Chăm Sóc Và Điều Trị Bỏng Toàn Diện (Total Burn Care – Tập 5)

157.e4 13  •  Anesthesia for Burned Patients
venipuncture and over guidewires. Crit Care Med. 1992;20(10):
1426-1430.
160. Sheridan RL, Weber JM, Peterson HF, Tompkins RG. Central venous
catheter sepsis with weekly catheter change in paediatric burn
patients: an analysis of 221 catheters. Burns. 1995;21(2):127-129.
161. Cobb DK, High KP, Sawyer RG, et al. A controlled trial of scheduled
replacement of central venous and pulmonary-artery catheters. N
Engl J Med. 1992;327(15):1062-1068.
162. Fraenkel D, Rickard C, Thomas P, et al. A prospective, random­
ized trial of rifampicin-minocycline-coated and silver-platinum-
carbon-impregnated central venous catheters. Crit Care Med.
2006;34(3):668-675.
163. Weber JM, Sheridan RL, Fagan S, et al. Incidence of catheter-
associated bloodstream infection after introduction of minocycline
and rifampin antimicrobial-coated catheters in a pediatric burn
population. J Burn Care Res. 2012;33(4):539-543.
164. Kagan RJ, Neely AN, Rieman MT, et al. A performance improvement
initiative to determine the impact of increasing the time interval
between changing centrally placed intravascular catheters. J Burn
Care Res. 2014;35(2):143-147.
165. White PF, Way WL, Trevor AJ. Ketamine: its pharmacology and
therapeutic uses. Anesthesiology. 1982;56(2):119-136.
166. Layon AJ, Vetter TR, Hanna PG, Bingham HG. An anesthetic
technique to fabricate a pressure mask for controlling scar
formation from facial burns. J Burn Care Rehabil. 1991;12(4):349-
352.
167. Maldini B. Ketamine anesthesia in children with acute burns and
scalds. Acta Anaesthesiol Scand. 1996;40(9):1108-1111.
168. Levanen J, Makela ML, Scheinin H. Dexmedetomidine premedi­
cation attenuates ketamine-induced cardiostimulatory effects
and postanesthetic delirium. Anesthesiology. 1995;82(5):1117-
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169. Ravipati P, Reddy PN, Kumar C, et al. Dexmedetomidine decreases
the requirement of ketamine and propofol during burns debridement
and dressings. Indian J Anaesth. 2014;58(2):138-142.
170. Han TH, Greenblatt DJ, Martyn JA. Propofol clearance and volume
of distribution are increased in patients with major burns. J Clin
Pharmacol. 2009;49(7):768-772.
171. Irving GA, Butt AD. Anaesthesia for burns in children: a review of
procedures practised at Red Cross War Memorial Children’s Hospital,
Cape Town. Burns. 1994;20(3):241-243.
172. Costello TG, Cormack JR. Anaesthesia for awake craniotomy: a
modern approach. J Clin Neurosci. 2004;11(1):16-19.
173. Talon MW, Sherwood LE. Regional sensory nerve blocks of the
scalp decrease the incidence of post-operative nausea and vomit­
ing in reconstructive burn children: a pilot study. J Burn Care Res.
2006;27(2):S149.
174. Sheridan RL, Szyfelbein SK. Trends in blood conservation in burn
care. Burns. 2001;27(3):272-276.
175. Criswell KK, Gamelli RL. Establishing transfusion needs in burn
patients. Am J Surg. 2005;189(3):324-326.
176. O’Mara MS, Hayetian F, Slater H, et al. Results of a protocol of trans­
fusion threshold and surgical technique on transfusion requirements
in burn patients. Burns. 2005;31(5):558-561.
177. Mann R, Heimbach DM, Engrav LH, Foy H. Changes in transfusion
practices in burn patients. J Trauma. 1994;37(2):220-222.
178. Sittig KM, Deitch EA. Blood transfusions: for the thermally injured
or for the doctor? J Trauma. 1994;36(3):369-372.
179. American Society of Anesthesiologists. Practice guidelines for blood
component therapy: a report by the American Society of Anesthe­
siologists Task Force on Blood Component Therapy. Anesthesiology.
1996;84(3):732-747.
180. Smoot ECIII. Modified use of extremity tourniquets for burn wound
debridement. J Burn Care Rehabil. 1996;17(4):334-337.
181. Missavage AE, Bush RL, Kien ND, Reilly DA. The effect of clysed and
topical epinephrine on intraoperative catecholamine levels. J Trauma.
1998;45(6):1074-1078.
182. Barret JP, Dziewulski P, Wolf SE, et al. Effect of topical and subcuta­
neous epinephrine in combination with topical thrombin in blood
loss during immediate near-total burn wound excision in pediatric
burned patients. Burns. 1999;25(6):509-513.
183. Mzezewa S, Jonsson K, Aberg M, Sjoberg T, Salemark L. A prospec­
tive double blind randomized study comparing the need for blood
transfusion with terlipressin or a placebo during early excision and
grafting of burns. Burns. 2004;30(3):236-240.
184. Teixeira PG, Inaba K, Shulman I, et al. Impact of plasma trans­
fusion in massively transfused trauma patients. J Trauma.
2009;66(3):693-697.
185. Pidcoke HF, Aden JK, Mora AG, et al. Ten-year analysis of transfu­
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increased plasma and platelet use correlates with improved survival.
J Trauma Acute Care Surg. 2012;73(6 suppl 5):S445-S452.
186. Shaz BH, Dente CJ, Harris RS, MacLeod JB, Hillyer CD. Trans­
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trauma
patients.
Anesth
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187. Cantle PM, Cotton BA. Prediction of massive transfusion in trauma.
Crit Care Clin. 2017;33(1):71-84.
188. Barret JP, Desai MH, Herndon DN. Massive transfusion of recon­
stituted whole blood is well tolerated in pediatric burn surgery. J
Trauma. 1999;47(3):526-528.
189. Bordes J, Joubert C, Esnault P, et al. Coagulopathy and transfusion
requirements in war related penetrating traumatic brain injury. A
single centre study in a French role 3 medical treatment facility in
Afghanistan. Injury. 2016.
190. Kashuk JL, Moore EE, Sawyer M, et al. Postinjury coagulopathy man­
agement: goal directed resuscitation via POC thrombelastography.
Ann Surg. 2010;251(4):604-614.
191. Spinella PC, Holcomb JB. Resuscitation and transfusion principles for
traumatic hemorrhagic shock. Blood Rev. 2009;23(6):231-240.
192. Dzik WH, Kirkley SA. Citrate toxicity during massive blood transfu­
sion. Transfus Med Rev. 1988;2(2):76-94.
193. Kruskall MS, Mintz PD, Bergin JJ, et al. Transfusion therapy in emer­
gency medicine. Ann Emerg Med. 1988;17(4):327-335.
194. Kendigelen P, Kamalak Z, Abat D. Should warm fresh whole blood be
the first choice in acute massive hemorrhage in emergency condi­
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195. Vlaar AP, Binnekade JM, Prins D, et al. Risk factors and outcome of
transfusion-related acute lung injury in the critically ill: a nested
case-control study. Crit Care Med. 2010;38(3):771-778.
196. Kim J, Na S. Transfusion-related acute lung injury; clinical perspec­
tives. Korean J Anesthesiol. 2015;68(2):101-105.
197. Dasararaju R, Marques MB. Adverse effects of transfusion. Cancer
Control. 2015;22(1):16-25.
198. Graves TA, Cioffi WG, Mason AD Jr, McManus WF, Pruitt BA Jr. Rela­
tionship of transfusion and infection in a burn population. J Trauma.
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199. 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;16(5):476-480.
200. Barrow RE, Hawkins HK, Aarsland A, et al. Identification of factors
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2005;24(6):523-528.

158
The Skin Bank
CHARLES D. VOIGT, STEVE WILLIAMSON, RICHARD J. KAGAN, and LUDWIK K. BRANSKI
14 
rewarming prior to implantation. This was followed by Mor­
ris’s16 report demonstrating the beneficial effects of using
allogeneic skin in the treatment of infected ulcers and other
contaminated wounds and Shuck et al.’s17 report suggest­
ing the potential use of allogeneic skin in the treatment of
traumatic wounds based on their Vietnam War experience.
These increased uses of allograft skin led to further research
into the beneficial effects of allograft skin on wound healing,
including its association with a reduced incidence of bacte­
rial infections18,19 and the stimulation 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
excision and allografting with temporary immunosuppres­
sion in children with extensive injuries.22 Today allograft
skin remains an ideal temporary cover for extensive or
excised cutaneous or soft tissue wounds, particularly when
sufficient autograft skin is not available or when temporary
wound coverage is desired.
Another biologic dressing with a long history in the treat­
ment of burned patients is amniotic membrane, with the
first use for the purpose taking place in 1912 by Sabella a
few short years after it was originally used in skin transplan­
tation by Davis in 1910.23,24 During the immediate period
following these reports, the use of amniotic membranes was
attempted as permanent skin replacements, although the
grafts were rejected. In 1952, Douglas was the first to report
the use of amniotic membrane as a temporary burn wound
covering. Since that time, amnion has been one of the tools
available in the treatment of partial-thickness burns. 25–30
Amnion has been shown to alleviate pain, prevent infec­
tion,23,28,31,32 reduce pruritus,30 and accelerate wound
healing.24,26,31 Our institution has used amniotic membrane
for temporary total ocular surface coverage in the treatment
of toxic epidermal necrolysis, which has shown improve­
ments in corneal clarity, conjunctival scaring, and dry eye
symptoms at 3-month follow-up as compared to a histori­
cal group that received maximal medical treatment.33 The
preparation and storage of amnion has been a role in many
skin banks around the world.
The Growth of Skin Banking
The widespread use of allograft skin in the management of
patients with extensive burn, traumatic, and soft tissue
injuries has had a major impact on the number of skin
banking facilities over the past two decades or so. Conse­
quently 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
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 generally so unsatisfactory for resurfac­
ing large areas that they were typically limited to the treat­
ment 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
Storage of human skin did not begin until the early
1900s, when Wentscher5 reported his experience with the
transplantation 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 begin­
ning of significant research related to the processing, pres­
ervation, and storage of human tissues. Baxter9 explored
the histologic effects of freezing on human skin and discov­
ered that the formation of ice crystals caused the destruc­
tion of skin architecture. This was followed in 1952 by the
pioneering research of Billingham and Medawar10 who
demonstrated that skin could be effectively cryopreserved
using glycerol. Soon afterward, Taylor11 was able to demon­
strate that the addition of glycerol to storage solutions
decreased ice crystal formation in frozen tissues. These
advancements permitted Brown12 and Jackson13 to popular­
ize the use of allogeneic human skin grafts as biologic dress­
ings 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 autologous skin grafts follow­
ing controlled-rate freezing in 15% glycerol and rapid

14  •  The Skin Bank
159
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 81 American Association of
Tissue Banks (AATB)-accredited tissue banks that recover,
process, store, and/or distribute skin for transplantation. 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.34 Fig. 14.1 shows the total number of
skin donors as well as total number of square feet of skin
distributed by skin banks throughout the United States and
Canada from 1995 through 2015.
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 because there was insuffi­
cient 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 complemented by the activities of the American Burn
Association’s Skin Banking Special Interest Group. The
Standards and Procedures Committees were created in
1977 and produced the first guidelines for tissue banking
in 1979. The first Standards for Tissue Banking were pub­
lished in 1984, and tissue-specific technical manuals
(including skin) were developed in 1987. Since that time,
the Standards have been modified and refined based on con­
sensus and, where available, supportive scientific research,
with the latest edition, the 14th, released in 2016. In addi­
tion, shortly after the development and promulgation of its
Standards for Tissue Banking, the AATB created an inspec­
tion and accreditation committee in 1982 and began con­
ducting voluntary inspections in 1986. This program
continues today and is important in ensuring that tissue
banks adhere not only to AATB Standards but also the U.S.
Food and Drug Administration (FDA) regulations governing
all aspects of human tissue banking. In 1992, the AATB
presented its Year 2000 Plan, outlining the institution’s
goals of supporting tissue and cell banks and ensuring the
safety and quality of tissues, as well as advancing and
strengthening the AATB.35 The AATB has worked with
many organizations, such as the FDA, the Centers for
Disease Control (CDC), and the American Burn Association,
to update standards and quickly respond when necessary,
such as through the timely creation of instructions and
methods to screen potential donors for emerging infectious
diseases, including West Nile, Ebola, and Zika viruses in
order to reduce risk of infection.
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 14.1. Allograft skin possesses many of the ideal
properties of biologic dressings and plays a major role in the
surgical management of extensive wounds when autolo­
gous tissue may not be immediately available (Box 14.2). It
reduces evaporative water loss and the exudation of protein-
rich fluids, prevents wound desiccation, and suppresses
microbial proliferation. Wound pain is lessened, and this is
associated with better patient compliance with occupa­
tional 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 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 on a number of its distinctive properties com­
pared to cryopreserved skin (Box 14.3). Its availability is
critically important for the surgeon faced with the need
to provide immediate coverage of large excised burn
wounds.
Fresh
allografts
become
well-vascularized,
Skin Donation & Distribution in the U.S. & Canada
35000
30000
25000
20000
15000
10000
5000
0
1995
2000
Donors
Sq Ft Distributed
2003
2007
2015
Fig. 14.1  Skin donation and distribution in the United States and
Canada from 1995 through 2015.
Box 14.1  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.

14  •  The Skin Bank
160
Alternative wound coverings such as Integra dermal
regeneration template have provided alternatives to
allograft skin for the treatment of excised burn wounds in
patients with extensive full-thickness burn injuries. When
compared with artificial dermis, fresh, refrigerated allograft
has been shown to have a better rate of engraftment than
the dermal regeneration template.36 A study performed at
our institution in 2007 indicated that Integra can safely be
used for wound coverage in children with burns of more
than 50% total body surface area (TBSA) burned with an
associated attenuation of post-burn hypermetabolism with
no increased risk of infection.37
COVERAGE OF WIDELY MESHED
ZSKIN AUTOGRAFTS AND PARTIAL-
THICKNESS WOUNDS
Another use of allograft skin has been its application as an
overlay on top of widely expanded, meshed autologous skin
grafts (Fig. 14.3). This technique was originally described
utilizing meshed allograft38 and provides immediate, as well
as both temporary and permanent, wound closure. Our
institution utilizes 2 : 1 meshed cadaver skin for the cover­
age of widely expanded autografts (with a ratio greater
than 2 : 1). 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 underlying wound
bed results in the relief of pain and the limitation of exuda­
tive and water losses, and it reduces the need for frequent
dressing changes. As the underlying wound bed reepitheli­
alizes, the allograft slowly separates without disturbing the
delicate underlying epithelium. These properties of frozen
allograft are also utilized in the coverage of partial-thickness
wounds. Studies by Rose39 and Naoum40 demonstrated
more rapid healing times and shorter hospital stays for chil­
dren with extensive partial-thickness burns when treated
with early wound débridement and allografting compared
to conventional topical antimicrobial therapy. However due
to lower costs and ease of use, Shriners Hospitals for Chil­
dren – Galveston primarily uses xenograft for partial thick­
ness burns.
There has been some concern that allografts may induce
an inflammatory rejection response resulting in delayed
reepithelialization of underlying autografts; therefore the
use of lyophilized tissue has been suggested because the
lyophilization process destroys cellular components and
results in a diminished immunologic response from the
graft recipient.41,42 A 2013 study of 11 patients treated
with lyophilized allograft showed no evidence of immuno­
logic reactions due to the administration of allograft.42
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.43 in 1981. Since that time, there have been numerous
reports supporting its use as a permanent skin replacement
for patients with extensive full-thickness burn injuries. This
methodology has not been without problems, however,
with many authors describing variable take rates and insta­
bility of the grafts. Cuono first advocated the use of
stimulate neovascularization in the underlying wound
bed, and prepare the recipient sites for permanent cover­
age with autologous skin. In addition, fresh allografts tol­
erate 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 reharvest­
ing or once autologous cultured skin is available for perma­
nent wound closure.
The use of fresh allografts has become extremely limited
in recent years, however, due to increased FDA regulations
put in place to reduce risk of disease transmission. When
fresh allograft is not available, cryopreserved skin is an
excellent alternative for temporary wound coverage.
Although frozen cryopreserved skin generally has less mea­
surable 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 prac­
tice 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. Fig. 14.2 depicts
the quantitative use of allograft skin and amnion in ther­
mally injured children treated at the Shriners Hospital for
Children in Galveston, Texas, since 2012.
Box 14.2  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 14.3  Advantages of Fresh Allograft Skin.
■ Rapidity and strength of adherence to the wound
■ Control of microbial growth
■ Rapidity of revascularization
■ Reproducible clinical results
Square feet
0
1200
800
400
200
1000
600
5-Year Tissue Utilization in Square Feet
2016
2015
2014
2013
2012
634.25
475.25
766
739.5
1040.25
0
0
31.25
57
39.25
Cadaver
Amnion
Fig. 14.2  Allograft and amnion skin usage at the Shriners Hospitals for
Children – Galveston, Texas.

14  •  The Skin Bank
161
microbial cultures prior to releasing the tissue for trans­
plantation. In fact, the AATB Standards50 require that skin
be discarded if pathogenic bacteria or fungi are present.
This is particularly important given the immuno­
compromised 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 donor51; 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 tested prior to receiving the allograft. To date, there
have been no other reported cases of HIV or hepatitis trans­
mission from skin allografts.
Kealey et al. have reported the transmission of cyto­
megalovirus (CMV) from cadaver skin allografts.52 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 pre­
dominantly adult donor pool to be CMV-positive.53 They
reasoned that while tissue from seronegative donors would
be ideal for use in seronegative patients, such a practice
would significantly limit the availability of fresh allograft
skin for most thermally injured patients. In addition,
while there is good evidence to support the transmis­
sion of CMV by allograft in burn patients, there is little
evidence that CMV seroconversion is clinically signifi­
cant or affects outcome in thermally injured patients.54,55
Furthermore Herndon and Rose54 reiterated that the
benefits of using cadaver allograft skin for the treatment
of burn patients clearly outweigh the small risks associ­
ated 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.
allogeneic skin with CEA, allowing the allograft skin to vas­
cularize before removing the antigenic epidermal layer by
dermabrasion.44 Hickerson et al. reported results on five
burn patients demonstrating more than 90% CEA take on
the allogeneic dermis and supple, durable grafts up to 4
years postoperatively.45 A recent multicenter randomized
trial compared patients with full-thickness burns who were
treated with split-thickness skin autografts to those who
were additionally treated with CEA. The application of CEA
resulted in faster wound epithelialization, improved percep­
tion of scarring, and improved pigmentation and elasticity
of the skin at follow-up.46
ACELLULAR DERMAL MATRIX
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.47 The potential advantage of the
dermal template is reasoned to be the use of a thinner autol­
ogous skin graft resulting in more rapid donor site healing
and reduced morbidity. A multicenter clinical trial demon­
strated 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.48 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.
Potential Disadvantages of
Allograft Use
INFECTION
Allograft skin has been reported to cause bacterial infec­
tion.49 It is therefore imperative that skin banks perform
1:1.5 Allograft
3:1 Autograft
Excised wound
Fig. 14.3  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. (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.)

14  •  The Skin Bank
162
■ Antibodies to hepatitis C virus (anti-HCV)
■ Nucleic acid test (NAT) for HCV
■ Syphilis (a non-treponemal or treponemal-specific
assay may be performed)
■ Nucleic acid test (NAT) for the hepatitis B virus (HBV)
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 experi­
ence 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 sero­
logic tests. A positive hepatitis B core antibody test accounted
for 52.3% of the serology-based discards, whereas hepatitis
B surface antigen testing accounted for 18.1%, and hepati­
tis C, HIV-1/2, HTLV-1, and syphilis tests accounted for
14.3%, 4.9%, 4.9%, and 5.5%, respectively.60 This finding
was substantiated by Plessinger et al. in their 5-year review
of 1235 donors, of whom 93 7.5%) were deferred based on
positive serologic tests.61
Although it is also necessary for the tissue bank medical
director to review the results of an autopsy (if one was
performed), a 10-month follow-up study of 264 donors
recovered following the 1998 changes in the AATB Stan­
dards revealed that none of the donors required deferral
based on autopsy findings alone.61 A review of 468 con­
secutive skin donors and 457 consecutive amnion donors
recovered by our tissue bank from February of 2014
through September of 2016 indicated that 50 skin donors
(10.7%) and 32 amnion donors (7.0%) required discard as
a result of the autopsy, serology, DRAI, or physical exam
findings. 62
SKIN RECOVERY
Once donor screening is complete and proper authorization
has been obtained, the recovery team must arrange the
time and location for skin recovery in an appropriate facility
(i.e., hospital morgue or operating room, medical examin­
er’s office, or the tissue bank). It is extremely important that
the time of death and body storage conditions be accurately
documented because these have a significant bearing on
skin viability and microbial contamination, as can the time
from skin recovery to banking.62 Current AATB Standards
require that skin prep begin within 24 hours of asystole,
provided the donor’s body was cooled (e.g., application of
sufficient amounts of wet ice or a cooling blanket, cold
weather conditions) or refrigerated within 12 hours of
asystole. The skin prep shall begin within 15 hours of death
if the deceased donor’s body has not been cooled or refriger­
ated. If the donor’s body is cooled for a period of time then
not cooled for a period of time, the time period the donor’s
body is not cooled cannot exceed 15 cumulative hours.50
In brief, the skin is recovered under aseptic conditions but
first a thorough physical assessment is 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 recovery by evaluating the
donor’s size and skin condition. Box 14.4 lists disease states
that are commonly associated with deferral of a potential
skin donor. Blood samples are also obtained for the required
infectious disease testing. The areas from which the skin is
REJECTION
While demonstrating many characteristics of an ideal
wound covering, allograft skin contains Langerhans cells
that 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
typically results in an acute inflammatory reaction and can
lead to wound infection. Vascularized allogeneic skin grafts
typically 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 immu­
nosuppression of extensive burn injury.56 Recent improve­
ments 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 incuba­
tion of the skin in glucocorticoids has been reported to result
in a modest prolongation of allograft survival compared to
nontreated 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 globulin57; however this regimen was associ­
ated with azathioprine-induced neutropenia, and the clini­
cal 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.58,59 In these studies, allograft rejection was generally
observed within a few days of discontinuing treatment;
however there were instances where engraftment persisted
after the completion of therapy. Further studies of these and
newer immunosuppressive agents may be warranted.
Technical Aspects of Skin Banking
DONOR SCREENING
It is vitally important that complete and accurate medical
information about the potential tissue 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 devel­
oped a Donor Risk Assessment Interview (DRAI) with the
cooperation and assistance of other organ and tissue recov­
ery organizations and the FDA.
A panel of serologic screening tests for transmissible dis­
eases is required.50 These include:
■ Antibodies to human immunodeficiency virus, types 1
and 2 (anti-HIV-1 and anti-HIV-2)
■ Nucleic acid test (NAT) for HIV-1
■ Hepatitis B surface antigen
■ Total antibodies to hepatitis core antigen (including
both IgG and IgM)

14  •  The Skin Bank
163
Microbiologic Testing
After returning to the skin bank, the tissue recovery team
should obtain cultures for aerobic and anaerobic bacteria,
yeast, and fungi. Tissue cultures can be obtained by swab­
bing, destructive testing of companion tissue, or by fluid
elution.65 Cultures from representative anatomical areas
shall be obtained prior to processing. Culture methods
shall be validated to ensure the suitability of the culture
method selected. Inhibitory substances (e.g., skin prep
solution(s), transport media, antibiotics, etc.) that may be
added to unprocessed skin during recovery or for trans­
port must not interfere with culture results (i.e., produce
false-negative results). Testing should be conducted in
accordance with adherence to relevant standards (e.g.,
CAP, ISO, ASTM, AAMI, USP), and the skin should not be
used for transplantation if it contains any of the following
microorganisms50:
■ Staphylococcus aureus
■ Group A, β-hemolytic Streptococci
■ Enterococcus spp.
■ Gram-negative bacilli
■ Clostridium spp.
■ 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 used for transplantation
within days of tissue recovery, the results of the microbial
cultures are frequently unavailable. 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. Although 14.3% of the cultures were positive for
microbial growth, only 1.8% of the cultures identified
organisms that required subsequent notification of the
transplanting surgeon. In each of these instances, there
was no adverse outcomes in any of the patients who received
the skin transplants.66 These findings were substantiated by
Britton-Byrd et al.67 in their review of tissue donors whose
skin was used after only 3 days of incubation. They reported
taken are shaved of hair and cleansed with an antimicrobial
agent approved for use in operative procedures (i.e.,
povidone-iodine, chlorhexidine). The tissue recovery tech­
nician wears the appropriate personal protective equipment
(PPE; i.e., surgical cap, mask with face shield, shoe covers),
performs a surgical scrub, and dons a sterile gown and
gloves while the circulating technician completes the
required documentation of the tissue recovery as well as
prepares the tissue and transport containers. This is usually
followed by a chlorhexidine prep surgical scrub of the tissue
donor, rinsing with 70% isopropyl alcohol after the required
contact time of the surgical scrub and allowing the skin
surface to dry. A back table with all the required supplies for
skin recovery is set up, and the donor is then surgically
draped. Split-thickness skin grafts are then removed using
a dermatome at a thickness of 0.012–0.018 inches. The
width of the grafts generally should range from 3 to 4
inches but ideally should be determined 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 yield of 4–6 square feet per donor is not unusual
for an experienced tissue recovery technician. After tissue
is obtained from the posterior surfaces, the donor is turned
to expose the anterior surface, reprepped, and draped prior
to completing the recovery process. The skin is then placed
in tissue culture medium and maintained at wet ice tem­
peratures (above freezing to −10°C) during transport to the
skin bank for processing.63
SKIN PROCESSING
Processing Environment
Skin should be processed under aseptic conditions in a bac­
teriologically and climate-controlled environment (Fig.
14.4). While current AATB Standards mandate the pro­
cessing of cardiovascular 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 difference in microbial growth whether the skin
was processed and packaged in a class 100 laminar flow
hood or a class 10 000 clean room.64
Box 14.4  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.
Fig. 14.4  Aseptic tissue processing environment.

14  •  The Skin Bank
164
structural integrity. AATB Standards dictate that refriger­
ated 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 recovery if the nutrient
medium is changed every 72 hours. If the medium is not
utilized or changed in this manner, AATB Standards dictate
that the skin must be frozen within 96 hours of recovery.50
The skin is generally incubated in cryoprotectant solution
for 30 minutes at 4°C. Skin that is to be frozen may be
meshed (Fig. 14.5) or kept as a sheet, and it should be folded
with fine mesh gauze or bridal veil covering the dermal
surface prior to placement in a flat packet (Fig. 14.6) to
ensure uniformity of the cooling process.75 This is followed
by slow-rate cooling at a rate of approximately −1°C/min.
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/min is equally
effective and does not compromise the metabolic activity of
the skin.76 The skin is frozen to a temperature of −70 to
−100°C prior to placement in either a mechanical freezer
three cases resulting in tissue recall due to positive micro­
biological cultures and concluded that 3-day culture results
do not result in significant microbiologic contamination of
allograft skin. White et al.68 have suggested that cadaver
allograft containing less than 103 organisms per gram 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 or 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 hours of death.69,70 The ideal
nutrient tissue culture medium also has not yet been identi­
fied. Eagle’s MEM and RPMI-1640 continue to be generally
accepted; however, Cuono demonstrated the potential ben­
efits of University of Wisconsin (UW) solution.71 To date, it
remains unclear which cryoprotectants offer the greatest
preservation of cell viability and structural integrity. Glyc­
erol (10%–20%) and dimethylsulfoxide (10%–15%) have
been reported to maintain skin viability following incuba­
tion times ranging from 30 minutes to 2 hours; however
the optimal concentrations of these cryoprotectants have
not been identified nor have these agents been compared for
efficacy. Last, factors such as age and gender do not appear
to influence skin viability.
REFRIGERATION
Refrigeration slows the metabolic rate of the viable cells,
and nutrient tissue culture medium supports cellular meta­
bolic activity. “Fresh” allograft skin is typically stored at 4°C
in tissue culture medium with or without antibiotics. The
skin should be free-floating in a sterile 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 weeks at 4°C if the nutrient medium is changed
every 3 days.72,73
It has been common practice to cryopreserve the skin
within 10 days of tissue recovery. This has been based on
the work of May et al., who demonstrated that glucose
metabolism declined at a rate of 10%–15% each day during
refrigerated storage.70 Recently demonstrated has been the
benefit of a two-layer storage method utilizing 95% oxygen-
enriched perfluorocarbon (O2PFC) combined with chang­
ing the nutrient medium every 3 days in an effort to prolong
the viability of refrigerated skin. This method results in
maintenance of skin viability for up to 41–63 days, as well
as maintenance of normal skin anatomy.74
CRYOPRESERVATION
When skin is frozen for long-term storage, it is important
that the methods utilized maintain cell viability and
Fig. 14.5  Processed tissue after being run through a 2 : 1 mesher.
Fig. 14.6  Completed, frozen, packaged tissue.

14  •  The Skin Bank
165
and the FDA, which resulted in the FDA’s publication
of an interim rule for the regulation of human tissues
intended for transplantation in 1993.80 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. Since then, the FDA has published
its proposed final rules concerning establishment regis­
tration and listing, donor eligibility, and good tissue prac­
tices 81. Numerous guidance documents are also posted on
its website (
TissueTissueProducts/default.htm). Burn centers should
only obtain allograft skin from tissue banks that comply
with these regulations and preferably from those facilities
accredited by the AATB. Obtaining tissue that complies
with FDA regulations is required for burn center verifica­
tion by the American Burn Association.
AMNION PROCESSING
The methods for processing amniotic membranes are
remarkably similar to that of cadaveric skin, with only a few
important differences. First, amniotic membranes are col­
lected from living donors, so first-person consent is obtained
from the donor prior to caesarean section. Following
consent, the medical chart is reviewed for exclusionary cri­
teria, and recent physical exam by a physician may be
examined in lieu of direct physical examination. The donor
completes a DRAI form, and blood is collected for serology
as described in the processing of cadaveric skin, with the
addition of testing for West Nile virus. During the caesarean
section, the amnion is aseptically collected into a specimen
container and refrigerated at 0–10°C until the tissue can be
delivered to the skin bank within hours. From this point, the
processing of the amnion is identical to cadaveric skin, with
the exception that amnion must be frozen within 5 days of
processing instead of 10 days.
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.
Allograft skin has the potential to play a major role in per­
manent skin reconstruction after extensive thermal injury;
however this will require interactive research with the burn
centers caring for these patients.
Moving forward, tissue banks have the opportunity to
play a major role in continued research into regenerative
medicine, stem cell therapies, and decellularized tissue that
may provide novel uses for human tissue in the treatment
of burns and many other conditions. Application of mesen­
chymal stem cells has been shown to result in faster healing
of burn wounds, decreased inflammation, and improved
scar quality, as well as improved corneal wound healing.82–84
Decellularized tissue is an important area of research for
tissue banking due to the improved compatibility of using
these products in patients. In burn care, decellularized
human allografts (AlloDerm) and porcine xenografts (Per­
macol) are already in use, although they are under continu­
ing research scrutiny. In addition, research into methods to
or liquid nitrogen. Skin stored in a mechanical freezer
(below −40°C) can be maintained for up to 5 years.
Although this methodology has been reported to result in
85% retention of viability, there is a need for research to
determine the optimal technology for skin preservation.77
LYOPHILIZATION
Skin can also be lyophilized by freeze-drying or incubation
in glycerol.78 This process has been reported to decrease
biologic degradation and antigenicity; however this also
results in epidermal cell destruction, the loss of barrier
function, and resulting poor adherence to the wound bed
and less effective control of microbial growth. Its clinical
use has been further limited by its high cost of production
compared to conventional allograft.
IRRADIATION
Human allograft skin can also be treated with γ-irradiation
to significantly reduce and possibly eliminate the risk for
viral disease transmission. The preservative and sterilizing
effects of this treatment allow it to be stored at room tem­
perature for up to 2 years. One such product, GammaGraft,
has been successfully utilized to treat partial-thickness 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.79
Transport
Refrigerated skin should be transported in tissue culture
medium at wet ice temperatures (above 0–10°C) in an insu­
lated container. Frozen allograft skin is transported on dry
ice in an insulated container to prevent the skin tempera­
ture from rising to greater than −40°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. Subse­
quent research75 has revealed that warming should be per­
formed in 2–4 minutes 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 intra­
cellular temperatures.
FDA Regulation of Human
Skin Banking
Concerns related to the potential transmission of disease
from tissue donors triggered concern within Congress

14  •  The Skin Bank
166
and processing while optimizing allograft viability. This will
become increasingly difficult as it becomes necessary to
perform additional infectious disease testing procedures to
ensure recipient safety. To accomplish these goals, it has
recently become necessary for many skin banking opera­
tions to consolidate, and tissue banks may even begin to
expand internationally. Such an undertaking could enhance
tissue supplies and availability and result in increased clini­
cal use by surgeons.
Complete references available online at

preserve tissue will continue to be an important avenue of
investigation. Tools such as glycerolization and irradiation
of tissue produce nonviable tissue, which are useful as tem­
porary wound coverage, as they result in decreased rejec­
tion and reduced risk of infectious disease transmission.85
It will become increasingly important for skin banks to
perform basic science and clinical research (in conjunction
with burn and wound healing centers) to demonstrate the
clinical indications and efficacy of allograft skin products in
various clinical applications.
Skin banks must also identify ways of increasing cadav­
eric skin donation, ensuring recipient safety from potential
disease transmission, and reducing costs of tissue recovery

166.e1
14  •  The Skin Bank
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Cryobiology. 1980;17(1):33-45.
76. Cuono CB, Langdon R, Birchall N, et al. Viability and functional per­
formance of allograft skin preserved by slow, controlled, non-pro­
grammed freezing. Proc Am Assoc Tissue Banks. 1988;20:55.
77. Aggarwal SJ, Baxter CR, Diller KR. Cryopreservation of skin: an
assessment of current clinical applicability. J Burn Care Rehabil.
1985;6(6):469-476.
78. Mackie DP. The Euro Skin Bank: development and application of glyc­
erol-preserved allografts. J Burn Care Rehabil. 1997;18(1 Pt 2):S7-S9.
79. Rosales MA, Bruntz M, Armstrong DG. Gamma-irradiated human
skin allograft: a potential treatment modality for lower extremity
ulcers. Int Wound J. 2004;1(3):201-206.
80. Department of Health and Human Services. Human tissue intended
for transplantation—FDA. Interim rule; opportunity for public
comment. Fed Regist. 1993;58(238):65514-66521.
81. Human Cells, Tissues, and Cellular and Tissue-Based Products, 21
C.F.R. § 1271. 2001.
82. Ghieh F, Jurjus R, Ibrahim A, et al. The use of stem cells in burn
wound healing: a review. Biomed Res Int. 2015;2015:684084.
83. Yao L, Li ZR, Su WR, et al. Role of mesenchymal stem cells on
cornea wound healing induced by acute alkali burn. PLoS ONE.
2012;7(2):e30842.
84. Clover AJ, Kumar AH, Isakson M, et al. Allogeneic mesenchymal
stem cells, but not culture modified monocytes, improve burn wound
healing. Burns. 2015;41(3):548-557.
85. Bohac M, Csobonyeiova M, Kupcova I, et al. Stem cell regenerative
potential for plastic and reconstructive surgery. Cell Tissue Bank.
2016;17(4):735-744.
57. Burke JF, May JW Jr, Albright N, Quinby WC, Russell PS. Temporary
skin transplantation and immunosuppression for extensive burns. N
Engl J Med. 1974;290(5):269-271.
58. Achauer BM, Hewitt CW, Black KS, et al. Long-term skin allograft sur­
vival after short-term cyclosporin treatment in a patient with massive
burns. Lancet. 1986;1(8471):14-15.
59. Sakabu SA, Hansbrough JF, Cooper ML, Greenleaf G. Cyclosporine
A for prolonging allograft survival in patients with massive burns.
J Burn Care Rehabil. 1990;11(5):410-418.
60. Barnett JR, McCauley RL, Schutzler S, Sheridan K, Heggers JP.
Cadaver donor discards secondary to serology. J Burn Care Rehabil.
2001;22(2):124-127.
61. Plessinger RT, Robb EC, Kagan RJ. The impact of autopsy report find­
ings on the acceptability of the potential tissue donor. Proc Am Assoc
Tissue Banks. 1999;48.
62. Pianigiani E, Tognetti L, Ierardi F, et al. Assessment of cryopreserved
donor skin viability: the experience of the regional tissue bank of
Siena. Cell Tissue Bank. 2016;17(2):241-253.
63. Holder IA, Robb E, Kagan R. Antimicrobial mixtures used to store har­
vested skin: antimicrobial activities tested at refrigerator (4 degrees C)
temperatures. J Burn Care Rehabil. 1999;20(6):501-504.
64. Plessinger RT, Robb EC, Kagan RJ. Allograft skin cultures II: should
allograft skin be processed in a class 10,000 or better environment?
Proc Am Assoc Tissue Banks. 1997;S23.
65. AATB Guidance Document, Microbiological Process Validation & Sur­
veillance Program. 2016.
66. Plessinger RT, Robb EC, Kagan RJ. Safe use of refrigerated allograft
skin in burn patients. Proc Am Assoc Tissue Banks. 2005;29:
A35.
67. Britton-Byrd BW, Lynch JP, Williamson S, McCauley RL. Early use
of allograft skin: are 3-day microbiologic cultures safe? J Trauma.
2008;64(3):816-818.
68. White MJ, Whalen JD, Gould JA, Brown GL, Polk HC Jr. Procurement
and transplantation of colonized cadaver skin. Am Surg. 1991;57(6):
402-407.
69. May SR, DeClement FA. Skin banking. Part III. Cadaveric allograft skin
viability. J Burn Care Rehabil. 1981;2(3):128-141.
70. May SR, DeClement FA. Development of a radiometric metabolic
viability testing method for human and porcine skin. Cryobiology.
1982;19:362-371.
71. Brown W, Cuono CB. Approaches to minimizing leakage of beneficial
glycosaminoglycans in processing skin for cryopreservation. Proc Am
Assoc Tissue Banks. 1992;S3.

167
Skin Substitutes and
‘the next level’
ESTHER MIDDELKOOP and ROBERT L. SHERIDAN
15 
Temporary Skin Substitutes
and Dressings
Partial-thickness wounds remain confined to the dermal
part of the skin. Usually, these wounds have a good healing
potential because epidermal cells present in (remnants of)
sebaceous glands, sweat glands, and hair follicles are avail­
able to close the wound.
In these wounds, the main demands to reach pain reduc­
tion and high-quality wound healing without scarring is to
warrant undisturbed wound healing. A moist environment
and protection against bacterial invasion are the most
important qualities that need to be provided.
Wound dressings for partial-thickness wounds should:
■ Provide a moist environment (migration of cells is more
difficult if when there is a dry scab on the wound).3
■ Protect the wound from excessive fluid loss and bacterial
invasion.
■ Require a limited number of dressing changes (pain
reduction).
Modern wound dressing are able to fulfil these require­
ments. Generally, membranous dressings such as hydrocol­
loids and hydrofibers fulfill these requirements better than
topical antimicrobial creams such as silver sulfadiazine
(SSD) cream.4-6 The main indication for temporary skin sub­
stitutes is partial-thickness wounds, of which donor sites
are a special category, but essentially are similar wounds.
We can classify temporary skin substitute materials by
their tissue origin into:
1. Biological tissues, such as allograft, xenograft, and
amnion (keratinocyte sheets and cells)
2. Synthetic
materials
such
as
hydrocolloids
and
hydrofibers
BIOLOGICAL TISSUES
Allograft
The first type of membranous wound coverage used was
human allograft skin. 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 tempo­
rary wound closures.7-9 It can be refrigerated for up to 7
days, but it can be stored for extended periods when cryo­
preserved. It is also used in a nonviable state after
Introduction
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 tra­
verse 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, mechanical resistance, and
elasticity. The thin epidermal layer is constantly refreshing
itself from its basal layer, with new keratinocytes undergo­
ing 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 among others collagen types IV and VII. When
this bond fails, serious morbidity results, as demonstrated
by the disease processes of toxic epidermal necrolysis (TEN)
(Fig. 15.1)1 and epidermolysis bullosa.2
CONSEQUENCES OF LOSS OF
BARRIER FUNCTION
Loss of the epidermal barrier has serious adverse physio­
logic effects. Direct and evaporative fluid losses are immedi­
ately 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. Microorganisms have unimpeded access to the
microcirculation with resulting systemic infection. Deep
tissues become desiccated with secondary cell death and
progression of wound depth.
Open wounds present a high risk of fluid loss, high
inflammation, bacterial colonization, infection, and
sepsis, which can lead to a poor prognosis in terms of
prolonged healing times and scarring. Timely wound
closure is therefore one of the key objectives in modern
burn care.
An increasingly effective group of temporary and perma­
nent wound coverings is available.
The objective of this chapter is to review the currently
available strategies for temporary and (semi-) permanent
skin substitutes in terms of origin of the material (tissue,
biological, or synthetic material) and wound indication
(partial-thickness vs full-thickness wounds).

15  •  Skin Substitutes and ‘the next level’
168
preservation in glycerol or after lyophilization. Viable split-
thickness allograft provides durable biologic cover until it is
rejected by the host, usually within 3 or 4 weeks. Prolonga­
tion of allograft survival, through the use of antirejection
drugs, has been advocated10 but is not generally practiced
for fear that antirejection drugs will increase the risk of
infection.11
A frequently used application of glycerolized allograft
skin is as a membranous dressing on partial-thickness
burns, especially scald burns in children (Fig. 15.2).12
Modern banking techniques and regulations warrant the
safety and quality of banked skin.13 Allograft is also effec­
tively 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.
Human Amnion
Human amniotic membrane is used in many parts of the
world as a relatively cheap temporary dressing for superfi­
cial wounds.14,15 Amniotic membrane is generally procured
fresh and used after brief refrigerated storage.16,17 It can
also be used in a nonviable state after preservation with
glycerol.
Beneficial effects have been described in a randomized
controlled trial comparing amnion membrane with SSD by
Mostaque et al on partial-thickness burns, with a better
outcome using amnion membrane on time to epithelializa­
tion, length of stay (LOS), pain, and frequency of dressing
changes.18
The principal concern with amnion is the difficulty in
screening the material for viral diseases unless preserva­
tion methods can eliminate potential viral contamina­
tion. 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.
Xenograft
Although various animal skins have been used for many
years to provide temporary coverage of wounds,19 only
porcine xenograft is widely used today. It has been used as
primary temporary cover and as a scaffold for dermal regen­
eration efforts.20 Porcine xenograft is commonly distributed
as a reconstituted product consisting of homogenized
porcine dermis that is fashioned into sheets and meshed.21
Split-thickness porcine skin is also used fresh, after brief
refrigeration, after cryopreservation, or after glycerol pres­
ervation. It effectively provides temporary coverage of clean
wounds such as superficial partial-thickness burns and
donor sites22 and has been used in patients with TEN.1,23
Porcine xenograft has been combined with silver to sup­
press wound colonization.24,25 Porcine xenograft does not
vascularize, but it adheres to clean superficial wounds and
can provide excellent pain control while the underlying
wound heals.
SYNTHETIC MATERIALS
Nowadays, synthetic membranous dressings are increas­
ingly capable of replacing biological membranous dress­
ings. Next to protection against bacteria and fluid loss, pain
reduction and mechanical protection, they provide a moist
environment in which wound healing can proceed undis­
turbed. 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 physio­
logic vapor transmission characteristics.26
The
main
advantages
of
synthetic
membranes
over biological ones are their constant composition, steril­
ity, and availability. Disadvantages include their higher
costs.
Nevertheless, in a number of recent studies, superiority
of synthetic membranes over topical creams and ointments
has been shown, especially with regard to healing time,
LOS, and pain management.4
Some examples are mentioned here:
Biobrane (Smith & Nephew, Andover, MA) 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.27
It is widely used to provide temporary closure of super­
ficial burns and donor sites.28 All synthetic membranes
Fig. 15.1  Patient with toxic epidermal necrolysis.
Fig. 15.2  Glycerolized allograft on a partial-thickness scald burn.

15  •  Skin Substitutes and ‘the next level’
169
& Nephew), and new materials appear on the market very
frequently.
Permanent Skin Substitutes
In contrast to partial-thickness wounds, full-thickness skin
lesions lack the availability of enough viable epidermal cells
that could close the wound within a reasonable time frame.
Therefore, for deep wounds, surgical intervention is indi­
cated. The main purpose of the surgery is to bring a new
source of epidermal cells to the wound to speed up wound
closure. This can be done in different ways, such as a
are occlusive and can foster infection if placed over con­
taminated wounds, especially in the presence of necrotic
tissue.29 Appropriate monitoring is essential to their
proper use.
Another category of silicone containing dressings is
formed by the silicone-coated dressings such as Mepitel and
Mepilex (Mölnlycke, Göteborg, Sweden) (Fig. 15.3) of which
advantages are reported in terms of time to healing, pain
reduction, and number of dressing changes.30,31
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.32 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
maintaining a moist wound environment.
Hydrofiber dressings absorb wound exudate and have
been used as temporary wound membranes. When com­
bined with ionic silver (Aquacel-Ag; ConvaTec, Flintshire,
UK), additional antimicrobial activity is seen. This mem­
brane has been used successfully in some burn programs as
an adjunct in the management of partial-thickness burns
and donor sites (Fig. 15.4).33
Alginate dressings (e.g., Kaltostat, ConvaTec; Comfeel,
Coloplast, Humlebaek, Denmark) are fibrous dressings
derived from seaweed. They have a high absorption capacity
because of strong hydrophilic gel formation.34 Their use in
burns is mainly as dressing for donor sites. Not many com­
parative prospective trials are available.
Other synthetic wound dressings include Suprathel
(a polylactic acid membrane; Polymedics, Denkendorff,
Germany), Urgotul (polyester mesh impregnated with
hydrocolloid and petroleum jelly; Urgo Medical, Chenove,
France), and Allevyn (a polyurethane foam dressing) (Smith
A
B
Fig. 15.3  Mepilex Ag for partial-thickness burn treatment, 7 days after burn.
Fig. 15.4  Aquacel Burn hydrofiber dressing, 2 days after application on
a partial-thickness burn.

15  •  Skin Substitutes and ‘the next level’
170
freshly isolated or proliferating epidermal cells to the
wound bed.46-48
DERMAL CONSTRUCTS
Tissues
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 dis­
sipation and conservation, lubrication, and sensation.
A dermal analog that is—in structure at least—closest to
the original dermis is based on freeze-dried allogenic dermis.
This material is intended to be combined with a thin epithe­
lial autograft at the time of initial wound closure. It is mar­
keted as AlloDerm (LifeCell Corporation, now Acelity, San
Antonio, TX).49,50 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
split-skin graft, cultured epithelial sheets, carriers or sprays,
or skin substitutes.35 Furthermore, full-thickness grafts or
flaps are also used for treatment of full-thickness wounds of
limited size.
In addition to providing epidermal coverage, replacement
of dermal tissue is also important. From the early studies on
treatments with cultured epithelial sheets, it is now known
that even after a prolonged time, the dermal–epidermal
junction is not fully regenerated, which leaves a rather vul­
nerable skin that is prone to mechanical damage.36 Healing
of full-thickness wounds is generally accompanied by scar
formation. The use of dermal substitutes in full-thickness
skin defects may contribute to a better quality of healing
with reduced scarring.37,38
EPIDERMAL CELLS AND CONSTRUCTS
For more than 40 years, it has been possible to culture vast
numbers of epithelial cells from a small skin biopsy,39,40 and
this has led to the widespread clinical use of cultured epi­
thelial grafts to cover burn wounds. Originally, epithelial
cells were procured from a full-thickness skin biopsy, the
cells were cultured in medium containing fetal calf serum,
insulin, transferrin, hydrocortisone, epidermal growth
factor, and cholera toxin, overlying a layer of murine fibro­
blasts that had been treated with a nonlethal dose of radia­
tion that prevented them from multiplying. After some
weeks, epithelial sheets were removed from the dishes after
treatment with Dispase.
When epithelial cultures were first used in patients with
large burns, it was hoped that they would provide the defini­
tive answer to the clinical problem of the massive wound.41-43
With more frequent use of epithelial grafts, specific liabili­
ties have become apparent, including suboptimal engraft­
ment rates and long-term durability.44,45 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 becoming
more acceptable as wound size increases.
The elimination of risks of transmission of animal derived
disease components such as viruses or prions to the patient
nowadays represent serious regulatory and safety issues
because from a regulatory point of view, these defined xeno­
biotic materials and cells should not be used for clinical
treatment of a patient.
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, although several early biotech startup compa­
nies providing these services frequently experienced prob­
lems to reach an acceptable level of funding. The limited
commercial volume of the products, high production costs,
and increasing demands in terms of regulatory issues rep­
resent some of the challenges for small biotechnology
companies.35
New developments in this line are found in eliminating
the murine fibroblasts and (most of) the animal derived
products in culture media, reducing culture time by trans­
planting subconfluent (proliferating) cells rather than
confluent sheets (Fig. 15.5) and by applying spray tech­
niques (Fig. 15.6) (Recell, Avita Medical, Northridge, CA;
Keraheal, MCTTBio, Seoul, South Korea) to deliver either
Fig. 15.5  Epidermal cells seeded onto Matriderm dermal matrix.
Fig. 15.6  Isolation of epidermal cells using a Recell kit.

15  •  Skin Substitutes and ‘the next level’
171
terms of scar quality even after as long as 12 years later
(Fig. 15.8).38 Other scaffolds in this same category are Per­
macol (a porcine dermal collagen implant, mainly indicated
for hernia and abdominal wall repair; Tissue Science
Laboratories, Hampshire, UK), Renoskin (Symatèse,
Chaponost, France), Pelnac (Smith & Nephew) (both
Renoskin and Pelnac are similar to Integra, consisting of a
bilayer of collagen with a silicone top layer), and Novomaix
(freeze-dried collagen scaffold with elastin fibers; (Matricel,
Herzogenrath, Germany). Hyalomatrix (Fidia Advanced
Biopolymers, Italy) consists of a bilayer of an esterified hyal­
uronan beneath a silicone membrane. The scaffold delivers
hyaluronan to the wound bed, and the silicone membrane
acts as a temporary epidermal barrier.
CELLULAR DERMAL SUBSTITUTES
Although some cellular constructs are or were (Dermagraft
for chronic wound healing, Transcyte for partial-thickness
burns; both Smith & Nephew) on the market using dermal
cells in a scaffold for improving wound healing, most of
these developments are still in the experimental stage. In
vivo studies are described using adipose-derived regenera­
tive cells in Integra,62 and attempts were made to design a
new generation of skin substitutes based on nanotechnol­
ogy using nanocomposite polymers.63 However, clinical
safety and effectivity still need to be demonstrated for this
technology.
A limited number of burn patients was already treated
with a construct of native horse collagen with cells from a
fetal skin bank.64 Nevertheless, this is not a commercially
available product yet. Furthermore, an experimental study
Akershoek and colleagues found superior effects of autolo­
gous dermal cells over fetal cells when used in a dermal
substitute (Novomaix).65
The fact that at present cell seeded skin replacement
constructs fall into the category of advanced technol­
ogy medicinal products (ATMPs) made it more difficult to
proceed with these developments into clinical application.
Production of these constructs should be strictly controlled,
intended to provide a nonantigenic dermal scaffold, leaving
basement membrane proteins (particularly laminin and
type IV and VII collagen) intact. The material is rehydrated
immediately before placement on wounds with overlying
ultrathin epithelial autograft. Clinical experience with this
material in burn surgery is limited,51 but early experiences
have been favorable.52,53 Nevertheless, these products now
seem to be used more in breast reconstructive surgery than
in acute burns.54 A similar product, based on allogeneic
dermis preserved in glycerol, is Glyaderm (Euro Tissue Bank,
Beverwijk, The Netherlands). Also here, antigenicity is
reduced by washing out the cells and preserving the origi­
nal extracellular matrix. Initial studies on burn patients
have been performed and reported favorable results.55
Dermal Scaffolds
The first dermal substitute used clinically was “artificial
skin,” also called Integra (IntegraLife, Plainsboro, NJ); it has
been used worldwide for several years now for burns as well
as reconstructive purposes. This material was developed in
the early 1980s by a biomaterials research team from the
Massachusetts General Hospital and Massachusetts Insti­
tute of Technology.56 The research team, led by surgeon
John Burke from the Massachusetts 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 providing a scaffold for later dermal
regeneration. The material was intended to be placed on
excised burn wounds. The silicone outer layer serves as a
temporary epidermis and is removed after vascular ingrowth
into the dermal replacement is completed (usually within
2–3 weeks). The inner layer of this material is a 1- to 2-mm-
thick combination of fibers of collagen isolated from bovine
tissue and the glycosaminoglycan chondroitin-6-sulfate. To
manufacture the device, glycosaminoglycan 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 characteristics similar to normal epi­
thelium. This membrane is intended to be placed on freshly
excised full-thickness burns and the outer silicone mem­
brane replaced with a thin epithelial autograft 2–3 weeks
later.57 Clinical reports in patients with large burns have
been generally favorable,58-60 although submembrane infec­
tion must be watched for. Integra has also been found to
be useful in selected burn reconstruction operations
(Fig. 15.7).61
Whereas Integra is applied in a two-stage operation—
first debridement and application of the substitute and 2–3
weeks later removal of the silicone layer and grafting of a
split-thickness skin graft—some substitutes can be applied
in a one-step procedure. The first dermal substitute that was
applied in this way was Matriderm (Medskin Solutions, Bill­
erbeck, Germany). Matriderm consist of bovine collagen
fibers mixed with 3% elastin hydrolysate, purified and freeze
dried into a dry scaffold that can be placed on the wound in
this form immediately or can be prewetted with a saline
solution. Clinical results indicate a somewhat retarded take
of the graft, reflecting the interpositioning of the unvascu­
larized scaffold between the wound bed and the graft;
however, this was compensated by a better outcome in
Fig. 15.7  Scar revision using Integra.

15  •  Skin Substitutes and ‘the next level’
172
gliding function of the skin. This is especially important
on anatomical locations where the skin is relatively thin,
such as the back of the hand and the tibia. In these areas,
a scar can easily become attached to underlying tendons
or bone if subcutaneous fat is also missing. Recent studies
have noted beneficial effects on scar quality of lipo-injection
with the patient’s own fat, harvested by liposuction.66–68
Although there is not enough solid clinical evidence yet, the
data gathered so far indicate that fat grafting could become
a new technique in improving scar quality and outcome
after burns. Further research should aim at elucidating the
best indications, timing and techniques, and frequencies of
application.
with clinical-grade ingredients for cell culture media. This
aspect stimulated investing in full skin equivalents rather
than designing an ATMP for dermal replacement only.
For developments in full skin equivalents, see the later
discussion.
SUBCUTANEOUS FAT
Although mostly skin is defined as consisting of dermis
and epidermis, in recent years, the subcutis has been noted
as important for skin function as well. Especially in recon­
structive areas, it has become more clear that subcutane­
ous fat—or the lack of it—plays an essential role in the
F
E
D
C
B
A
Fig. 15.8  Application and long-term results of Matriderm application. A, Full-thickness burn at postburn day (PBD) 3. B, Application of Matriderm
during surgery, PBD 15. C, Application of split-skin mesh graft over Matriderm in a single stage procedure, PBD 15. D, Five days after grafting. E, Five
months postoperatively. F, Eighteen months postoperatively.

15  •  Skin Substitutes and ‘the next level’
173
on genes, cells or tissue engineering.” A tissue-engineered
product may contain or consist of engineered cells or
tissues, with the purpose to regenerate, repair, or replace
a human tissue, and it may contain viable or nonviable
cells or tissues of human or animal origin. Therefore, skin
substitutes containing living autologous cells, of dermal,
adipose, or epidermal origin are considered as ATMPs and
fall under the regulatory issues associated with these. One
of the main features of these regulations is that produc­
tion of ATMPs for human use must take place under good
manufacturing practice conditions. For many research lab­
oratories, such conditions are not feasible. Furthermore,
a considerable administrative burden is represented by
import and export procedures over international borders.
Yet given the fact that commercial exploitation of this
type of high technological wound treatment is only pos­
sible in an international context, these hurdles need to be
overcome to allow a successful market position for these
products.
Conclusion
Over the past decade, important clinical evidence has been
gathered on dermal substitutes, and improvement were
achieved in epidermal analogs, both in culture techniques
and in application methods. Based on recent reports in pre­
clinical research, we can expect to see further improve­
ments in the next decade in the refinement of full skin
equivalents, in incorporation of skin appendages, vascula­
ture, and nerves.
Another area of improvement has been the development
of the field of temporary dressings. More synthetic,” well-
controlled dressings were tested in clinical application. The
incorporation of “actives” in these dressings, which was
expected previously, was not realized, however. Rather than
the addition of single growth factors in wound dressings,
the technology of genetic modification might be one of the
new clinical developments in the years to come. Cells (e.g.,
keratinocytes) can be engineered to overexpress platelet-
derived growth factor, human growth hormone, insulinlike
growth factor 1, and other growth factors.81,82 On the other
hand, mesenchymal stem cells are another tool that could
likely lead to innovative technology in burn care.83 When
these can be developed into a readily applicable source for
epidermal coverage, the dependence on autologous epider­
mal cells for wound closure will end.
Nevertheless, there is also an ongoing need for more evi­
dence in clinical science, such as on the comparison of
various temporary or permanent scaffolds in promoting
wound healing, on the use of growth factors to stimulate
the healing process, or on the optimal timing of physical
techniques during scar management. Standardized and
validated outcome measures should definitely receive more
attention and development in clinical evaluation. Patient-
reported outcomes can be considered an indispensable part
of clinical evaluation. Clinical treatment should therefore
focus not only on the treatment itself but also on adequate
outcome evaluation of therapy.
Complete references available online at

Full Skin Substitutes
Ideally, a skin replacement technique would provide imme­
diate replacement of both the dermal and epidermal layers.
Combining epithelial cells with a dermal analog in the labo­
ratory seems logical. A completely biological composite skin
substitute, culturing human fibroblasts in a dermal matrix,
and then growing keratinocytes on this, has been developed
by several research groups.69,70
The first full composite skin construct to appear on the
market was Apligraf (Organogenesis, Canton, MA). It con­
sists of cultured human foreskin–derived neonatal fibro­
blasts in a bovine type I collagen matrix over which human
foreskin–derived neonatal epidermal keratinocytes are then
cultured and allowed to stratify. Because the cells are allo­
geneic, ultimately, the keratinocytes are rejected; therefore,
for definite wound closure, an autologous source of kerati­
nocytes needs to be present. Apligraf is therefore mainly
used in chronic wound healing and not so much for healing
of full-thickness burns.71
Another bilayered cellular skin substitute is Orcel (Fort­
cell Bioscience, Englewood Cliffs, NJ),72 which contains a
layer of cultured human allogeneic neonatal dermal fibro­
blasts and a layer of cultured human allogeneic neonatal
epidermal keratinocytes into a type 1 bovine collagen
sponge. Also here, the cells are of allogeneic origin and do
not survive for more than 2–3 weeks in a wound. Its working
mechanism is thought to be predominantly through the
excretion of physiological levels and mix of growth factors
and cytokines.
Full skin substitutes that make use of autologous (patient-
own) cells have also been described in recent papers.73-76
Apart from regulatory issues (see later discussion), major
problems in the application of these constructs are the long
culture times; high costs; and in some cases, the lack of
pigment cells. Nevertheless, these are important develop­
ments because e in the end, they may lead to novel, clini­
cally applicable truly regenerative full skin analogs,
comprising not only dermal and epidermal structures but
also vasculature, skin appendages, and even nerves.77,78
Regulatory Issues
New developments in regenerative medicine have indicated
that the use of living cells in tissue engineered products
might prove clinical benefit in terms of promoting wound
healing and reducing scar formation.79 During the past
decade, however, new regulations have become effective,
designating cell-based therapy as ATMPs. The European
Medicines Agency (an agency of the European Union) is
dedicated to the scientific evaluation and supervision of
market access of medicines. Also, ATMPs fall into this cat­
egory. Regulation (EC) No. 1394/2007 provides the overall
framework on production and use of ATMPs in Europe.80 In
the United States, similar tasks are entrusted to the Food
and Drug Administration), where the Office of Cellular,
Tissue and Gene Therapies exerts the tasks to evaluate and
supervise market access of ATMP products.
According to the EU Regulation No 1394/2007 defini­
tion, an ATMP is a “medicine for human use that is based

173.e1
15  •  Skin Substitutes and ‘the next level’
32. 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(2):145-148.
33. Blome-Eberwein S, et al. Hydrofiber dressing with silver for the man­
agement of split-thickness donor sites: a randomized evaluation of
two protocols of care. Burns. 2010;36(5):665-672.
34. Brenner M, et al. Management of pediatric skin-graft donor sites: a
randomized controlled trial of three wound care products. J Burn Care
Res. 2015;36(1):159-166.
35. Gardien KL, Middelkoop E, Ulrich MM. Progress towards cell-based
burn wound treatments. Regen Med. 2014;9(2):201-218.
36. Compton CC, et al. The generation of anchoring fibrils by epidermal
keratinocytes: a quantitative long-term study. Epithelial Cell Biol.
1995;4(3):93-103.
37. Bloemen MC, et al. Clinical effectiveness of dermal substitution in
burns by topical negative pressure: a multicenter randomized con­
trolled trial. Wound Repair Regen. 2012;20(6):797-805.
38. Bloemen MC, et al. Dermal substitution in acute burns and
reconstructive surgery: a 12-year follow-up. Plast Reconstr Surg.
2010;125(5):1450-1459.
39. Rheinwald JG, Green H. Serial cultivation of strains of human epider­
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cells. Cell. 1975;6(3):331-343.
40. 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(11):5665-5668.
41. Green H. Cultured cells for the treatment of disease. Sci Am.
1991;265(5):96-102.
42. Gallico GG 3rd, et al. Permanent coverage of large burn wounds
with autologous cultured human epithelium. N Engl J Med.
1984;311(7):448-451.
43. Sheridan RL, Tompkins RG. Cultured autologous epithelium in
patients with burns of ninety percent or more of the body surface.
J Trauma. 1995;38(1):48-50.
44. Rue LW 3rd, et al. Wound closure and outcome in extensively burned
patients treated with cultured autologous keratinocytes. J Trauma.
1993;34(5):662-667, discussion 667-668.
45. Barret JP, et al. Cost-efficacy of cultured epidermal autografts in
massive pediatric burns. Ann Surg. 2000;231(6):869-876.
46. Wood F, et al. A prospective randomised clinical pilot study to compare
the effectiveness of Biobrane(R) synthetic wound dressing, with or
without autologous cell suspension, to the local standard treat­
ment regimen in paediatric scald injuries. Burns. 2012;38(6):830-
839.
47. Yim H, et al. Clinical study of cultured epithelial autografts in liquid
suspension in severe burn patients. Burns. 2011;37(6):1067-1071.
48. Lee H. Outcomes of sprayed cultured epithelial autografts for full-
thickness wounds: a single-centre experience. Burns. 2012;38(6):
931-936.
49. Callcut RA, 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.
50. Yim H, et al. The use of AlloDerm on major burn patients: AlloDerm
prevents post-burn joint contracture. Burns. 2010;36(3):322-328.
51. Wainwright DJ, Bury SB. Acellular dermal matrix in the management
of the burn patient. Aesthet Surg J. 2011;31(7 suppl):13S-23S.
52. Sheridan RL, Choucair RJ. Acellular allogenic dermis does not hinder
initial engraftment in burn wound resurfacing and reconstruction. J
Burn Care Rehabil. 1997;18(6):496-499.
53. Sheridan R, et al. Acellular allodermis in burns surgery: 1-year results
of a pilot trial. J Burn Care Rehabil. 1998;19(6):528-530.
54. Skovsted Yde S, Brunbjerg ME, Damsgaard TE. Acellular dermal
matrices in breast reconstructions – a literature review. J Plast Surg
Hand Surg. 2016;1-10.
55. Pirayesh A, et al. Glyaderm((R)) dermal substitute: clinical application
and long-term results in 55 patients. Burns. 2015;41(1):132-144.
56. Tompkins RG, Burke JF. Progress in burn treatment and the use of
artificial skin. World J Surg. 1990;14(6):819-824.
57. Tompkins RG, et al. Increased survival after massive thermal inju­
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1989;17(8):734-740.
58. Jeschke MG, et al. Wound coverage technologies in burn care: novel
techniques. J Burn Care Res. 2013;34(6):612-620.
59. Sheridan RL, et al. Artificial skin in massive burns – results to 10
years. Eur J Plast Surg. 1994;17(2):91-93.
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174
The Pathophysiology of
Inhalation Injury
PERENLEI ENKHBAATAR, LINDA E. SOUSSE, ROBERT A. COX, and DAVID N. HERNDON
16 
Texas led to the establishment of centers for the care of
burn victims and research into the pathophysiology of burn
injury.
In many ways, the September 11, 2001, disaster at the
Pentagon was similar to these two earlier disasters since the
burn and inhalation injuries involved combustion of petro­
leum products. Among the 790 injured survivors of the
terrorist attack on the World Trade Center in New York on
September 11, 49% suffered from inhalation injury. The
situation was the same as in the Pentagon attack in that
inhalation injury was seen in some patients who were not
burned.21
Inhalation injury can be classified as follows: (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, and the concentration and
solubility of the toxic gases generated. For instance, hot air
and smoke chemical compounds usually cause upper
airway injury. Water-soluble materials such as acrolein and
the other aldehydes damage the proximal airways and set
off reactions that inflame in the bronchi and parenchyma,
whereas agents with lower water solubility such as chlo­
rine, phosgene, nitrogen oxide, nitrogen dioxide (N2O3 or
even N2O4) are more likely to cause insidious injury.22
Pathophysiology
INJURY TO THE OROPHARYNX
Many of the pathophysiological changes occurring after
inhalation injury are related to edema formation in the oro­
pharynx, bronchial areas, and parenchyma. This edema
results from an increased transvascular fluid flux from vas­
cular beds in these respective tissues. Before discussing the
changes that occur in these structures following inhalation
injury, a review of the forces responsible for the variables of
the Starling-Landis equation should be reviewed23,24:
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
transvascular 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 microcircula­
tion were perfused or if there were more pores per given
Introduction and Epidemiology
It has been more than three decades since Herndon and
colleagues’ first manuscript on inhalation injury was pub­
lished.1 It was initially reported in 1985 that inhalation
injury was a major determinant of mortality in severely
burned patients.2. The standard of care has evolved over
time, but inhalation injury still remains a major problem.3.
Although sepsis is reportedly the most frequent cause of
death among burned children,4, roughly two-thirds of
burned patients who have died at the Shriners Hospitals for
Children suffer from inhalation injuries.5 Based on data
from 506,628 admissions to burn units from 1988 to
2008, burn patients with inhalation injury are more likely
to die than those without inhalation injury (P <0.001).6
Furthermore when 791 burned patients from 44 hospitals
were retrospectively reviewed in 2014, the mortality rate of
patients with inhalation injury was 17.9% compared to
0.7% in patients without inhalation injury (P <0.05).7
Smoke inhalation causes 5000 to 10,000 deaths annu­
ally in the United States and more than 23,000 injuries,
including approximately 5000 firefighter injuries.8 In fact,
the United States has the tenth highest fire death rate per
million people among industrialized countries.9 Approxi­
mately 15% of burned individuals with over 80% total
burned surface area (TBSA) who are admitted to burn
centers in the United States have a concomitant smoke
inhalation injury.6 Greater percentages of fire victims who
have sustained smoke inhalation are seen in several other
countries.10–13 The lung is a critical organ, and progressive
respiratory failure associated with pulmonary edema is a
pivotal determinant of mortality.14–16 Although not as
lethal, smoke inhalation alone is a serious problem. Accord­
ing to World Health Organization estimates, more than 4
million people die from household air pollution from cooking
with solid fuels (Fig. 16.1).17
The inhalation of toxic materials has been of interest for
a number of years, particularly because of the use of toxic
gases in civilian mass casualty events. In the 1940s, two
very large fires focused attention on smoke inhalation in fire
accidents. The first was a fire at the Cocoanut Grove night­
club in Boston, Massachusetts, where a large number of
people were trapped in a burning building and consequently
sustained severe inhalation injury.18,19 The second disaster
occurred in 1947, in Texas City, Texas.20 A ship loaded with
ammonium nitrate fertilizer exploded in the harbor and set
off a chain of explosions and fires among 50 refineries and
chemical plants, resulting in more than 2000 hospital
admissions. Many of the victims were burned and simulta­
neously inhaled smoke, while many others suffered from
smoke inhalation alone. Disasters like those in Boston and

16  •  The Pathophysiology of Inhalation Injury
175
and the insult of fluid administration is massive edema.
This is probably nowhere more apparent than in soft tissues
of the face and oropharynx. The danger to the patient is
extreme. The edema may obstruct the airway, making it
not only laborious or impossible to breath, but also diffi­
cult for the anesthesiologist to intubate the patient (Fig.
16.3A). To avoid this problem, many units prophylactically
perform tracheostomies on 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.44 It
may be time to reconsider some of these practices. Perhaps
some consideration should be given to fluid resuscita­
tion with colloids, which can prevent some of this soft
tissue edema and reduce the volume of fluids required for
resuscitation.45,46
INJURY TO THE TRACHEOBRONCHIAL AREA
With rare exceptions such as inhalation of steam, the injury
to the airway is usually from chemicals in smoke. The heat
capacity of air is low, and the bronchial circulation is very
efficient in warming or cooling airway gases so that most
gasses are at body temperature as they pass the glottis.47
Flames must almost be in direct contact with the airway to
induce thermal injury.48 The chemicals in smoke depend on
the materials that are being burned; however, for the most
part, the host response is similar. In most instances biologi­
cal materials such as cotton fabric, wood, grass, or products
of these such as cattle feces (commonly used as fuel in
developing countries) are the fuel for the fire. Burning of
these materials produces ROS and RNS, organic acids, and
aldehydes49 that, upon inhalation, cause damage to the
respiratory epithelium. The inhaled chemicals interact with
the airway to induce an initial inflammatory response. In
sheep that have inhaled cooled cotton smoke, there is
area of the microcirculation. These pores are the same size
as water and electrolytes, as opposed to the larger pores
associated with permeability to protein. Pc and Pif are the
hydrostatic pressures in the microcirculation and intersti­
tial space, respectively. The reflection coefficient, σ, is an
index of microvascular permeability to protein. If σ is 1, the
membrane 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 interstitial spaces, respectively.
The major pathophysiology seen in the oropharynx fol­
lowing inhalation injury is induced by microvascular
changes similar to those seen with thermal injury in other
areas of the body. Heat denatures protein that, in turn,
activates complement. Complement activation causes the
release of histamine.25,26 Histamine then causes the forma­
tion of xanthine oxidase, an enzyme involved in the break­
down of purines to uric acid.27 During this conversion,
reactive oxygen species (ROS) are released.28,29 ROS combine
with NO, constitutively formed in the endothelium, to form
reactive nitrogen species (RNS).30 The latter produce edema
in the burned area by increasing the microvascular pres­
sure and permeability to protein.31,32 Eicosanoids and pro-
inflammatory cytokines are also released.33–35 These, along
with oxygen free radicals and interleukin-8 (IL-8), attract
polymorphonuclear cells to the area.36 These neutrophils
then amplify the release of oxygen radicals, proteases, and
other materials into burned areas (Fig. 16.2).
The massive edema occurring in the soft tissue of the
oropharynx following burns involves most variables in the
Starling equation. There is a large increase in microvascu­
lar hydrostatic pressure,37 a decrease in interstitial hydro­
static pressure,38 a fall in the reflection coefficient,37 and
an increase in interstitial oncotic pressure.38,39 The usual
treatment for burn resuscitation calls for the administra­
tion of large amounts of crystalloid solutions, which has
the effect of reducing the plasma oncotic pressure.40,41 This
reduction not only affects the oncotic pressure gradient in
the microcirculation, but also has been reported to increase
the filtration coefficient.42,43 The result of this almost com­
plete breakdown in control of the microvascular function
Fig. 16.1  An example of direct exposure to smoke as result of open fire
using various materials as a fuel.
Burn/smoke
Heat denaturization of protein
Complement activation
Histamine release
Conversion of xanthine oxidase
Release of superoxide ion
Permeability changes
Neutrophil adherence
Fig. 16.2  Mechanism for edema formation in the oropharynx.

16  •  The Pathophysiology of Inhalation Injury
176
develop the signs of pulmonary edema characteristic of
inhalation injury. Airway inflammation plays a major role
in the overall response to inhalation injury (Fig. 16.3B
and C).
As noted, there is a large sustained increase in blood flow
in the airway following smoke inhalation.58 These changes
in blood flow are associated with increased bronchial micro­
vascular permeability to protein and small particles59 and
pressure.60 Simultaneous with changes in bronchial micro­
vasculature function, there is a loss or shedding of the bron­
chial columnar epithelium.35,50,61 These changes result in
a perfuse transudate with a protein content similar to an
ultrafiltrate of the plasma.62 There are also copious secre­
tions from the goblet cells of the lining and mucosal epithe­
lium.63 Early in the response, these secretions form a foam
material in the airway that many have mistaken for severe
pulmonary edema in patients.64 After several hours the
transudate/exudate, exfoliated epithelium, secreted mucus,
and inflammatory cells form obstructive materials in the
airways.65 The degree of obstruction at this early stage sta­
tistically correlates with decreasing pulmonary function.
damage to the tracheobronchial50,51 and alveolar epithe­
lium. Injury and loss of these cells lead to an intense inflam­
matory response.35
Many of the studies on bronchial circulation following
smoke inhalation injury have been performed in sheep
because these animals have a single bronchial artery52 and
a single lymphatic draining the lung, thus allowing mea­
surement of pulmonary transvascular fluid flux.53 In these
animals, a 10-fold increase in bronchial blood flow occurs
within 20 minutes of smoke inhalation.54 These same
animals demonstrate a sixfold increase in pulmonary trans­
vascular fluid flux and a fall in PaO2/FiO2 to 200 or less, but
these changes are delayed, occurring around 24 hours after
injury. Similar findings have been reported in patients with
smoke inhalation alone or a combination of large cutane­
ous thermal injury and smoke inhalation.55
Hyperemia of the airway is such a consistent finding in
smoke inhalation that it is used to diagnose the injury.56,57
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
C
B
A
Fig. 16.3  Facial and airway injury after burn and smoke inhalation. (A) A facial burn is often associated with thermal injury to the upper airway. (B)
Hyperemia of airway epithelium. (C) Formation of airway obstructive cast. (A is from Cancio LC. Airway management and smoke inhalation injury in the
burn patient. Clin Plast Surg. 2009;36(4):555–567.)

16  •  The Pathophysiology of Inhalation Injury
177
environment has not yet been reported. Airway mucosal
edema and luminal obstruction following an inhalation
injury occur alongside airway smooth muscle hyperreac­
tivity. Adrenergic72,73 and antimuscarinic bronchodilator74
therapies have been shown to be beneficial in reducing ven­
tilatory peak pressure and improving pulmonary function.
The initial hyperreactive response of the airways to injury
and inflammation is followed by a more long-term patho­
genesis of inhalation injury that includes bronchopneumo­
nia.2 Pneumonia is the leading complication in the critical
care of burn victims,75 with the incidence of pneumonia in
a burn patient with inhalation injury being two- to fourfold
greater than that seen in burn patients without inhalation
injury.15,76 Conceptually the high incidence of pneumonia
in burn patients with inhalation injury is associated with
the loss of airway epithelium and the essential properties of
these cells in innate defense. Studies that have focused on
the repair of the epithelium after burn injury are limited.
With increasing time after injury, these obstructive materi­
als formed in the upper airway may appear in the lower
airway and alveoli.63,66 This obstructive material is prob­
lematic from several stand-points. In some rare instances
of severe airway injury these materials can induce total
obstruction and are life-threatening (Fig. 16.4).67–69 Occlu­
sion of some of the bronchi or bronchioles in the setting of
high NO production can lead to a loss of hypoxic pulmonary
vasoconstriction and thus increased shunt fraction. Loss of
hypoxic pulmonary vasoconstriction has been reported with
inhalation injury. If single bronchi are occluded while the
patient is on a volume-limited ventilator, there may be over­
stretch, and barotrauma to the alveoli of the nonoccluded
portion of the lung can occur. Nebulized anticoagulants
have been used to combat the upper airway obstruction
that can occur with severe inhalation injury. These are
beneficial in reducing cast formation and improving pul­
monary performance,70,71 although their use in the clinical
D
C
B
A
Fig. 16.4  Airway obstructive cast. (A) Macroscopic views of an airway obstructive cast in sheep 48 hours after burn and smoke inhalation injury. (B)
Macroscopic views of an airway cast taken from a patient with burn and smoke inhalation injury by bronchoscope.69 (C) Microscopic views of bronchi
totally blocked by obstructive cast in sheep.35 (D) Mucus totally obstructing a bronchiole in a patient after burn and smoke inhalation injury. The tissue
had been immunostained for mucin 5B, an upper airway-specific mucin subtype.66 (B is from Nakae H, Tanaka H, et al. Failure to clear casts and secretions
following inhalation injury can be dangerous: report of a case. Burns 2001;27(2):189–191; C is from Cox RA, Burke AS, et al. Acute bronchial obstruction in
sheep: histopathology and gland cytokine expression. Exp Lung Res. 2005;31(9–10):819–837; D is from Cox RA, Mlcak RP, et al. Upper airway mucus deposition
in lung tissue of burn trauma victims. Shock 2008;29(3):356–361.)

16  •  The Pathophysiology of Inhalation Injury
178
FiO2, decreased compliance, and increased edema forma­
tion.96 The delay is dependent on the severity of the airway
injury.49,97 Lung injury is associated with an increased pul­
monary transvascular fluid flux.98 The degree of transvas­
cular fluid is proportional to the duration of smoke
exposure49 and is not caused by carbon monoxide (CO) in
the inhalant gas.99 However the degree of arterial CO is
related to severity of inhalation injury.100 The factors
responsible for fluid leak are codified in the Starling-Landis
equation.23,24 The variables of this equation relate fluid
movement to pressure and permeability variations. With
inhalation of smoke, there is a reduction in the reflection
coefficient (permeability to protein), an increase in the fil­
tration coefficient (permeability to small particles), and an
increase in pulmonary microvascular pressure.101,102
Animals 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 injury103 and show a good relationship to histologic
injury scores and changes in transvascular fluid flux.93 In
addition, there is a loss of hypoxic pulmonary vasoconstric­
tion in the injured animals that may help to explain the loss
of oxygenation.104
As in the oropharynx, injury to the lung parenchyma is
associated with PARP activation and 3-nitrotyrosine, and it
is markedly reduced by the administration of iNOS or PARP
inhibitors.92
The venous outflow of the bronchial circulation drains
into the pulmonary microcirculation at the precapillary
level.105 Given that initial damage to the airway appeared to
drive the pathophysiology of the parenchyma, investigators
hypothesized that bronchial blood might deliver cytotoxic
materials or cells to the pulmonary microcirculation. To test
this hypothesis, several investigators have tied off the bron­
chial artery of sheep and then exposed the animals to
smoke.59,96,106 Lung parenchymal changes are reduced by
this approach, affirming the hypothesis. It has also been
shown that increased bronchial blood flow following smoke
inhalation injury carries inflammatory mediators to the
parenchyma, augmenting the injury process.107–109 Recent
ovine studies demonstrate that nebulized epinephrine (non­
specific adrenergic agonist) has similar effects following
smoke inhalation injury: reduced airway blood flow, attenu­
ated pulmonary edema, and reduction in proinflammatory
mediators to levels seen in sheep with ablated bronchial
circulation.73,110 The latter observation is of particular clini­
cal importance because the ligation/ablation of bronchial
artery is not feasible in clinical practice.
What could be the linkage among 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.111 Since these cells have been dehydrated in
alcohol as part of the fixation process, unfixed cells are
much larger, on the order of 12 µm. The pulmonary capil­
lary is small, with an average diameter of 6 µm.111 Nor­
mally, large neutrophils can traverse the pulmonary
capillary by changing shape. However, following injury,
many of the neutrophils in the bronchial areas have their
F-actin activated. As result, these cells are stiff and cannot
In an ovine model with a selected area of smoke injury
to the tracheal epithelium, the epithelial repair process
was completed at 18 days.77 Further study by this team
of investigators revealed that nebulization of cefazolin and
growth factors78 could improve the rate of airway healing.
Because of the effects of pneumonia and inhalation injury
on burn patient morbidity and mortality, further studies
on the dynamics of airway damage and airway epithelial
repair following toxic exposure are needed to improve criti­
cal burn care.
The airway is richly innervated with vasomotor and
sensory nerve endings.79 These fibers are known to release
neuropeptides that can engender inflammatory responses.80
Neuropeptides in the upper airway are also involved in
mucus secretion, thus their release and interaction with the
mucosal gland epithelium can increase the early obstruc­
tive pathology that occurs with inhalation injury.81,82
Neuroinflammation is responsible for pathophysiological
changes associated with a number of clinical conditions
including tissue injury induced by chemicals.83,84 Lange
and colleagues reported that antagonists to substance P
and calcitonin gene-related peptide had a marked effect on
this response when administered to sheep and mice that
were injured with both burn and smoke inhalation.51,85 In
an ovine model, the combination of burn and smoke inha­
lation injury caused a 10-fold increase in pulmonary trans­
vascular fluid flux and a reduction of PaO2/FiO2 to 200 or
less. These changes were reversed by neuropeptide receptor
blocking agents.85 Released neuropeptides can activate
nitric oxide synthase (NOS), have chemokine activity, and
change microvascular permeability.86 The resultant activi­
ties lead to the formation of ROS and RNS.87 Some of the
latter are very potent oxidants that can damage DNA.30
Damage to DNA triggers activation of a DNA repair enzyme,
poly(ADP-ribose) polymerase (PARP).88 This enzyme
depletes the cell of high-energy phosphates and causes the
activation of nuclear factor-κB (NF-κB)89,90 NF-κB activa­
tion induces upregulation of inducible NOS (iNOS) and
IL-8, thus accelerating production of ROS and RNS.91 NO
and 3-nitrotyrosine (an index of RNS), and iNOS mRNA
and protein have been reported to be in the airway after
smoke inhalation.87,92 Compounds that catalyze the break­
down of peroxynitrite reduce the response to smoke inhala­
tion. Poly(ADP-ribose) (PAR), the product of the constitutive
enzyme PARP, is detectable in airway tissues following
smoke inhalation.87 PARP inhibition prevents PAR forma­
tion, NF-κB upregulation, and 3-nitrotyrosine formation.93
Similarly, Lange and colleagues have reported that com­
pounds that inhibit peroxynitrite by catalyzing its rapid
breakdown likewise prevent the formation of these materi­
als.94 It is interesting to note that mice missing the PARP
genes or given a PARP inhibitor will not show the typical
inflammatory changes usually observed with asthma.95
Thus, in many ways, inhalation of smoke may be similar to
other 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 is similar.
INJURY TO THE LUNG PARENCHYMA
As noted earlier, burn and smoke inhalation induce delayed
lung parenchymal changes as reflected by reduced PaO2/

16  •  The Pathophysiology of Inhalation Injury
179
supplementation with recombinant human antithrombin
has been shown to attenuate pulmonary edema, downreg­
ulate proinflammatory mediators, and improve pulmonary
gas exchange.71,122 In pilot clinical studies, antithrombin
deficiency following cutaneous burn was correlated with
TSBA, presence of smoke inhalation, length of ICU and
hospital stay, morbidity severity, and mortality.123–126 Recent
unpublished observations showed that of six sheep exposed
to smoke inhalation, all developed some degree of pulmo­
nary vascular emboli (clot) observable by computed tomog­
raphy scan. The pathophysiology of acute lung injury
secondary to burn and smoke inhalation injury is summa­
rized in Fig. 16.5.
In addition to exhibiting a depletion of antioxidants as
discussed earlier, burn patients are depleted of arginine.127
When arginine levels are low, NOS produces superoxide
rather than NO.128 Following smoke inhalation, arginase
activity is also elevated.129 This enzyme also depletes argi­
nine by converting it to ornithine.130 Administration of
arginine may assist in reducing the oxidation that occurs
with inhalation injury.131 However the necessity of admin­
istering arginine as arginine hydrochloride (because of
solubility) limits the amount that may be given intrave­
nously without producing acidosis.
deform. These stiff cells are carried to the pulmonary micro­
vasculature where they are captured by the narrow pulmo­
nary capillaries. The activated neutrophils release ROS and
proteases that damage the parenchyma. The following evi­
dence supports this concept of neutrophil cytotoxicity. Oxi­
dative processes are well established following inhalation
injury, with lipid peroxidation and release of proteolytic
enzymes following injury.112–114 Moreover, administration
of protease inhibitors or ROS scavengers will reduce the
response to smoke inhalation113,115–117 when activated
PMNs lose L-selectin on their surfaces. This L-selectin shed­
ding is prevented by treatment with an L-selectin anti­
body,118 which prevents changes in transvascular fluid flux
and other aspects of parenchymal damage.119 Final proof
of this hypothesis is provided by studies of how the response
to inhalation injury is affected by depleting animals of neu­
trophils. In these studies of sheep depleted of their leuko­
cytes, a large portion of the response to smoke inhalation
was blocked.120
Coagulopathy has increasingly been described as a criti­
cal complication of burn and smoke inhalation injury. Fol­
lowing burn injury, there is a hypercoagulable state
associated with severe deficiency of the potent endogenous
anticoagulant antithrombin.121 In preclinical studies,
Smoke Inhalation
Increased airway blood flow
Draining into pulmonary
circulation
Surge of various inflammatory
mediators into pulmonary circulation
Upregulation of adhesion
molecules on endothelial cells
Adherence of neutrophils
to endothelium
Airway epithelium exfoliation
Mucus secretion
Bronchospasm
Cast formation
Airway obstruction
Narrowing of
airway lumen
Prevention of
alveolar ventilation
Pulmonary
microvascular clots
Impaired pulmonary
gas exchange
Neutrophil migration
into airways
Exudate into airways
containing procoagulants
Airway fibrin
Airway wall edema
Increased pulmonary
transvascular fluid flux
Pulmonary vascular
hyperpermeability
Pulmonary edema
Pulmonary Dysfunction
Shunt fraction
Loss of hypoxic
vasoconstriction
Cellular dysfunction
ATP depletion
PARP activation
DNA single strand break
Peroxynitrite
Nitric oxide
iNOS
Superoxide
NF-κB
NF-κB
Coagulopathy
Stimulation of sensory nerves of airway
Release of neuropeptides
Fig. 16.5  Pathophysiology of burn and smoke inhalation induced acute lung injury. iNOS, inducible nitric oxide synthase; PARP, poly(ADP-ribose)
polymerase. (From Fishman, ed. Pulmonary diseases and disorders, 5th edn., vol 2., McGraw-Hill Companies, China. ch. 94. 2015: 1428–1440.)

16  •  The Pathophysiology of Inhalation Injury
180
organ damage, including central nervous system (CNS)
dysfunction.
The Fire Environment and Toxic
Smoke Compounds
Smoke toxicity is an increasing concern because modern
industrial products are changing from woods and natural
materials toward lighter construction materials, synthetics,
and petrochemical-based materials. These materials ignite
and burn two to three time hotter and faster than conven­
tional material and, when heated, emit a gas or smoke that
is more toxic than natural biological materials. Conse­
quently firefighters have less time to gain control of a fire,
and victims are more likely to be incapacitated by breathing
toxic gases and to sustain smoke inhalation because they
have less time to escape from the burning area.8 Inhalation
injury is caused by steam or toxic inhalants such as fumes,
gases, and mists. Fumes consist of small particles with
various adherent irritants or cytotoxic chemicals that are
dispersed in air. Mists consist of aerosolized irritant or cyto­
toxic liquids. Smoke consists of a combination of fumes,
gases, mists, and hot air. Heat, toxic gases, and low oxygen
levels are the most common causes of death in fires. A large
variety of toxic gases and chemicals can be generated
depending on the fire environment (Table 16.1).
Many of these compounds may act together to increase
death, especially CO and hydrogen cyanide (CH).149,150 A
synergism between these compounds has been found to
increase tissue hypoxia and acidosis150 and may also
decrease cerebral oxygen consumption and metabo­
lism.22,151 Hydrogen sulfide would also be predicted to syn­
ergize with CO since both cyanide and hydrogen sulfide are
inhibitors of mitochondrial cytochrome oxidase. Victims
may be incapacitated by the blinding and irritating effects
of smoke, as well as by the decreasing oxygen concentration
that occurs with combustion and results in progressive
hypoxia.
Toxic gases such as CO and cyanide rarely damage the
airway, but instead affect gas exchange and produce more
systemic effects. Thus it is important to obtain information
on the source of the fire and the combustion products gen­
erated when treating a fire victim (see Table 16.1). It is also
important to know the duration of exposure and the extent
to which the fire victim was in an enclosed area since this
relates to the dose of toxic materials received.
CARBON MONOXIDE
CO is an odorless, colorless gas that is produced by incom­
plete combustion of many fuels, especially cellulolytic (cel­
lulose) products such as wood, paper, and cotton.152 CO
toxicity remains one of the most frequent immediate causes
of death following smoke-induced inhalation injury. The
predominant toxic effect of CO is attributed to its binding to
hemoglobin (Hb) to form carboxyhemoglobin (COHb). The
affinity of CO for Hb is approximately 200 to 250 times
higher than that of oxygen.153 Inhalation of a 0.1% CO
mixture may result in generation of a COHb level as high
as 50% of the total Hb. The competitive binding of CO to Hb
reduces delivery of oxygen to tissues, leading to severe
LONG-TERM EFFECTS OF INHALATION INJURY
When earlier editions of this book were published, mortal­
ity from inhalation injury was high and the acute inflam­
matory aspects of the injury were considered a major vector
of mortality. Now 85% of our patients survive inhalation
injury.5 Thus the long-term aspects of this injury are of
considerable interest. When patients are examined years
after burn injury, they demonstrate symptoms of restrictive
lung disease and reduced diffusion capacity, both of which
are signs of lung fibrosis.132 At autopsy, both patients and
animals reportedly show hyaline membrane and deposition
of collagen in their lungs, changes similar to those seen in
other forms of acute lung injury.61,129 As stated earlier, two
enzymes compete for arginine: NOS and arginase.134 NOS
forms NO and RNS. Arginase forms ornithine, which is con­
verted into polyamines and proline, leading to the forma­
tion of collagen.135 When NOS is active, it forms N
(omega)-hydroxy-nor-L-arginine (NOHA). NOHA is broken
down into NO and citrulline. NOHA is a potent inhibitor of
arginase.136,137 Thus, as long as NOS activity is elevated,
arginase is inhibited. It has recently been reported that the
endogenous NOS inhibitor asymmetric dimethylarginine
(ADMA) begins to rise in the lung of sheep following com­
bined burn and smoke inhalation injury.129 As ADMA
increases, NO production falls and tissue levels of collagen
increase. The increase in collagen results in hyaline mem­
brane formation and thickening of the alveolar septum that
interferes with the diffusion of oxygen into the lung. ADMA
is formed in the lung on a regular basis but it is rapidly
catabolized by dimethylarginine dimethylaminohydrolase
(DDAH).138,139 DDAH is inactivated by oxidation. Following
burn and inhalation injury, lung levels of DDAH fall as
markers of oxidation rise, and, as these events occur, levels
of ADMA, arginase, and collagen increase.129 We have pre­
viously determined that oxidation is such a serious problem
that survival is dependent of the degree of oxidation.115 In
addition, it was recently reported that levels of γ- and
α-tocopherol are markedly depleted in thermally injured
children.140 In sheep depleted of α- and γ-tocopherols fol­
lowing burn and smoke exposure, the administration of
tocopherol, especially γ- tocopherol, either orally or through
nebulization into the airways (more effective) restored not
only lung levels of tocopherol, but also normal oxidation
status and pulmonary function during the acute phase of
injury.140–146 Preliminary experiments using the long-term
model reported by Sousse et al. indicate that the nebuliza­
tion of γ-tocopherol also reduces collagen deposition; blocks
elevation in arginase, proline, and ADMA levels; and
restores DDAH levels.
Finally, recent preclinical ovine studies indicate that
smoke inhalation causes structural damage in the brain as
seen by neuronal and astrocyte death and microhemor­
rhage (unpublished data). It has previously been reported
that smoke-induced oxidative DNA damage in the brain is
extensive, and compromised fidelity of DNA repair may
underlie neurotoxicity and contribute to delayed death of
hippocampal neurons.147 Furthermore, acute smoke expo­
sure significantly compromises the respiratory capacity of
hippocampal mitochondria.148 These results suggest that
fire victims, especially those with smoke inhalation injury,
should carefully be monitored for possible nonpulmonary

16  •  The Pathophysiology of Inhalation Injury
181
describes the clinicopathological sequelae in acute CO
toxicity.159
Symptoms and Diagnosis of Carbon
Monoxide Poisoning
Symptoms of CO poisoning predominantly manifest in
organs and systems with high oxygen utilization. The sever­
ity of clinical manifestations varies depending on CO con­
centration. For instance, CNS symptoms such as headache,
confusion, and collapse may occur when the blood COHb
level is 40–50%. Symptoms such as unconsciousness, inter­
mittent convulsions, and respiratory failure may occur if
the COHb level exceeds 60%, eventually leading to death if
exposure continues. The cardiovascular manifestations
may result in tachycardia, increase in cardiac output, dys­
rhythmias, myocardial ischemia, and hypotension depend­
ing on severity of poisoning. The correlation between
clinical manifestation and severity of CO poisoning is sum­
marized in Table 16.2.
Diagnosis should be based on direct measurement of
COHb levels in arterial or venous blood by co-oximetry,
taking into account that venous blood underestimates the
arterial COHb content.160 Diagnosis may be facilitated 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
sulfur dioxide (SO2) based on measurement of dissolved PO2
should also be avoided. Measuring acid–base balance,
plasma lactate levels, and bicarbonate is helpful in
hypoxia, especially in the most vulnerable organs such as
the brain and heart where oxygen extraction is considerably
higher than that in most other organs. The oxygen–Hb dis­
sociation curve loses its sigmoid shape and is shifted to the
left, thus further impairing tissue oxygen availability.149,154
In addition, the ability of CO to bind to intracellular cyto­
chromes and to other metalloproteins contributes to CO
toxicity. This competitive inhibition with cytochrome
oxidase enzyme systems (most notably cytochromes a and
P-450) results in an inability of cellular systems to use
oxygen.154,155 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.156
Miro and colleagues reported that CO inhibits cytochrome-c
oxidase activity in lymphocytes.157 The electron chain dys­
function induced by CO may cause electron leakage, leading
to superoxide production and mitochondrial oxidative
stress.158
Although smoke inhalation commonly affects the respi­
ratory system, CNS disturbances can also develop. CNS
signs can be classified as being related to either acute or
delayed toxicity. The veterinary literature contains a few
reports on the neurological consequences of smoke inhala­
tion. In dogs, smoke inhalation produces lesions that are
consistent with acute CO toxicity. Lesions are confined to
the caudate nucleus, globus pallidus, and the substantia
nigra bilaterally, as well as the cerebellum, cerebral cortex,
and dorsal thalamus. A case report by Kent and colleagues
Table 16.1  Origin of Selected Toxic Compounds
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 Prien T, Traber DL. Toxic smoke compounds and inhalation injury: a review. Burns 1988;14:451–460.

16  •  The Pathophysiology of Inhalation Injury
182
(116.4 mol/L) were significantly higher than those in control
subjects (5.0 mol/L) and that levels in fire victims who died
were significantly higher than those in survivors.163 A study
of 144 fire victims in Dallas County, Texas, showed results
consistent with the Paris study.164 Elevated CN concentra­
tions are directly related to the probability of death, suggest­
ing that CN poisoning rather than CO poisoning may be the
predominant cause of death in some fire victims. CN also
played a greater role in mortality following an aircraft fire
at Manchester International Airport in the United Kingdom
in 1985. These patients were not severely burned. The large
majority (87%) of the 54 individuals who died had poten­
tially lethal levels of CN in their blood, whereas only 21%
of these fire victims had COHb levels exceeding 50%. This
strongly suggests that, under certain conditions, CN can be
a more important determinant of morbidity and mortal­
ity following smoke inhalation than CO, which is usually
regarded as the primary toxic threat.8 Smoke is also an often
overlooked source of CN exposure in terrorist bombings.
Following the first World Trade Center bombing in 1993,
traces of CN were found in the vans where the explosion
originated. The U.S. Centers for Disease Control and Preven­
tion and the Department of Homeland Security consider
CN among the most likely agents of chemical terrorism.165
CN possesses all attributes of an ideal terrorist weapon: it
is plentiful, readily available, and easily obtainable because
of its widespread use in industry and laboratories. In addi­
tion the use of CN does not require any special knowledge.
It is capable of causing mass incapacitation and casual­
ties, and it can cause mass confusion, panic, and social
disruption.166
Symptoms and Diagnosis of Cyanide Poisoning
Diagnosis at the fire scene may be difficult. Poisoning may
results in CNS, respiratory, and cardiovascular dysfunction
due to inhibition of oxidative phosphorylation, depending
on the concentration of CN inhalation (Table 16.3).
Electrocardiographic changes such as S-T segment ele­
vation that mimic an acute myocardial infarction167 may
be suggestive. Laboratory findings of anion gap metabolic
acidosis and lactic acidemia aid in confirming the diagno­
sis.168 Lactic acidosis that is not rapidly responsive to oxygen
therapy may be a good indicator for CN poisoning.100,163
Also, an elevated mixed venous saturation is suggestive of
managing CO poisoning with accompanying lactic or meta­
bolic acidosis. It is important to note that high oxygen con­
centrations are usually administered to the victim in transit
to the hospital, and some delay from cessation of exposure
to measurement of CO may limit evaluation of the true
extent of exposure.161 A nomogram has been developed
that can relate the COHb 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 inhala­
tion injury.100
HYDROGEN CYANIDE
Hydrogen cyanide (CN), the gaseous form of cyanide, is gen­
erated by the combustion of nitrogen- and carbon-
containing substances, such as wool, silk, cotton, and paper
as well as synthetic substances like plastic and other poly­
mers. Combustion of these materials may produce the rapid
and lethal incapacitation of a victim at the fire source.162
CN is a colorless gas with the odor of bitter almonds;
however it is difficult to detect at the site of the fire. CN is
cytotoxic mainly owing to its reversible inhibition of cyto­
chrome c oxidase, the thermal oxidase of the respiratory
chain, through interaction with the ferric ion of cyto­
chrome a3.161 This suppresses cellular oxygenation and
causes tissue anoxia. CN also adversely affects a number of
other enzyme systems. CN is also toxic by virtue of its com­
bination with essential metal ions, formation of cyanohy­
drins with carbonyl compounds, and sequestration of sulfur
as a thiocyanate.
The importance of CN in smoke inhalation injuries is
reflected by a study of residential fires in Paris, France,
showing that mean blood CN concentrations in both fire
victims who survived (21.6 mol/L) and those who died
Table 16.2  Symptoms and Signs at Varying
Concentrations of Carboxyhemoglobin (COHb)
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 less than 1 h
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;11:163–189; and Schulte JH. Effects of mild carbon monoxide
intoxication. Arch Environ Health 1963;7:524–530.
Table 16.3  Symptoms of Cyanide Toxicity
Symptoms in Low or
Moderate
Inhaled Cyanide
Concentrations
Symptoms in Moderate
or High
Inhaled Cyanide
Concentrations
Faintness
Flushing
Anxiety
Excitement
Perspiration
Vertigo
Headache
Drowsiness
Tachypnea
Dyspnea
Tachycardia
Prostration
Hypotension
Tremors
Cardiac arrhythmia
Convulsions
Stupor
Paralysis
Coma
Respiratory depression
Respiratory arrest
Cardiovascular collapse

16  •  The Pathophysiology of Inhalation Injury
183
form ammonium hydroxide, a very caustic alkaline solu­
tion. It causes cutaneous, ocular, and pulmonary injuries.
Inhaled ammonia can rapidly produce laryngeal injury and
obstruction. It also causes upper tracheobronchial mucosal
necrosis with sloughing and severe pulmonary edema.174
There are no specific antidotes to counter the toxicity of
irritant gases (phosgene, chlorine, and ammonia). Depend­
ing on the severity of exposure, supportive therapy such as
airway management and ventilation should be provided.
Early intubation is required if any significant upper airway
symptoms such as stridor are present (Table 16.5).
Complete references available online at

CN toxicity. CN increases ventilation through carotid body
and peripheral chemoreceptor stimulation. Increasing ven­
tilation may augment toxicity in the early stages. Low levels
of CN are routinely found in the blood of healthy individu­
als at levels of 0.02 µg/mL in nonsmokers 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.169 Correlation of blood CN
concentrations with clinical symptoms is summarized in
Table 16.3.
OTHER TOXIC CHEMICALS
Other toxic chemicals may also substantially contribute to
morbidity and mortality in a burn victim. Hydrogen chlo­
ride 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 they 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
great importance. Because of their widespread availability
and high toxicity, there is concern that these chemicals may
be used as weapons by terrorists.165,170
Phosgene is a colorless, nonflammable, heavier-than-air
gas at room temperature and has an odor of newly mown
hay. At temperatures lower than 8°C phosgene is an odor­
less and fuming liquid. The inadequate warning properties
of phosgene and the delayed nature of the symptoms that
follow exposure make it a potential terrorist weapon.171,172
Phosgene is only slightly soluble in water, hence its deeper
penetration in the pulmonary system. On contact with
water it hydrolyzes into carbon dioxide and hydrochloric
acid, resulting in direct caustic damage. It also undergoes
acylation reactions with amino-, hydroxyl-, and sulfhydryl-
groups of cellular macromolecules, resulting in cellular
damage and apoptosis.171,173 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 symptoms of upper
airway irritation (eye irritation, rhinorrhea, cough) and
then lower respiratory symptoms such as shortness of
breath, substernal burning, and chest tightness. The devel­
opment of overt pulmonary edema within 4 hours of expo­
sure portends a poor prognosis (Table 16.4).
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,
hydrochloric acid, and oxygen free radicals. It causes irri­
tant effects throughout the respiratory tree but mostly in
the nasal mucosa and upper airways. It induces cellular
damage through its strong oxidizing ability.174 Phosgene
and chlorine gases were extensively used as weapons during
World War I.
Ammonia is a colorless gas at room temperature with a
very pungent odor. Ammonia readily dissolves in water to
Table 16.4  Hydrogen Cyanide Concentrations in Air
and Associated Symptoms in Humans
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 h without difficulty
100
Death in 1 h
110–135
Fatal in 0.5–1 h
181
Fatal in 10 min
280
Immediately fatal
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Table 16.5  Mean Levels of Airway Obstruction in
Uninjured Sheep and 48 h After Burn, Smoke Inhalation,
and Combined Smoke Inhalation and Burn Injury
AIRWAY LEVEL
Injury
Bronchi
Bronchiole
Terminal
Brochioles
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%
0.04 ± 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%*†
1.5 ± 6.7%*†
1.2 ± 1.9%*†
Data are presented as mean ± SD (n, number of animals in each group).
*Significantly different from uninjured animas 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 29: 295, 2003.

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183.e4 16  •  The Pathophysiology of Inhalation Injury
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184
Diagnosis and Treatment of
Inhalation Injury
LEE C. WOODSON, LUDWIK K. BRANSKI, PERENLEI ENKHBAATAR, and MARK TALON
17 
instability because volume requirements for resuscitation
may be increased by as much as 50% when cutaneous
burns are accompanied by inhalation injury.10,11 Parenchy­
mal injury from inhaled irritants or hot gases can lead to
impaired gas exchange, pneumonia, and acute respiratory
distress syndrome (ARDS). When severe, these changes
increase the risk of multiorgan failure and mortality. After
recovery from inhalation injury pulmonary function dis­
orders may persist due to pulmonary fibrosis or bronchi­
ectasis.12 Improvements in the survival of patients with
inhalation injury have been attributed to better overall burn
outcomes, improved ventilator management, and improved
management of pneumonias.7
Improvements in the care of cutaneous burns have out­
paced advancements in the treatment of inhalation inju­
ries. 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, treatment 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 exchange and
radiographs. Inhalation injury results both from direct
effects of heat and chemical irritants as well as from indirect
effects from an inflammatory response to the initial insult.
Despite extensive studies, these processes are incompletely
understood and no specific therapies have been identified.
Because inhalation injury has such broad and critical
clinical implications, 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 phys­
ical examination and confirmed by diagnostic procedures.
Diagnosis
There is no consensus on the diagnostic criteria for inhala­
tion injury. In the clinical setting the diagnosis is a relatively
subjective judgment based on history and physical exami­
nation, often confirmed by additional diagnostic procedures
such as bronchoscopy. One of the reasons for the lack of
consensus for early diagnosis is that much of the impaired
pulmonary function following inhalation injury results
from obstruction of small airways and an inflammatory
response to the initial direct injury. These changes develop
over a period of days after injury. In addition, it is our clini­
cal impression that progressive respiratory failure is not
always proportional to the intensity of smoke exposure.13 It
is also possible for thermally injured patients to experience
acute lung injury from the systemic effects of the
Introduction
Inhalation injury is a nonspecific term that refers to damage
to the respiratory tract or pulmonary parenchyma by heat
or chemical irritants carried into the airways during
respiration.
Along with total body surface area (TBSA) burned and
age, inhalation injury is one of the three features most asso­
ciated with mortality following thermal insult.1 Issues
related to diagnosis and management of inhalation injury
have been most recently reviewed by Walker et al.2
Inhalation injury may occur in conjunction with cutane­
ous burns or in isolation. The severity of injury varies
depending on the chemical composition of the agent(s)
inhaled, the intensity of exposure, and pre-existing comor­
bidities. 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.
The upper airway serves as an efficient heat exchanger that
protects lower structures from extremes of heat or cold.
Reflex laryngeal closure also protects subglottic areas. As a
result, direct thermal injury is generally restricted to the
upper airway and rarely involves subglottic structures.3
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 irri­
tants 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. Fumes
consist of particles of various size dispersed in 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, thus, the nature of the tissue injury.4
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 drop­
lets. Systemic toxicity may occur when toxins such as
carbon monoxide (CO) or cyanide are present in the inhaled
gases.
The reported incidence of inhalation injuries has varied
greatly over time and from region to region. Smith and
others reported 19.6% incidence among burn patients in
the United States.5 In Israel Haik and colleagues found as
few as 1.9% in association with burns,6 whereas Luo and
others found 8.01% in China.7 Regional differences are to
be expected as a result of differences in local customs, build­
ing materials, and other factors.
The presence of inhalation injury is clinically significant
for a variety of reasons, as listed in Box 17.1. Inhalation
injury has been found to be an independent risk factor
for mortality.8,9 It is also associated with hemodynamic

17  •  Diagnosis and Treatment of Inhalation Injury
185
nasal hair implies a very intense exposure to heat. When
gases hot enough to burn tissue are near the airway inlet it
suggests that oropharyngeal or nasopharyngeal structures
may also suffer thermal injury. Soot deposits on the face and
carbonaceous sputum suggests inhalation of smoke. Phys­
ical examination may reveal signs and symptoms such as
stridor, hoarseness, drooling, and dysphagia that are con­
sidered classic evidence of thermal injury to the orophar­
ynx. Presence of these findings, however, does not always
indicate that tracheal intubation is necessary.18 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 injury or to follow the progression
of injury. Since manifestations of respiratory dysfunction
may be delayed after inhalation injury, pulse oximetry and
arterial blood gas analysis are insensitive indicators of lung
injury during the initial stages. Despite this, it is important
to employ these tools as soon as possible. Early impairment
of gas exchange is an ominous sign of severe injury and
requires early and aggressive intervention. Diagnosis of CO
or cyanide toxicity may be facilitated by blood gas analy­
sis. It is also important to have baseline values to judge
progress.
Lee and O’Connel assessed the chest radiographs of 45
patients admitted to their hospital following injury in an
enclosed space fire.19 Of those patients, 33 had abnormal
findings consistent with inhalation injury. They suggested
that the initial radiograph is an important predictor of
injury and need for mechanical support of respiration.
However, Wittram and Kenny examined admission chest
radiographs over a 3-year period for all patients requiring
ventilatory support for inhalation injury.16. Out of 25
patients, 12 had normal initial chest radiographs despite
ultimately requiring mechanical ventilation. The initial
chest radiograph is considered an insensitive early indicator
of parenchymal injury after smoke inhalation. Although an
admission chest radiograph should be obtained in all
patients suspected of inhalation injury a normal study does
not rule out the possibility of significant pulmonary injury.16
Flexible fiberoptic bronchoscopy was early recognized as
a powerful tool in the diagnosis of inhalation injury.20 Fiber­
optic bronchoscopy allows direct visualization of tissue
damage to the upper airway and bronchi from heat and
chemical irritants. This procedure can quickly and reliably
identify patients with upper airway compromise who will
benefit from intubation and, at the same time, avoid intuba­
tion of patients who will not benefit.21 Bronchoscopic evi­
dence of inhalation injury includes soot deposits, erythema,
edema (as indistinct tracheal rings and/or blunting of the
carina), mucosal blisters and erosions, hemorrhages, and
bronchorrhea (Fig. 17.1). Flexible fiberoptic bronchoscopy
has been considered the gold standard for diagnosis of inha­
lation injury and is often used to confirm the diagnosis of
inhalation injury.22 However, Hunt noted that, in some
cases, bronchoscopy performed soon after injury may not
show mucosal injury.20 In addition, because acute lung
injury and tracheobronchitis can be a result of systemic
inflammation due to cutaneous burns,14,23 endoscopic
inflammatory response to severe cutaneous burns.14 Thus
it is not uncommon to see acute lung injury in children
with large scald burns when inhalation of hot or caustic
gases did not occur.15 This makes it difficult to determine
what component of respiratory failure is due to inhalation
injury and what component is an effect of systemic inflam­
mation associated with large cutaneous 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 often
normal.16 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 inhalation
injury. Normal gas exchange and chest radiograph on
admission do not rule out significant inhalation injury.
Early diagnosis is important to recognize the potential for
airway compromise, manage fluid resuscitation, and to rec­
ognize systemic toxicity that may lead to permanent neuro­
logical 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
exposure 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 occurs in
some industrial accidents. Information regarding the mech­
anism of injury also includes the source of combustion,
which could identify specific chemical irritants. The history
can also provide information regarding the intensity of
exposure. Duration of exposure is an important determi­
nant of intensity of exposure. When a victim’s avoidance
behavior is impaired, as when trapped in an enclosed space,
intoxicated, unconscious, or in the case of extremes of age,
exposure to injurious inhalants is increased.
History of the mechanism of injury is especially impor­
tant in the case of scalds due to ingestion of hot liquids.
Although patients may appear asymptomatic initially, oro­
pharyngeal scalds have led to delayed fatal airway occlu­
sion. Intraoral scalds can present in a manner similar to
epiglottitis.17 The larynx should be examined for evidence
of compromise in all patients who present with significant
risk (either by history or physical exam) of intraoral scald.
The physical examination can reveal additional risk
factors for inhalation injury. We guard our face vigorously,
and the presence of burns to the face or singed eyebrows or
Box 17.1  Clinical Significance of
Inhalation Injury
■ Increased mortality
■ Airway closure secondary to oropharyngeal edema
■ Increased resuscitation fluid requirements
■ Impaired pulmonary gas exchange
■ Pneumonia
■ Risk of systemic inflammatory response syndrome and
multiorgan failure
■ Chronic pulmonary dysfunction
■ Laryngeal damage

17  •  Diagnosis and Treatment of Inhalation Injury
186
increased fluid needs has been inconsistent. Endorf and
Gamelli found that an initial P:F ratio of less than 350 was
a more reliable predictor of increased fluid requirements
than was diagnosis of inhalation injury by bronchoscopy.27
In their patients, fluid requirements during initial resuscita­
tion were not correlated with severity of findings at initial
bronchoscopy. Cancio and colleagues found that diagnosis
of inhalation injury per se was not related to increased fluid
needs but that mechanical ventilation was related.30 They
suggested that mechanical ventilation may be a surrogate
variable for more severe inhalation injury, and this could
explain its closer correlation with fluid needs. These obser­
vations reinforce the possibility that findings of bronchos­
copy are relatively proximal and may not always reflect the
severity of more distal parenchymal injury. Need for
mechanical ventilation and decreased P:F are more depen­
dent on parenchymal injury and therefore may be more
accurate predictors of inhalation injury.
Mackie and colleagues have offered an alternative mech­
anism for increased fluid requirements in burn patients
who also have inhalation injury.31 They found that venti­
lated patients with burns but no inhalation injury required
more fluid than did patients with similar burns but who did
not receive mechanical ventilation. Fluid balance was not
significantly affected in patients who also had burns, inha­
lation injury, and were mechanically ventilated. Mackie
suggests that positive pressure ventilation increases intra­
thoracic pressure, which impairs venous return to the
heart. More intravenous fluid is then required to maintain
cardiac preload. These findings are consistent with a greater
effect of mechanical ventilation on fluid balance than inha­
lation injury.32
Although bronchoscopy does not reliably predict respira­
tory failure, endoscopic assessment of the upper airway has
been found to be highly useful in identifying patients with
glottic or supraglottic changes who would benefit from early
intubation. Just as important, this exam also helps avoid
unnecessary intubations that expose patients to serious risk
without benefit.21
Radionuclide studies represent an additional tool that
has been used to provide evidence of pulmonary injury
distal to the more proximal views permitted by flexible bron­
choscopy. Intravenously administered xenon-133 is
excreted by the lungs and exhaled. Delayed clearance of
xenon-133 is a sensitive indicator of inhalation injury.33
Lung scintigraphy using technetium-99 aerosol inhalation
has also been used to identify areas of pulmonary dysfunc­
tion in patients with respiratory dysfunction after smoke
inhalation. Delayed clearance and inhomogeneous lung
distribution of radioactivity are evidence of injury.34 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.
The poor correlation of clinical outcome with severity of
bronchoscopic findings in patients with smoke inhalation
injury has led some clinicians to evaluate the possibility
that chest computed tomography (CT) could provide more
accurate prognostic information. CT can reveal regional
differences in structural changes that impair pulmonary
function, such as atelectasis, consolidation, and fibrosis,
more effectively than chest radiographs. Yamamura and
changes after 36–48 hours may be caused by mechanisms
other than inhalation of chemical irritants. As an example,
a small fraction of young pediatric patients with large scald
injuries develop acute lung injury and require mechanical
ventilation.15 Bronchoscopic examination of these patients
can reveal inflammatory changes characteristic of smoke
inhalation. Moreover, although fiberoptic bronchoscopy
can definitively identify tissue damage from inhalation
injury, it has been recognized that the observed changes are
relatively proximal and may be more severe than more
peripheral parenchymal injuries.24 As a result, a broncho­
scopic diagnosis of inhalation injury does not always iden­
tify which patients will experience progressive respiratory
dysfunction.
Numerous attempts have been made to grade severity of
inhalation injury based on bronchoscopic findings in order
to identify patients who may need increased levels of support
regarding airway management, respiratory support, or
increased volume of fluid during the initial resuscitation.
In their retrospective study, Hassan et al. found that mortal­
ity among patients with inhalation injury correlated with
severity of bronchoscopic findings.25 However, Spano and
colleagues also performed a retrospective review to evaluate
the effectiveness of bronchoscopy to predict outcomes for
patients with inhalation injuries.26 They used an abbrevi­
ated injury score (AISD INH) introduced by Endorph and
Gameli27 that grades the severity of bronchoscopic findings
associated with smoke inhalation injury. They also reviewed
the three previous studies that specifically compared the
AIS INH with clinical outcome.27–29 All these studies found
trends that were suggestive of poorer clinical outcome in
patients with more severe bronchoscopic changes, but these
trends were not statistically significant. Spano et al. sug­
gested that further studies to allow refinement in descrip­
tions of severity grades will be needed before bronchoscopic
evaluation produces reliable prognostic information.26
It is generally accepted that patients with smoke inhala­
tion injury require increased fluid volume for resuscitation
of cutaneous burns.10,11,30 Increases of up to 40–50% have
been observed.10 While this has been a fairly consistent
observation, the value of bronchoscopy in predicting
Fig. 17.1  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

17  •  Diagnosis and Treatment of Inhalation Injury
187
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 solu­
tions. The initial response to this insult is direct injury to the
respiratory epithelium, resulting in hyperemia, edema,
increased mucous secretions, impaired ciliary clearance,
and bronchoconstriction. Work in experimental animals
has also demonstrated an early separation of ciliated respi­
ratory 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 also 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 pro­
duced by aspiration of acidic gastric contents. The direct
injury to tissues from the initial insult causes local accumu­
lation of inflammatory cells and initiation of a cascade of
inflammatory mediators that exacerbate and sustain tissue
damage (see later discussion). Airways become blocked by
edema, bronchoconstriction, fibrin casts, necrotic debris,
and inflammatory infiltrate (Fig. 17.2). Degraded surfac­
tant causes alveolar instability and collapse. These changes
result in impaired hypoxic pulmonary vasoconstriction and
areas of atelectasis and in post-obstruction sequestration of
material that provides a medium for bacterial growth and
risk of pneumonia. Impaired function of alveolar macro­
phages slows the removal of these materials and facilitates
the development of infection. Pulmonary compliance is
reduced, which can greatly increase the work of breathing
or require higher ventilator pressures and associated risk of
ventilator-induced lung injury.
others used admission chest CT to measure bronchial wall
thickness in patients with suspected inhalation injury.35
Increased bronchial wall thickness was associated with
total number of ventilator days, ICU days, and pneumo­
nia. Oh and colleagues obtained CT scans shortly after
admission for patients at risk for smoke inhalation. A
grading system was used to provide a score for each CT
scan based on interstitial markings, ground-glass opacifi­
cation, and consolidation. This score was compared with
clinical outcomes described as a composite endpoint based
on pneumonia, ALI/ARDS, and mortality. Injury detected
by bronchoscopy alone was associated with an 8.3-fold
increase in the composite score, while the combination of
bronchoscopic evidence of inhalation injury and a high
CT score was associated with a 12.7-fold increase in the
composite endpoint. The authors were cautiously optimistic
that with additional clinical experience and refinement of
image analytical techniques, CT scans alone or in combi­
nation with bronchoscopic evaluation may provide more
accurate early prognosis for patients with smoke inhalation
injury. The risks of taking an acutely ill patient to the CT
scanner were also acknowledged.
Pathophysiology of
Pulmonary Insufficiency with
Inhalation Injury
As stated earlier, except in special cases such as inhalation
of steam, injury to airways below the larynx and pulmo­
nary parenchyma nearly always results from chemical irri­
tation rather than thermal injury. A number of reviews are
available to describe the pathophysiology of pulmonary
failure associated with smoke inhalation.4,36,37 Chemicals
Fig. 17.2  Small airway occluded by inflammatory exudate in a patient who had a smoke inhalation injury.

17  •  Diagnosis and Treatment of Inhalation Injury
188
causing activation of NOS, leading to the formation of NO.
It has also been reported that an inhibitor of the neuro
isoform of NOS would block the hyperemia and much of the
pathophysiology mentioned earlier, including the loss of
hypoxic pulmonary vasoconstriction.53,54 These findings
have led us to the following hypothesis: the chemicals in
smoke activate sensory nerves to release neuropeptides that
activate neuronal NOS1 to release NO and superoxide to
form peroxynitrite, which damages DNA, activating PARP,
which stimulates NF-κB, which in turn will up-regulate the
inducible form of NOS (iNOS), leading to massive formation
of ROS and RNS, tissue damage, and hypoxia and dyspnea.
Some of the activated polymorphonuclear cells that escape
from the pulmonary and bronchial circulation into the sys­
temic circulation are carried to systemic organs, promoting
multiorgan system damage.
Treatment
Currently there are no specific therapeutic interventions for
inhalation injury, and treatment consists of supportive
modalities. However, if systemic toxicity is suspected (i.e.,
cyanide or CO), there are specific interventions recom­
mended. When mechanical ventilation is required, mea­
sures should be taken to minimize ventilator-induced lung
injury. Surveillance cultures and other measures should be
initiated to allow early recognition and treatment of pulmo­
nary infection.
Treatment should begin at the scene of injury. Pulmo­
nary 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 insuffi­
ciency 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
(Box 17.2). Early hypoxemia due to impaired gas exchange
after inhalation injury is an ominous sign, and those with
respiratory distress that is 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 aspira­
tion. It is recommended that, even in the absence of inhala­
tion injury, those with large full-thickness burns covering
30–40% or more of their total body surface area (TBSA)
should be intubated because of the risk of associated hemo­
dynamic instability.55 Another indication for early prophy­
lactic intubation is the risk of upper airway occlusion due
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.38 It has been suggested
that this mechanism of pulmonary dysfunction is funda­
mentally different from other types of ARDS.22 Other etiolo­
gies 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. By contrast, in ARDS due to other etiolo­
gies 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. Just as
the bronchi are the focus of the diagnosis of inhalation
injury, it is also the focus of its pathology.39 The hyperemia
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.40,41
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.42 One of the latter, peroxynitrite,
damages DNA. DNA damage results in activation of poly-
(ADP ribose) polymerase (PARP).43 Poly-(ADP ribose) pro­
tects the damaged DNA but also activates the nuclear factor
(NF)-κB.44 This causes the formation of the inducible form
of nitric oxide synthase (NOS) and additional release of
IL-8, attracting and activating additional neutrophils and
forming more reactive nitrogen and oxygen species.45 The
oxidation, nitration, and nitrosation of lung tissues results
in membrane damage, edema formation, and impaired
oxygen diffusion.46,47 Alveoli that are not ventilated are not
perfused with blood because alveolar hypoxia causes pul­
monary vasoconstriction. NO released by NOS causes a loss
of hypoxic pulmonary vasoconstriction, leading to perfu­
sion of unventilated alveoli and thus a fall in arterial oxygen
saturation.48
In experimental animals ablation of the bronchial blood
flow will prevent most of the pathophysiology involved in
inhalation injury to the pulmonary parenchyma.39,49,50
These changes in bronchial blood flow are not associated
with heat. They can be produced in experimental animals
by smoke that has been cooled to body temperature.41 As
mentioned earlier, the blood flow to the airway is so effective
in cooling or heating inhaled air that it is almost impossible
for heat carried by dry gases to reach the bronchi.3,51 These
changes in blood flow also appear to be independent of the
chemical composition of smoke because they are mediated
by neuroinflammation. We have reported that, following
insufflation of smoke into deeply anesthetized sheep, the
airway blood flow increased 10-fold, but, after administra­
tion of an inhibitor of the neuropeptide calcitonin gene-
related peptide (CGRP), the smoke-induced hyperemia was
markedly reduced.52 Neuropeptides (peptides released from
nerves within the lung tissue) induce vasodilatation by
Box 17.2  Indications for Early Tracheal
Intubation after Inhalation Injury
■ Extensive burns over face and neck
■ Overt signs and symptoms of airway obstruction by edema
■ Inability to protect airway from aspiration
■ Significant toxicity from carbon monoxide or cyanide
■ Respiratory failure
■ Hemodynamic instability

17  •  Diagnosis and Treatment of Inhalation Injury
189
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 impending airway compro­
mise and will more likely benefit from early prophylactic
intubation. Those who do not require early intubation can
be observed and repeat evaluations performed if their clini­
cal condition changes. An algorithm for airway manage­
ment in burn patients is illustrated in Fig. 17.3.
Another potential complication of inhalation injury
requiring early attention is systemic toxicity from CO and/
or cyanide. Intoxication should be considered in all patients
suspected of significant exposure to smoke. The predomi­
nant toxic effect of CO is to prevent binding of oxygen to
hemoglobin by the formation of carboxyhemoglobin
(COHb). CO has an affinity for hemoglobin approximately
200 times that of oxygen. CO can also prevent cellular uti­
lization of oxygen by binding to mitochondrial cytochromes.
Early symptoms include headache, nausea, dizziness, and
lowered mental status. Diagnosis requires direct measure­
ment of COHb. Conventional pulse oximetry will not distin­
guish between oxyhemoglobin and COHb. COHb can be
measured by arterial or venous CO oximetry or pulse CO
oximetry.58
Increased oxygen partial pressure will speed elimination
of CO. Oxygen supplementation by face mask is usually suf­
ficient, but in more severe cases (COHb >15%) 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.59 Moreover,
hyperbaric facilities are not widely available.
Cyanide is another toxic component of smoke, especially
when the fuel is composed of certain plastic products.
Cyanide causes cellular anoxia by binding to mitochondrial
cytochromes and preventing intracellular oxygen utiliza­
tion. Arterial oxygen partial pressures are not reduced by
cyanide. Clinical signs of hypoxia despite adequate arterial
oxygen tension or metabolic acidosis despite apparently ade­
quate oxygen delivery suggest cyanide toxicity. The earlier
treatment is initiated, the more likely it will be successful.
Supplemental oxygen can cause nonenzymatic oxidation
of reduced cytochromes, displace cytochrome oxidase, and
potentiate the effects of administered antidotes. Pharma­
cological intervention includes methemoglobin genera­
tors such as nitrates (amyl nitrite 0.2 mL by inhalation, or
sodium nitrite 10 mL of 3% solution intravenous for adults
and 0.13–0.33 mL/kg of 3% solution for children) and
dimethylaminophenol (3.25 mg/kg) to increase methemo­
globin 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 chil­
dren 1.65 mL/kg of 25% solution) accentuate the body’s
to edema from thermal injury. In some patients with burns
to the face and neck or after inhalation of hot gases or
steam, early intubation can be life-saving. Training sup­
ported by the American Burn Association has encouraged
early tracheal intubation in patients at risk for airway
occlusion. However, intubation is not a benign interven­
tion, and there is growing recognition of the associated
risks. Eastman and colleagues at the Parkland Burn Center
published a retrospective study of pre-burn center intuba­
tions of burn victims.56 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 extubated on the
day of admission. In addition, 41.1% were extubated within
48 hours of injury. It is unlikely that pathological changes
requiring intubation would resolve so quickly. These find­
ings suggest that many patients may have been exposed to
the risks of intubation without commensurate benefit. Box
17.3 lists risks associated with unnecessary tracheal intu­
bations. Intubation is especially dangerous during trans­
portation outside a hospital. These patients require deep
sedation to avoid unplanned extubation. With extubation
during transport, impaired respiratory drive due to sedation
may cause dangerous hypoventilation. The risk is even
greater when muscle relaxants are used during transport.
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.21
They reported that of 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 intuba­
tion. The high negative predictive value of normal flow–
volume loops for airway compromise in patients with
inhalation injury that they also observed had been previ­
ously reported by Haponik et al.57
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.18 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 respiratory distress or who have other
Box 17.3  Risks of Unnecessary Tracheal
Intubation of Burned Patients
■ Impairs communication with patient (impairs history and
consent)
■ Urgent attempts are more likely to fail or cause injury
■ Facial burns make it difficult to secure the endotracheal tube,
and unintended extubations are common
■ Acute burn patients often require heavy sedation when
intubated, which increases morbidity associated with
unintended extubation
■ A translaryngeal endotracheal tube can exacerbate a laryngeal
injury

17  •  Diagnosis and Treatment of Inhalation Injury
190
angle to reduce upper airway edema and limit the effect of
pressure from abdominal contents on the diaphragm.
Meticulous pulmonary hygiene is a vital component of the
management of inhalation injury. Frequent airway suc­
tioning, chest physiotherapy including percussive and
coughing techniques, and early mobilization all help clear
debris and prevent build-up of secretions, which can cause
airway obstruction, atelectasis, and predispose to the devel­
opment of pneumonia.63,64 Care should be taken when suc­
tioning to avoid hypoxia and bradycardia. Preoxygenation
and suctioning for short periods of 10–15 sec can reduce
the incidence of these problems. Postural drainage can be
useful, although sometimes skin graft location and fragility
impede use of this technique.65 Percussive and vibratory
techniques such as high-frequency chest wall oscillation
also help clear mucoid secretions.65,66 It is also important to
maintain good nutritional status in these patients.
Inhalation of smoke produces damage to the airways
resulting in sloughing of epithelial cells, increased micro­
vascular permeability, and a dramatic increase in bronchial
blood flow.41 As a result, the airways are flooded with plasma
exudate and cellular debris. This mix combines with mucus
to form a fibrinocellular cast or pseudomembrane that par­
tially or completely obstructs airways. This process is exac­
erbated by an intense inflammatory infiltrate. In an attempt
to disrupt this sequence, Desai and colleagues administered
enzymatic conversion of cyanide to thiocyanate in the pres­
ence of the mitochondrial enzyme rhodanese, reducing its
toxicity and increasing elimination.60
As mentioned earlier, inhalation injury has been consis­
tently observed to significantly increase fluid requirements
for resuscitation of patients with cutaneous burns.10 The
presence of an inhalation injury might intuitively be viewed
as an indication to restrict fluids to avoid pulmonary edema.
In fact, fluid restriction has been found to exacerbate pul­
monary capillary leak and increase lung lymph formation
in sheep that have sustained cutaneous burns and smoke
inhalation injury.61 Although it is important to avoid fluid
overload in all patients, including those with inhalation
injury, inadequate fluid resuscitation can also cause further
injury to the lungs of patients with inhalation injury.62 A
combination of cutaneous burns and inhalation injury
reduces the margin for error in managing fluid resuscita­
tion. It becomes more difficult to reach a balance where
sufficient volume is administered for resuscitation but not
so much that it drives 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 helps prevent inspissation of the airway secretions.
The head of the bed should be placed at a 30- to 45-degree
Patient at risk 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
Fig. 17.3  An algorithm to assist airway management decisions in patients at risk for inhalation injury.

17  •  Diagnosis and Treatment of Inhalation Injury
191
directed toward early mobilization. In the adult burn popu­
lation, especially those with inhalation injury and at high
risk for extubation failure who have been receiving mechan­
ical ventilation for more than 24 hours and who have
passed a spontaneous breathing trial, extubation to preven­
tive noninvasive ventilation is recommended.
The aim is to provide adequate ventilation to maintain
airway and alveolar patency without exacerbating the pul­
monary injury by overdistension or barotrauma. Ventila­
tion with low tidal volumes (≤ 7 mL/kg) is now generally
accepted as a routine practice in patients with acute lung
injury, and most burn centers have adopted this approach
to reduce ventilator-induced injury. In patients with inhala­
tion injury the small airways may be narrowed by edema
and bronchospasm, which increases airway resistance and
hence airway pressures during mechanical ventilation.
Under these circumstances it is often difficult to provide
adequate ventilation of patients with inhalation injury
with tidal volumes of less than 7 mL/kg. How this strategy
applies to patients with inhalation injury has not been
established.75 Permissive hypercapnia has been found to be
a safe technique to assist in limiting airway pressures in
burn patients.76,77 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 higher than 7.2–7.25.
A common ventilation strategy is to determine the
level of positive end-expiratory pressure (PEEP) by using
a pressure–volume curve. This helps maintain 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 can be
set just above this pressure. FiO2 should be weaned down
as tolerated to reduce oxygen-related complications. The
PaO2 can be maintained between 80 and 100 mm Hg,
although values of 65–70 mm Hg can support adequate
tissue oxygenation.
Conventional mechanical ventilation is either volume-
or
pressure-controlled.
Volume-controlled
ventilation
delivers a consistent tidal volume and minute ventilation
to the lungs, but this can result in increased airway pres­
sures depending on the compliance of the lungs. Pressure-
controlled ventilation limits the inflating pressure used, but
the tidal volume then varies depending on compliance and
inspiratory time.77 High-frequency percussive ventilation
(HFPV) is a ventilatory mode that delivers subtidal breaths at
a high frequency along with tidal, low-frequency breaths.78
HFPV has become a preferred mode of ventilation in some
burn centers.22 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. It appears to be associated with decreased
work of breathing, improved oxygenation (higher PaO2/FiO2
ratios), and lower peak pressures.79,80 Pediatric patients at
our hospital (SBH-Galveston) managed with HFPV also had
a significant reduction in the incidence of pneumonia com­
pared to a conventionally ventilated control group.80
High-frequency oscillatory ventilation (HFOV) uses a
reciprocating diaphragm to deliver respiratory rates in the
aerosolized heparin and N-acetylcysteine to slow formation
of fibrin and thin mucous secretions in pediatric patients
with smoke inhalation injury.67 They observed a decrease in
atelectasis, frequency of re-intubations, and mortality.
Treatment with aerosolized heparin is utilized in many
burn centers because it is intuitively attractive and does not
affect systemic coagulation. The preclinical and clinical evi­
dence of the effectiveness of inhaled anticoagulants for the
treatment of smoke inhalation has been reviewed by Miller
et al.68 At the time of writing there were reports of improved
survival in experimental animals and in patients, along
with improved oxygenation, ventilation, and attenuation of
markers of lung injury when smoke inhalation injury is
treated with nebulized heparin or other anticoagulants in
various protocols, but no large prospective studies have
been done in burn patients. More recently, in a prospective
randomized trial of 214 mechanically ventilated non-burn
ICU patients, Bandeshe et al.69 examined regular saline
nebulization against unfractionated sodium heparin (5000
iU/2 mL four times daily) and found no difference in terms
of the development of ventilator-associated pneumonia
(VAP) or amount of secretions. They concluded that nebu­
lized heparin cannot be recommended for prophylaxis
against VAP or to hasten recovery from pneumonia in
patients receiving mechanical ventilation.
When chest physiotherapy and pharmacological agents
still fail to facilitate expectoration of secretions or amelio­
rate 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.
Antibiotics are indicated for suspected or proven pulmo­
nary infection.64,70
Mechanical ventilation is indicated when the signs of
respiratory failure are either present or imminent. Indica­
tions include impaired gas exchange due to pulmonary
parenchymal injury, decreased pulmonary compliance, or
impending collapse of effort due to fatigue. Burns involving
the head and neck may make intubation technically diffi­
cult. In these circumstances avoidance of muscle relaxants
and the use of an intubation technique that maintains
spontaneous ventilation is safest. The flexible fiberoptic
bronchoscope is well suited to this task. A nasal endotra­
cheal tube may be preferable for patient comfort, oral
hygiene, and stability. A nasal endotracheal tube can be
secured by a nasal septal bridle, which is much more secure
than tape or ligatures over burned skin and prevents irrita­
tion of wounds and disruption of grafts.
Currently there is no consensus on the ideal mode of
mechanical ventilation for burn patients. The intricacies of
mechanical ventilation in burn patients have been reviewed
previously.22,71–73 Recommendations by the American Tho­
racic Society (ATS) and the American College of Chest Phy­
sicians74 can generally be applied to the population of
mechanically ventilated burn patients: minimize the time
the patient is on the ventilator; conduct a spontaneous
breathing trial with inspiratory pressure augmentation
(5–8 cm H2O) rather than without (using a T-piece or con­
tinuous positive airway pressure [CPAP]); and, for acutely
hospitalized patients who have been mechanically venti­
lated for more than 24 hours, protocolized rehabilitation

17  •  Diagnosis and Treatment of Inhalation Injury
192
also take into consider the metabolic state and burn-related
decrease in strength of the patient. Increased generation of
CO2 must be matched by increased minute ventilation and
respiratory effort. Work of breathing is often also increased
by poor pulmonary compliance and diaphragmatic eleva­
tion due to hepatomegaly.85 At the same time skeletal
muscle wasting and decreased strength are also products
of the hypermetabolic and catabolic state.86 If the patient’s
physiological reserve is marginal it may be best to carefully
weigh the risks and benefits of extubation to decide if it is
best to continue mechanical ventilation. Once the patient
is extubated, supplemental, humidified oxygen should be
provided, and the patient should be carefully observed for
any signs of respiratory compromise that might necessitate
re-intubation.
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
facilitates gas exchange through a semipermeable mem­
brane.87 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. Asmus­
sen et al. have published a meta-analysis of experimental
and clinical evidence available for the use of ECMO for treat­
ment of hypoxemic respiratory failure associated with burn
and smoke inhalation injury.88 Interpretation of these data
and evaluation of the effectiveness of ECMO in burn patients
are limited by the small number of studies and patients. In
addition, Asmussen and colleagues point out that those
available studies with designs suitable for comparison were
performed over a long time period during which ECMO
techniques and equipment have varied greatly. This, along
with absence of control groups, further complicates com­
parisons of outcomes. As a result, the available literature is
insufficient to provide guidelines. Further experience and
research with these improved techniques and equipment is
necessary.
Opinions on the use of tracheostomy in burn patients
are divided and have fluctuated over the years. The most
common indication is a need for prolonged mechanical ven­
tilation. This allows removal of the translaryngeal endotra­
cheal tube, which reduces the chance of laryngeal injury
and provides a more secure airway. When multiple surgi­
cal treatments are predicted, a tracheostomy tube obvi­
ates the need for repeated intubation for each procedure.
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 pul­
monary contamination with burn wound bacterial flora
and mortality, tracheostomy was discouraged in the past.89
More recently, with advances in burn care, several studies
have found that the risk of pneumonia is not increased by
tracheostomy in burn patients.90,91 As a result, many burn
centers routinely perform tracheostomy not only in patients
who require prolonged ventilation but in those with exten­
sive burns who will require multiple anesthetics for surgical
procedures. In studies involving small groups of patients,
tracheostomy has been used without complications.91 Tra­
cheostomy is an invasive procedure, however, and in larger
range of 3 to 15 Hz (up to 900 breaths/min) through a
standard endotracheal tube. This rate is so fast that the
airway pressure merely oscillates around a constant mean
airway pressure. A retrospective review of HFOV in severely
burned pediatric patients showed significant, early, and sus­
tained improvement in oxygenation.81
Airway pressure release ventilation (APRV) is a pressure-
controlled time-cycled mode of ventilation that also allows
spontaneous breathing during the ventilatory cycle without
changing the preset pressure settings.82 Recruitment of
alveoli and oxygenation occur at a high-pressure setting,
and ventilation occurs by controlled releases to the lower
pressure. The mechanical inspiratory phase can be pro­
longed 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 oxygen­
ation values were achieved while using lower peak airway
pressures.83 This mode may be useful in the burn popula­
tion as a means to ventilate while reducing barotrauma.
Although it has become standard practice to use tidal
volumes of 7 mL/kg or less when ventilating patients
with acute lung injury or ARDS in order to avoid further
damage to the lung, it is occasionally difficult to maintain
adequate gas exchange with these small tidal volumes. The
hypermetabolic state associated with major burns produces
larger amounts of CO2 that require higher minute ventila­
tion to excrete. A certain amount of permissive hypercap­
nia can be tolerated safely,76 which facilitates the use of
lower tidal volumes to an extent, but an additional feature
of the pathophysiology of inhalation injury is the small
airway narrowing by edema, bronchospasm, inflamma­
tory infiltrate, fibrinous exudate, and sloughed epithelium.
These small airway changes can require higher pressures
to support ventilation. Sousse and colleagues did a retro­
spective comparison of clinical outcomes of patients with
inhalation who were ventilated with high tidal volumes
(15 mL/kg) with patients after a change in practice to
lower tidal volumes (9 mL/kg). In this retrospective study
with historical controls, high tidal volumes were associ­
ated with decreased ventilator days, atelectasis, and ARDS.
The incidence of pneumothorax was increased with high
tidal volumes.84 Further experience is needed before the
use of higher tidal volumes becomes a generally accepted
practice.
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 respiratory requirements
without assistance. Criteria for a trial of extubation include
ability to protect the airway (awake and relatively alert),
cough and deep breath (negative inspiratory pressure
>25 cm H2O), adequate minute ventilation (tidal volume
6 mL/kg and respiratory rate adequate without hypercar­
bia or tachypnea), adequate oxygenation (PaO2 >60 mm Hg
on FiO2 ≤0.4), and hemodynamic stability (no vasoactive
infusions other than lower dose of dobutamine). The pres­
ence of acidemia is a relative contraindication to a trial
of extubation, and the decision should take into consider­
ation the patient’s physiological reserve and the etiology of
the metabolic disturbance. The decision to extubate must

17  •  Diagnosis and Treatment of Inhalation Injury
193
long-term clinical effects of inhalation injuries related to
burns.109 Any study of long-term changes in pulmonary
function after inhalation injury must distinguish between
changes due to the effects of inhaled irritants at the time of
injury and those that result from ventilator-induced lung
injury or acute lung injury due to the systemic inflamma­
tory response syndrome (SIRS) or sepsis. In addition, out­
comes may change over time due to alterations in clinical
management. Massive burn injury also impairs muscle
mass and strength along with chest wall compliance, which
can affect respiratory effort even in the absence of inhala­
tion injury. As Palmieri has pointed out, none of the previ­
ous reports of long-term pulmonary changes after
inhalation injury relates the degree of acute pulmonary
insult to the long-term changes.109 Pre-existing lung disease
was also not considered in previous studies. Most studies
involved relatively small groups of patients studied at differ­
ent times and by different means, which makes it difficult to
compare results between studies. In a more recent Cana­
dian review of ARDS incidence in 162 mechanically venti­
lated burn patients, Cartotto et al.110 found a significant
correlation of development of ARDS with the size of burn
injury, size of full-thickness injury, and the duration of intu­
bation, but not with the incidence of inhalation injury. The
authors concluded that ARDS develops early after burn and
that the extent of full-thickness burn predicted develop­
ment of moderate to severe ARDS. Increasing severity of
ARDS based upon the Berlin definition was associated with
a significantly greater duration of mechanical ventilation
and a trend toward higher mortality.
One way post-injury pulmonary function has been
shown to be manifest is by a hyperactive or bronchospastic
condition 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 inflamma­
tory cytokine tumor necrosis-α (TNF-α), interferon (IFN-γ),
and interleukin (IL)-2 levels in serum and bronchioalveolar
lavage fluid. The majority of subjects, however, had normal
pulmonary function tests.111
Longer-term studies have in some cases shown the devel­
opment of obstructive and restrictive patterns on pulmo­
nary function testing, indicating that normal lung function
may not always be regained following recovery from inhala­
tion injury.103,112,113 In a pediatric burn cohort, no differ­
ence in exercise tolerance was noted between children who
had sustained an inhalation injury and those who had not.
However, those children who had had an inhalation injury
achieved their goal with a significantly higher respiratory
rate and had a higher incidence of abnormal lung func­
tion.113 Conversely an adult study found no evidence of
altered respiratory function after inhalation injury or any
significant exercise intolerance in those tested.114
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 Fig. 17.4. As a result, voice production
may be affected, and this may not resolve without
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 ran­
domized to early tracheostomy.92 Because 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 tracheostomy in burn patients remains a matter
of clinical judgment, but, in each case, the risk of potential
complications should be considered in the decision.
Potential Future
Therapeutic Strategies
The pathophysiological processes described offer the possi­
bility for future development of numerous pharmacological
interventions. One of the most obvious areas for treatment
would be the use of antioxidants. Burned patients are
immensely depleted of antioxidants, especially vitamin
E.93,94 In this clinical scenario ROS and RNS play major roles
in organ damage in addition to mediation of the patho­
physiology.47 Nebulization of γ-tocopherol, a form of
vitamin E that scavenges both ROS and RNS, has been
shown to be beneficial.95,96 On the other hand, inhibitors of
NOS1,54,97 NOS2,98 and PARP,99 as well as compounds that
catalyze the breakdown of peroxynitrite, have also been
shown to be effective in reversing the acute changes in
pathophysiology.42,45,98,99
Recently there have been reports that hydrogen sulfide
may have therapeutic benefits in lung injury.100 We have
tested hydrogen sulfide in both murine and ovine models of
burn injury and found therapeutic benefit.101,102 As we have
learned more about the pathophysiology and treatment of
inhalation injury, there have been more survivors. Exami­
nation of these individuals several years after injury showed
that many had evidence of excessive deposition of collagen
in their lungs.103 Perhaps initial treatment of patients might
have an important effect on long-term pathophysiology.
This is certainly an area for future investigation. NOS, 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 deposi­
tion.104 Thus inhibition of NOS could make more arginine
available for the arginase, and hence increase collagen
deposition. In a consensus conference, the faculty from the
Shriners Hospitals met to discuss potential therapies for
inhalation injury.105–108 Clinical trials will be necessary
before the effectiveness of these novel interventions is
established.
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 theoretical reasons why it is difficult to evaluate the

17  •  Diagnosis and Treatment of Inhalation Injury
194
with a laryngologist may make such interventions more
timely.
Complete references available online

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.115 It is important
to recognize laryngeal injuries as early as possible. When
recognized, tracheostomy can help minimize exacerbation
of the injury from a translaryngeal airway. Consultation
B
A
Fig. 17.4  (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.

194.e1
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