inhalation is similar to the injury produced by aspira­
tion of acidic gastric contents. The direct injury to tissues
Figure 19.1  Bronchoscopic view of the trachea from a patient with smoke
inhalation injury. Note generalized inflammation and erythema. Edema is
manifest as indistinct tracheal rings and blunting of the carina. There are
patchy areas of denuded mucosa and a fibrinous exudate is forming at the
carina.

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232
cyanide or carbon monoxide poisoning, there are specific
interventions. When mechanical ventilation is required,
measures must be taken to avoid ventilator-induced injury.
Treatment should begin at the scene of injury. Pulmonary
function must be supported in coordination with care of
cutaneous burns and other possible injuries. The history
along with a rapid physical examination can identify victims
at risk of inhalation injury as well as respiratory insufficiency
and other indications for early intervention.
Initially, special attention must be given to the airway
evaluation. There are many potential indications for early
and even prophylactic intubation in victims of serious burn
injury (Table 19.2). Early hypoxemia due to impaired gas
exchange after inhalation injury is an ominous sign, and
those with respiratory distress not corrected by supplemental
oxygen may require intubation. Patients unable to protect
their airway owing to diminished mental status due to injury
or intoxication should be intubated to prevent aspiration. It
is recommended that, even in the absence of inhalation
injury, those with large burns covering 40% or more of their
total body surface area (TBSA) should be intubated because
of the risk of associated hemodynamic instability.17 Another
indication for early prophylactic intubation is the risk of
cooled to body temperature.36 As mentioned above, the
blood flow to the airway is so effective in cooling or heating
inhaled air that it is almost impossible for hot gases to reach
the bronchi.36,37 These changes in blood flow also appear to
be independent of the chemical composition of smoke, as
they are mediated by a neuroinflammation. We have recently
reported that following insufflation of smoke into deeply
anesthetized sheep, the airway blood flow increased 10-fold,
but after administration of an inhibitor of the neuropeptide
calcitonin gene-related peptide (CGRP) the smoke-induced
hyperemia was markedly reduced.38 Neuropeptides (peptides
released from nerves within the lung tissue) induce vasodila­
tation by causing activation of nitric oxide synthase, leading
to the formation of NO. It has also been reported that an
inhibitor of the neuro isoform of nitric oxide synthase would
block the hyperemia and much of the pathophysiology men­
tioned above, including the loss of hypoxic pulmonary vaso­
constriction.39,40 These findings have led us to the following
hypothesis: the chemicals in smoke activate sensory nerves to
release neuropeptides that activate NOS1 to release NO and
superoxide to form peroxynitrite, which damages DNA, acti­
vating PARP, that stimulates NF-κB which in turn will upregu­
late the inducible form of nitric oxide synthetase, leading to
massive formation of ROS and RNS, tissue damage and
hypoxia and dyspnea. Some of the activated polymorphonu­
clear cells that escape from the pulmonary and bronchial
circulation into the systemic circulation are carried to sys­
temic organs, promoting multiorgan system damage.
Treatment
In general, there are no specific therapeutic interventions for
inhalation injury and treatment consists of supportive
modalities. However, if systemic toxicity is suspected, e.g.
Table 19.2  Indications for early tracheal intubation
• Overt signs and symptoms of airway obstruction
• Extensive burns to the head and neck
• Inability to protect airway from aspiration
• Significant toxicity from carbon monoxide or cyanide
• Respiratory failure
• Extensive burns (>40 % TBSA)
• Hemodynamic instability
Figure 19.2  Small airway occluded by inflammatory exudate in a patient who had a smoke inhalation injury.

Diagnosis and treatment of inhalation injury
233
performed if their clinical condition changes. An algorithm
for airway management in burn patients is illustrated in
Figure 19.3.
Another potential complication of inhalation injury
requiring early attention is systemic toxicity from carbon
monoxide (CO) and/or cyanide. Intoxication should be con­
sidered in all patients suspected of significant exposure to
smoke. The predominant toxic effect of CO is to prevent
binding of oxygen to hemoglobin by the formation of
carboxyhemoglobin (COHb). CO has an affinity for hemo­
globin approximately 200 times that of oxygen. CO can also
prevent cellular utilization of oxygen by binding to mito­
chondrial cytochromes. Early symptoms include headache,
nausea, dizziness, and lowered mental status. Diagnosis
requires direct measurement of COHb. Conventional pulse
oximetry will not distinguish between oxyhemoglobin
and COHb. COHb can be measured by arterial or venous
CO oximetry or recently developed pulse CO oximetry.43
Increased oxygen partial pressure will speed elimination of
CO. Oxygen supplementation by face mask is usually suffi­
cient, but in more severe cases (COHb >15–20%) it may be
necessary to provide 100% oxygen via an endotracheal tube.
Hyperbaric oxygen has also been used to treat CO poisoning,
but there is no consensus on the indications, treatment
parameters, or outcome benefits.44 Moreover, hyperbaric
facilities are not widely available.
Cyanide is another toxic component of smoke, especially
when the fuel is certain plastic products. Cyanide causes cel­
lular anoxia by binding to mitochondrial cytochromes and
preventing intracellular oxygen utilization. Arterial oxygen
partial pressures are not reduced by cyanide. Clinical signs
of hypoxia despite adequate arterial oxygen tension, or meta­
bolic acidosis despite apparently adequate oxygen delivery
suggest cyanide toxicity. The earlier treatment is initiated
the more likely it will be successful. Supplemental oxygen
can cause non-enzymatic oxidation of reduced cytochromes,
and displace cytochrome oxidase and potentiate the effects
of administered antidotes. Pharmacological intervention
includes methemoglobin generators such as nitrates (amyl
nitrite inhalation 0.2 mL, or sodium nitrite intravenous
10 mL of 3% solution for adults and 0.13–0.33 mL/kg of 3%
solution for children) and dimethylaminophenol (3.25 mg/
kg) to increase methemoglobin levels. Methemoglobin
competes with cytochrome oxidase for cyanide. Caution is
required because excessive levels of methemoglobin lead to
decreased oxygen-carrying ability of hemoglobin and may
cause toxicity. Some agents can bind cyanide directly.
Dicobalt edetate (20 mL of 15% solution for adults or
0.3–0.5 mL/kg of 15% solution for pediatric patients) has a
rapid effect but carries a risk of toxicity. Hydroxocobalamin
(adults 5–10 g or children 70 mg/kg) is the precursor of
vitamin B12 and has been shown to be safe, with few side
effects. Sulfur donors such as sodium thiosulfate (adults
25 mL of 50% solution or children 1.65 mL/kg of 25%
solution) accentuate the body’s enzymatic conversion of
cyanide to thiocyanate in the presence of the mitochondrial
enzyme rhodanese, reducing its toxicity and increasing
elimination.45
As mentioned above, inhalation injury has been consist­
ently observed to significantly increase fluid requirements
for resuscitation of patients with cutaneous burns.8 The pres­
ence of an inhalation injury might intuitively be viewed as
upper airway occlusion due to edema from thermal injury.
In some patients with burns to the face and neck or inhala­
tion of hot gases or steam, early intubation can be life-
saving. Training supported by the American Burn Association
has encouraged early tracheal intubation in patients at risk
for airway occlusion. However, intubation is not a benign
intervention and there is growing recognition of the associ­
ated risks. Eastman and colleagues at the Parkland Burn
Center recently published a retrospective study of pre-burn
center intubations of burn victims.41 This was in response to
what may have been a preventable death of a burn victim
intubated prior to hospitalization. Out of 879 burn patients
intubated before admission to hospital, 11.9% were extu­
bated on the day of admission. In addition, 41.1% were
extubated within 48 hours of injury. These findings suggest
that many patients may have been exposed to the risks of
intubation without significant benefit. A list of risks of
unnecessary tracheal intubations are listed in Table 19.3.
Intubation is especially dangerous during transportation
outside a hospital.
Otolaryngologists at the Baltimore Regional Trauma
Center used spirometry (flow–volume loops) and flexible
fiberoptic bronchoscopy to prospectively evaluate indica­
tions for intubation in patients at risk of inhalation injury.16
They reported that in 11 patients who were admitted to the
emergency department with evidence of inhalation injury,
six met their institutional criteria for intubation. However,
when these patients were examined by fiberoptic bronchos­
copy no significant airway compromise was observed, and
they were managed safely and effectively without intubation.
The high negative predictive value of normal flow–volume
loops for airway compromise in patients with inhalation
injury has been previously reported by Haponik et al.42
Madnani and colleagues have also demonstrated that the
presence of signs and symptoms that have been considered
classic evidence of inhalation injury does not always predict
the need for tracheal intubation. Further evaluation is needed
to avoid morbidity associated with unnecessary intubations.
When burn victims first present, the history and physical
examination can identify those who are in significant respi­
ratory distress or who have other indications for immediate
endotracheal intubation. For other patients with risk factors
for inhalation injury but who may only be experiencing mild
distress, spirometry (flow–volume loops) and/or endoscopic
evaluation can be used to identify those who have impend­
ing airway compromise and will more certainly benefit from
early prophylactic intubation. Those who do not require
early intubation can be observed and repeat evaluations
Table 19.3  Risks of unnecessary tracheal intubation in
burned patients
• Impairs communication with patient (impairs taking history and
obtaining consent)
• Urgent attempts more likely to fail or cause injury
• Acute burn patients often require heavy sedation after intubation
• The endotracheal tube is difficult to secure in the presence of facial
burns and self-extubations are common (heavy sedation or muscle
relaxants make this more dangerous)
• Inhalation injury and a translaryngeal endotracheal tube are synergistic
in producing laryngeal and tracheal injuries

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suctioning for short periods of 10–15 seconds can reduce the
incidence of these problems. Postural drainage can be useful,
although sometimes skin graft location and fragility impede
use of this technique.50 Percussive and vibratory techniques
such as high-frequency chest wall oscillation also help clear
mucoid secretions.50,51 It is also important to maintain good
nutritional status in these patients.
As a result of inhaled irritants, patients can suffer from
severe bronchospasm. This can usually be managed by using
inhaled β agonists such as albuterol or salbuterol. Aero­
solized heparin is used in many centers to reduce bronchial
cast formation by reducing fibrin formation in the exudate
formed at denuded areas of epithelium.52–54 It does not cause
systemic anticoagulation in the doses used clinically. Aero­
solized and intravenous acetylcysteine has also been used as
a mucolytic and was shown to improve pulmonary antioxi­
dant capacity in one study.55 In a pediatric study, a combina­
tion of aerosolized heparin and acetylcysteine was used and
resulted in a significant reduction in reintubations, the inci­
dence of atelectasis, and in mortality following smoke inha­
lation injury.54
When physical therapy and pharmacological agents still
fail to facilitate expectoration of secretions or ameliorate cast
formation, fiberoptic bronchoscopy can be effective for
removal of secretions, and also to obtain microbiological
specimens through bronchoalveolar lavage in suspected
cases of pneumonia. Attempts to replace surfactant have
also been studied, but are not in widespread clinical use.
an indication to restrict fluids to avoid pulmonary edema.
In fact, fluid restriction has been found to exacerbate pulmo­
nary capillary leak and increase lung lymph formation in
sheep that have sustained cutaneous burns and smoke inha­
lation injury.46 Although it is important to avoid fluid over­
load in all patients, including those with inhalation injury,
inadequate fluid resuscitation can also further injury to the
lungs of patients with inhalation injury.47 A combination of
cutaneous burns and inhalation injury reduces the margin
for error in managing fluid resuscitation. It becomes more
difficult to reach a balance where sufficient volume is admini­
stered for resuscitation but not too much to drive up filling
pressures, which may increase transudation from pulmonary
capillaries that already have increased permeability.
Supplemental humidified oxygen should be used for
patients suspected of having inhalation injury, the humidi­
fication helping to prevent inspissation of the airway secre­
tions, and the head of the bed should be placed at a 30–45°
angle. This helps reduce upper airway edema and reduces the
effect of pressure from abdominal contents on the dia­
phragm. Meticulous pulmonary hygiene is a vital compo­
nent of the management of inhalation injury. Frequent
airway suctioning, chest physiotherapy including percussive
and coughing techniques, and early mobilization all help
prevent build-up of secretions, which can cause airway
obstruction, atelectasis, and predispose to the development
of pneumonia.48,49 Care should be taken when suctioning
to avoid hypoxia and bradycardia. Preoxygenation and
Figure 19.3  An algorithm to assist airway
management decisions in patients at risk for
inhalation injury.
Patient at risk for for inhalation injury
• Facial burns
• Hoarseness
• Evidence of smoke exposure
• Other classical signs of inhalation injury
ATLS primary survey
ATLS primary survey
Serial exams
Intubate
Glottic compromise
due to edema
Mild respiratory distress
No other indications for intubation
Flow volume loops
and/or fiberoptic bronchoscopy
Continued observation
Repeat studies if clinical change
No flow loop evidence
of obstruction
No compromise by endoscopy
Significant respiratory distress
or other indications for intubation
(massive burns, aspiration risk, etc.)
Mild flow volume changes,
but no significant obstruction
by bronchoscopy

Diagnosis and treatment of inhalation injury
235
It appears to be associated with decreased work of breathing,
improved oxygenation (higher PaO2/FiO2 ratios) and lower
peak pressures.63,64 A pediatric study group also had a signifi­
cant reduction in the incidence of pneumonia compared to
a conventionally ventilated control group.63
Airway pressure release ventilation (APRV) is a more
recently developed pressure-controlled time-cycled mode of
ventilation that can allow spontaneous breathing during the
ventilatory cycle without changing the preset pressure set­
tings.65 It has a high-pressure and a low-pressure setting.
Recruitment of alveoli and oxygenation occur at the high-
pressure setting, and ventilation occurs by controlled releases
to the lower pressure. The mechanical inspiratory phase can
be prolonged to achieve higher mean airway pressures
without high peak airway pressures. It has so far shown
promising results in trauma patients and pediatric patients
with mild to moderate lung disease. Comparable or superior
oxygenation values were achieved while using lower
peak airway pressures.66 This mode may be useful in the
burn population as a means to ventilate while reducing
barotrauma.
Extracorporeal membrane oxygenation (ECMO) is a tech­
nique that can be used in patients with severe respiratory
failure, in which the patient’s blood is circulated through an
extracorporeal cardiopulmonary bypass circuit that facili­
tates gas exchange through a semipermeable membrane.67
While this is taking place, much lower ventilatory pressures
and a low FiO2 can be used to allow the lung to heal without
the additional complications of mechanical ventilation.
Anticoagulation is necessary during treatment, which makes
surgical care of burn wounds difficult. Although numbers in
burn patient studies are small, this may offer a salvage
therapy for patients with severe respiratory disease on con­
ventional ventilation.67,68
Mechanical ventilation should be weaned as the patient’s
condition improves, and discontinued as soon as it is no
longer necessary. During the weaning process, the FiO2, PEEP
and rate should be reduced as tolerated, until the patient is
capable of supporting their own respiratory requirements.
Parameters used as indicators for extubation include the
presence of the following: an alert patient; resolution of
upper airway edema with an audible air leak around the
endotracheal tube with the cuff deflated; PaO2/FiO2 ratio
>200; an adequate tidal volume (6 mL/kg); and negative
inspiratory pressure > 20 cmH2O.56 The patient should also
not be acidotic and should be hemodynamically stable.
Once the patient is extubated, supplemental, humidified
oxygen should be provided, and the patient should be care­
fully observed for any signs of respiratory compromise that
might necessitate re-intubation.
Opinions on the use of tracheostomy in burn patients are
divided. The most common indication is a need for pro­
longed mechanical ventilation. This allows removal of the
translaryngeal endotracheal tube, which reduces the chance
of laryngeal injury and provides a more secure airway. When
multiple surgical treatments are predicted a tracheostomy
tube obviates the need for repeated intubation for each pro­
cedure. When prolonged mechanical ventilation is needed
patient comfort can also be enhanced with a tracheostomy,
and pulmonary toilet is facilitated. Owing to high rates of
pulmonary contamination with burn wound bacterial flora
and mortality, tracheostomy was discouraged in the past.69
Antibiotics are indicated for suspected or proven pulmonary
infection.49,56
Mechanical ventilation is indicated when the signs of res­
piratory failure are either present or imminent. Indications
include impaired gas exchange due to pulmonary parenchy­
mal injury, decreased pulmonary compliance, or impending
collapse of effort due to fatigue. Burns involving the head
and neck may make intubation technically difficult. In these
circumstances avoidance of muscle relaxants and the use of
an intubation technique that maintains spontaneous venti­
lation is safest. The flexible fiberoptic bronchoscope is well
suited to this task. A nasal endotracheal tube may be prefer­
able for patient comfort, oral hygiene and stability. In addi­
tion, a nasal endotracheal tube can be secured by a nasal
septal bridle, which is much more secure than tape or liga­
tures over burned skin and prevents irritation of wounds and
disruption of grafts.
There is no consensus on the ideal mode of mechanical
ventilation for burn patients. The intricacies of mechanical
ventilation in burn patients have recently been reviewed.17,57,58
The aim is to provide adequate ventilation to maintain
airway and alveolar patency without exacerbating the pul­
monary injury by over-distension or barotrauma. In this
patient population the airways may be narrowed by edema,
which increases airway resistance and hence airway pres­
sures. The Lower Tidal Volume Trial (ARMA) conducted by
the ARDS Network found that lower tidal volumes (limited
to 6 mL/kg) were associated with decreased mortality in
patients with ARDS.59 Most burn centers now have adopted
this approach to reduce ventilator-induced injury.60 Permis­
sive hypercapnia has also been found to be a safe technique
for avoiding higher airway pressures in burn patients.52,61
This allows lower airway pressures and smaller tidal volumes
to be used when ventilating the patient, and is well tolerated
when gradual in onset and the pH is kept > 7.2–7.25.52,61 The
optimal positive end-expiratory pressure (PEEP) should be
determined using a pressure–volume curve. This helps main­
tain alveolar patency and reduces trauma caused by the shear
forces imparted as alveoli collapse and are re-expanded with
each breath. The lower inflection point of the pressure–
volume curve of a mechanical breath is where the slope of
the lower curve begins to increase, and is the airway pressure
below which the alveoli collapse. The PEEP value should be
set just above this. FiO2 should be weaned down as tolerated
to reduce oxygen-related complications. The PaO2 can
be maintained between 80 and 100 mmHg, although
values over 65–70 mmHg can support adequate tissue
oxygenation.
Conventional mechanical ventilation is either volume or
pressure controlled. Volume-controlled ventilation delivers
a consistent tidal volume and minute volume to the lungs,
but this can result in increased airway pressures depending
on the compliance of the lungs. Pressure-controlled ventila­
tion limits the inflating pressure used, and thus the tidal
volume varies depending on compliance and inspiratory
time.52 High-frequency percussive ventilation (HFPV) is a
ventilatory mode that delivers subtidal breaths at a high
frequency along with tidal, low-frequency breaths.62 HFPV
has become the preferred mode of ventilation in some burn
centers.17 Proponents suggest that HFPV allows gas exchange
at lower peak and mean pressures and may also dislodge and
facilitate the removal of secretions and debris in the airways.

Total Burn Care
19
236
not always be regained following recovery from inhalation
injury.75–77 In a pediatric burn cohort, no difference in exer­
cise tolerance was noted between children who had sus­
tained an inhalation injury and those who had not. However,
the children who had had an inhalation injury achieved
their goal with a significantly higher respiratory rate, and had
a higher incidence of abnormal lung function.77 Conversely,
an adult study found no evidence of altered respiratory
function after inhalation injury, or any significant exercise
intolerance in those tested.78
Damage to the larynx by inhaled toxins and thermal
injury, and also by intubation as a treatment for inhalation
injury or upper airway edema, is common and can result in
persistent hoarseness, dysphonia, or even exercise intoler­
ance due to dyspnea on exertion. Injury to the laryngeal
mucosa can cause scarring that can affect the flexibility and
vibratory capacity of the vocal cords, and also their ability
to open and close properly. Laryngeal morbidity can be
severe, as seen in Figure 19.4. As a result, voice production
may be affected, and this may not resolve without treatment.
Some of the phonation problems can be helped by voice
therapy, and some of the laryngeal scarring may be amenable
to surgical or laser excision.79 It is important to recognize
More recently, with advances in burn care several studies
have found that the risk of pneumonia is not increased by
tracheostomy in burn patients.70,71 As a result, many burn
centers routinely perform tracheostomy not only in patients
who require prolonged ventilation but in those with exten­
sive burns that will require multiple anesthetics for surgical
procedures. In studies involving small groups of patients
tracheostomy has been used without complications.71 Tra­
cheostomy is an invasive procedure, however, and in larger
patient populations there is a risk of significant morbidity.
Saffle et al. found that burn patients treated with conven­
tional ventilation were extubated sooner than those rand­
omized to early tracheostomy.72 As clinical outcomes were
otherwise not different between groups, it appears that there
was no significant benefit of the more invasive tracheostomy.
In the absence of clear evidence of benefit the use of trache­
ostomy in burn patients remains a matter of clinical judg­
ment, but in each case the risk of complication should be
balanced by a significant benefit.
Long-term changes in pulmonary function
Although the pathophysiology associated with the acute
phase of inhalation injury has been studied extensively both
clinically and through experimental models, the same cannot
be said for the long-term alterations in pulmonary function
that occur in the months and years following a burn and
inhalation injury. Palmieri has discussed some of the theo­
retical reasons why it is difficult to evaluate the long-term
clinical effects of inhalation injuries related to burns.73 Any
current study of long-term changes in pulmonary function
after inhalation injury will find it difficult to determine
which changes are due to the effects of inhaled irritants at
the time of injury and which result from ventilator-induced
lung injury when mechanical ventilation often was accom­
plished with higher tidal volumes and airway pressures than
are currently used. Likewise, persistent changes resulting
from ARDS caused by systemic inflammatory responses to
the burn injury or sepsis also contribute an undetermined
component to the morbidity. Massive burn injury also
impairs muscle mass and strength along with chest wall
compliance, which can affect respiratory effort even in the
absence of inhalation injury. As Palmieri points out, none
of the reports of long-term pulmonary changes after inhala­
tion injury relate the degree of acute pulmonary insult to the
long-term changes.73 Pre-existing lung disease was also not
considered in previous studies. Most studies involve rela­
tively small groups of patients studied at different times and
by different means, which make it difficult to compare
results between studies.
One way post-injury pulmonary function has been shown
to be manifest is by a hyperactive or bronchospastic condi­
tion of the airways. This was shown to persist for at least 6
months in one study, along with inflammatory changes in
the bronchial mucosa and elevated inflammatory cytokine
(TNFα), interferon (IFNγ), and interleukin (IL)-2 levels in
serum and broncheoalveolar lavage fluid. The majority of
subjects, however, had normal pulmonary function tests.74
Longer-term studies have in some cases shown the develop­
ment of obstructive and restrictive patterns on pulmonary
function testing, indicating that normal lung function may
A
Figure 19.4  (a) Thermal necrosis of laryngeal structures as seen in this
photograph is an indication for tracheostomy to minimize laryngeal injury.
A tracheostomy was performed on this patient soon after admission, and
after recovery from his burns and decannulation of his trachea his voice
was normal. (b) Thermal and mechanical injury to the larynx can result in
posterior glottic scars and webs, as in this endoscopic image. Early diagnosis
of injury can facilitate care to minimize long-term effects.
B

Diagnosis and treatment of inhalation injury
237
initial treatment of patients might have an important effect
on the latter long-term pathophysiology. This is certainly an
area for future investigation. Nitric oxide synthase, the
enzyme that plays a major role in the acute aspects of injury,
has the amino acid arginine as its substrate, as does arginase,
the enzyme that is the basis of collagen deposition.95 Thus
inhibition of NOS could make more arginine available for
the arginase and hence collagen deposition. In a consensus
conference, the faculty from the Shriners Hospitals met to
discuss potential therapies for inhalation injury.96–99 Clinical
trials will be necessary before the effectiveness of these novel
interventions is established.
Further reading
Demling RH. Smoke inhalation lung injury: an update. Eplasty.
2008;8:e27.
Dries DJ. Key questions in ventilator management of the burn-injured
patient (first of two parts). J Burn Care Res. 2009;30(1):128-138.
Enkhbaatar P, Herndon DN, Traber DL. Use of nebulized heparin in
the treatment of smoke inhalation injury. J Burn Care Res. 2009;
30(1):159-162.
Kealey GP. Carbon monoxide toxicity. J Burn Care Res. 2009;30(1):
146-147.
Saffle JR, Morris SE, Edelman L. Early tracheostomy does not improve
outcome in burn patients. J Burn Care Rehabil. 2002;23(6):
431-438.
Sheridan RL. Airway management and respiratory care of the burn
patient. Int Anesthesiol Clin. 2000;38(3):129-145.
laryngeal injuries as early as possible. When they are recog­
nized, tracheostomy can help minimize exacerbation of the
injury by a translaryngeal airway. Consultation with a laryn­
gologist may make such interventions more timely.
Potential future therapeutic strategies
The hypothesis described above offers the possibility for
future development of numerous pharmacological interven­
tions. One of the most obvious areas for treatment would
be the use of antioxidants. Burned patients are immensely
depleted of antioxidants, especially vitamin E.80,81 In this
clinical scenario ROS and RNS play major roles in organ
damage in addition to mediation of the pathophysiology.82
Nebulization of γ tocopherol, a form of vitamin E that scav­
enges both ROS and RNS, has been shown to be benefi­
cial.83,84 On the other hand, inhibitors of NOS1,39,85 NOS286
and PARP,87 as well as compounds that catalyze the break­
down of peroxynitrite, have also been shown to be effective
in reversing the acute changes in pathophysiology.30,87–90
Recently there have been reports that hydrogen sulfide may
have therapeutic benefits in lung injury.91 We have tested
hydrogen sulfide in both murine and ovine models of burn
injury and found therapeutic benefit.92,93
As we have learned more and more about the pathophy­
siology and treatment of inhalation injury, there have been
more survivors. Examination of these individuals several
years after the injury showed that many had evidence of
excessive deposition of collagen in their lungs.94 Perhaps
 
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