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

37  •  Surgical Management of Complications of Burn Injury
392
of recurrences.90 Novel treatment strategies in development
include the use of new antibiotics (ridinilazole, surotomy­
cin, cadazolid), luminal antibodies (oral administration of
whey protein concentrate prepared from hyperimmune
bovine colostrum against C. difficile toxins), intravenous
immunoglobulins, vaccines, and nontoxigenic C. difficile
strains.95–98
Vascular Complications
SUPPURATIVE THROMBOPHLEBITIS
Suppurative thrombophlebitis is characterized by venous
thrombosis associated with inflammation and bacteremia.
Not all of these infections occur in association with venous
thrombosis, and specific risk factors for suppurative throm­
bophlebitis include both burn injury and prolonged intra­
venous catheterization. The diagnosis may be made based
on culture results together with evidence of thrombosis.
The classic physical examination findings of edema, ery­
thema, pain, and a palpable cord may not all be present.
Burned patients frequently have positive blood cultures and
clinical sepsis without an obvious source, and, in the setting
of suppurative thrombophlebitis, the most commonly cul­
tured organisms from infected veins reflect those cultured
from the burn wound.
The incidence of suppurative thrombophlebitis complica­
tions in burn patients has been estimated to be as high as
7%, with significant risk in patients with greater than 20%
TBSA burns, and it is associated with significant mortal­
ity.99 The principles of treatment include removing the
source of infection, administration of intravenous antibiot­
ics, and/or anticoagulation.100 Surgical treatment consists
of surgical cut-down and evacuation of vein contents. If
pus or clot is found, the vein segment should be excised to
a normal-appearing vein (usually up to the first uninvolved
tributary). If exploration is negative at one site, then
thermally injured patients, the overall incidence of C. diffi­
cile infection (CDI) was ~8% with a mean burned TBSA of
42%.88 Toxic megacolon is a potential complication and
places patients at higher risk for colonic perforation.89 Thus,
symptoms of colitis, such as leukocytosis, abdominal pain,
distension, and grossly bloody diarrhea, must be promptly
recognized. Stool samples are tested for C. difficile antigen.
All unnecessary systemic antibiotic therapy should be dis­
continued, and appropriate CDI treatment should be initi­
ated. Guidelines for the treatment of CDI are rapidly
evolving. Currently treatment options for the first episode
of CDI include oral or IV metronidazole, oral or rectal
vancomycin, and fidaxomicin; choice of drug, route of
administration, and dosing depend on the severity of the
infection, the presence of complications, and other patient-
related factors (e.g., drug allergies, pregnancy, prior colonic
surgery).90,91
Surgical intervention may be required for patients with
complicated or fulminant CDI; in addition, surgical inter­
vention must be considered in patients with progressive
abdominal distension, peritonitis, shock, signs of sepsis,
altered mental status, leukocytosis and lactic acidosis, or
failure to improve after 5 days of medical therapy. Subtotal
or total abdominal colectomy with end ileostomy has been
advocated as the operation of choice.92,93 An alternative
surgical approach is to create a loop ileostomy with intra­
operative colonic lavage using warmed polyethylene glycol
3350/balanced electrolyte solution (Go-Lytely) followed by
postoperative vancomycin colonic flushes via the ileostomy
in an antegrade fashion, with a reported mortality of 19%
versus 50% for patients undergoing colectomy. This opera­
tion can be performed laparoscopically with a high rate
(80%) of reversal of ileostomy for GI tract continuity
restoration.92,94
Therapeutic options for recurrent infections include fecal
microbiota transplant (FMT) and fidaxomicin in addition to
the above-mentioned antibiotics; similarly, choice of drug,
route, and dosing will depend on the severity and number
B
A
Fig. 37.3  Necrotizing enterocolitis. (A) Representative radiograph demonstrating multiple, dilated, persistently “fixed” bowel loops, an ominous sign
for full-thickness necrosis of involved segments of bowel. (B) At operation, multiple necrotic bowel loops were found.

37  •  Surgical Management of Complications of Burn Injury
393
can confirm the clinical suspicion, and pericardiocentesis or
pericardial window is therapeutic.103
DISTAL LIMB ISCHEMIA
Arterial monitoring is frequently required in patients with
major burns. Although radial and femoral arterial cathe­
ters are routinely placed without significant complications,
they can be associated with problems such as hematoma,
thrombosis, and pain. Occasionally the common femoral
artery is considered for access, given its larger caliber.
Because the femoral artery is the major blood supply to the
lower extremity, this site should be approached with caution
for fear that thrombosis could lead to distal limb ischemia.104
Especially in pediatric burn patients, the femoral artery is
small, and the catheter within the vessel can result in near
complete occlusion of blood flow to the distal limb. However
reported complication rates after catheterization of the
femoral artery in burn patients are low (1.9%) while provid­
ing a more accurate measure of hemodynamic parameters
(Table 37.2).105 Nonetheless, complications can be devas­
tating, ranging from transient distal limb ischemia to
amputation. Management of distal limb ischemia starts
with removal of the catheter along with systemic heparin­
ization. If there is no full recovery after 24 hours, surgical
intervention is warranted. Should conservative manage­
ment fail, exploration of the femoral artery with thrombec­
tomy, fasciotomy, and completion arteriography is
recommended. Although rare, amputation may be required
if flow is not re-established and tissue salvage is not
possible.
Thoracic Complications
PNEUMOTHORAX
Several factors increase the risk of pneumothorax in burn
patients; these factors can be related to the traumatic injury
itself (barotrauma associated with explosions or blast inju­
ries, concomitant rib fractures, etc.) or associated with the
treatment of burns (barotrauma secondary to positive pres­
sure mechanical ventilation, iatrogenic injuries during
placement of central venous catheters, etc.). Additionally
pneumothorax can occur following electrical injury; the
exact mechanisms responsible for pneumothoraces in
electrical injuries are debatable, and a blast-like injury due
to a high-voltage electric arc is one of the proposed
explanations.106,107
Pneumothoraces are classified into small or large based
on the separation from the pleural surface (lung edge) to the
chest wall. A pneumothorax is considered small if the dis­
tance is less than 3 cm.108 Typically, stable patients with a
small pneumothorax (<3 cm) are managed conservatively
with observation and oxygen supplementation. Conversely,
patients who are symptomatic and/or have a large pneumo­
thorax (>3 cm) require thoracostomy. However, several
operations and the possible need for reintubation are
common scenarios in the hospital stay of severely burned
patients. Thus, conservative management of pneumotho­
rax, regardless of size, is not recommended. The placement
of a small-caliber (8–14F) pigtail tube is advocated; it is a
sequential exploration of other sites is necessary until the
source of infection is identified. Prompt surgical interven­
tion is necessary to prevent hematogenous dissemination
and septic emboli that can result in endocarditis and osteo­
myelitis. The wound should be loosely packed and allowed
to heal either by secondary intention or by delayed closure
upon resolution of the infection.101
To minimize the incidence of catheter-related complica­
tions, the current standard of practice for central venous
access at most institutions involves aseptic care at the cath­
eter insertion site along with regularly scheduled catheter
site dressing changes.
COMPLICATIONS RELATED TO
CENTRAL VENOUS ACCESS
Adequate venous access is imperative in the acute post-
burn period for aggressive fluid resuscitation. Although
large-bore peripheral intravenous catheters are the pre­
ferred route for resuscitating trauma patients, placement
can be extremely difficult in those with major burns involv­
ing the extremities. Therefore, central venous catheters
have become standard practice in major burns. Particular
attention should be given to the use of various available
cannulation sites, depending on the size of the patient, as
well as taking into consideration the clinical condition of
the burn wounds. The rate of catheter-related bloodstream
infections in burn patients is estimated to be 20 per 1000
catheter days.102 Therefore, compulsory site care is required.
Because it is more difficult to relocate lines in severely
burned than in nonburned patients, guidewire exchange is
acceptable unless there is clinical evidence of infection,
such as erythema, drainage from the site, or bacteremia.
Central venous line placement is associated with poten­
tially serious complications. In order to reduce the risk of
bleeding complications, many burn centers rely on fluoro­
scopic or ultrasound guidance during the insertion of
central venous catheters.
Bleeding complications associated with central venous
access vary in location and can be local, mediastinal, intra­
thoracic, or pericardial. Local hemorrhage typically occurs
in patients with a coagulopathy and can be controlled with
local pressure. Hemorrhage into the thoracic space can
occur at the time of catheter insertion, but it can also be
seen when the catheter erodes through the vein wall. The
most common situation leading to venous wall perforation
occurs during the insertion of the percutaneous introducer
sheath over a guidewire. As the sheath is introduced, it can
fail to negotiate the path of the vein and traumatize the vein
wall. Consequently, blood may accumulate into the medias­
tinum, pleural space, or pericardium.
If the injury is small, it should resolve on its own. However,
in cases of a larger venous tear, rapid bleeding into the
thoracic cavity can occur, and emergency thoracotomy
may be necessary. Bleeding or infusion of fluid into the peri­
cardial space can rapidly compromise cardiac function and
result in hemodynamic collapse. Pericardial tamponade
typically presents with hypotension, muffled heart sounds,
and distended neck veins (Beck’s triad). However all compo­
nents of the classic triad of symptoms are rarely present,
and a physician must have a high index of suspicion in
order to recognize this condition early. Echocardiography

37  •  Surgical Management of Complications of Burn Injury
394
video-assisted thoracoscopic surgery [VATS], open decorti­
cation or open thoracotomy). Choice of procedure will be
influenced by cavity size, loculations, and pleural thick­
ness.114 Goals of treatment consist of sterilization of the
empyema cavity, complete pleural fluid drainage, and oblit­
eration of the empyema cavity by lung expansion. The
intrapleural administration of fibrinolytic agents is debat­
able; however a recent double-blind randomized crossover
trial reported that intrapleural instillation of alteplase was
associated with lower treatment failure compared to
placebo.115 In the pediatric population, randomized con­
trolled trials have demonstrated that VATS has no therapeu­
tic or recovery advantages over fibrinolysis. Conversely,
VATS is associated with increased costs and longer paren­
teral antibiotic administration. With the implementation of
a standardized protocol, only 16% of these patients are
expected to require VATS after fibrinolysis.116–118 These
results have promoted the adoption of fibrinolysis as the
first therapeutic option for the treatment of empyema in
children.
Urologic Complications
Urologic complications following thermal injury are rare.
Direct injury to the external genitalia only comprises 1.7%
of cases but has increased morbidity, with elevated risk of
infections. More importantly, it is an independent predictor
of mortality.119 Furthermore, these injuries should prompt
the burn care team to carefully assess the events leading up
to the injury. One study found that child abuse was the
cause in 46% of cases involving males and 48% of cases
involving females.120 Surgical repair of urologic complica­
tions is rarely reported. Electrical injury resulting in bladder
rupture, urinary fistula, and erectile dysfunction have been
reported in small studies and case reports.121–123 The pres­
ence of these injuries should be managed by a
less invasive procedure compared to a standard chest tube.
Pigtail catheters cause less pain and muscle spasms, with a
potential to decrease atelectasis and risk of pneumonia.
Although the use of large-bore chest tubes (24–28F) is
advocated for patients who need mechanical ventilation,108
current practice trends and recent studies support the use
of pigtail catheters in burn patients.109–111
EMPYEMA
Parapneumonic effusions, or empyemas, are pleural effu­
sions located in anatomical contiguity to bacterial pneumo­
nia.112 Most of the empyemas are small and resolve after
antibiotic therapy. However, complicated empyemas, char­
acterized by bacterial invasion of the pleural space, may
occur. Burn patients are particularly susceptible to the
development of empyema owing to high bacterial coloniza­
tion and impaired immune defenses.
Common clinical features include cough, fever, pleuritic
chest pain, dyspnea, and sputum production. In general,
the presenting symptoms, other than pleuritic pain and
duration of fever, are not helpful in determining which
patients have pneumonia versus pneumonia with empyema.
Patients with empyema may report a longer course, with
several days of fever and malaise rather than hours. The
presence of empyema is first suggested by a chest radio­
graph showing a pleural-based opacity that has an abnor­
mal contour or does not flow freely on lateral decubitus
views. When these features are noted, additional imaging
with ultrasound allows for identification of loculations and
helps to rule out the presence of a solid mass. Optimal eval­
uation of an empyema or loculated effusion requires a chest
CT scan with intravenous contrast. The use of contrast
enhances the pleural surface and assists in delineating
pleural fluid loculations.113
Management of empyema includes appropriate antibi­
otic therapy and a drainage procedure (tube thoracostomy,
Table 37.2  Complications of Femoral Arterial Catheterization105
Age
(yr)
Weight
(kg)
% TBSA
Burn/3rd
Catheter
Size (Fr.)
Cather
Site Burn
Burns to
Limb
Operator
*Onset of
Ischemia (Hr)*
Surgical
Exploration†
  1
2.2
17.7
36-5/36-5
3
No
Yes
Anesthesiologist
6
Yes
  2
0.9
12.5
95/95
3
No
Yes
Surgeon
12
Yes
  3
2.0
12.7
51/51
3
No
No
Surgeon
4
Yes
  4
0.5
6.5
18/1
2.5
No
No
Surgeon
24
No
  5
2.1
15.8
70/70
3
No
Yes
Surgeon
4
No
  6
12.4
36-3
48/20
3
No
No
Surgeon
12
No
  7
2.2
13.5
62/58
3
Yes
Yes
Surgeon
4
No
  8
1.7
13.1
64/59
3
No
Yes
Surgeon
6
No
  9
2.7
13.7
69/18
3
No
Yes
Surgeon
4
No
10
3.8
15.1
57/5
3
No
Yes
Surgeon
6
No
11
6.3
22.0
87/87
3
Yes
Yes
Anesthesiologist
6
No
12
1.9
13.3
47/47
3
No
No
Anesthesiologist
4
Yes
*Hours after catheter placement.
†All patients received IV heparin therapy.

37  •  Surgical Management of Complications of Burn Injury
395
must be thorough in the evaluation of patients with a sig­
nificant burn injury.
Complete references available online at

Further Reading
Gasior AC, Knott EM, Sharp SW, et al. Experience with an evidence-based
protocol using fibrinolysis as first line treatment for empyema in chil­
dren. J Pediatr Surg. 2013;48(6):1312-1315.
Kirkpatrick AW, Ball CG, Nickerson D, D’Amours SK. Intraabdominal
hypertension and the abdominal compartment syndrome in burn
patients. World J Surg. 2009;33(6):1142-1149.
Ng JWG, Cairns SA, O’Boyle CP. Management of the lower gastrointestinal
system in burn: a comprehensive review. Burns. 2016;1-10.
Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treat­
ment, and prevention of Clostridium difficile infections. Am J Gastroen­
terol. 2013;108(4):478-498.
multidisciplinary approach with consultation with pediat­
ric surgery and urology specialists.
Conclusion
When presented with patients with multiple organ injuries,
the protocols for ATLS should be initiated first, followed by
a systematic approach to the management of any and all
other injuries. Complications requiring operative manage­
ment in the setting of a burn injury are common and can
compound an already overwhelming physiological response.
When there is an exaggerated systemic inflammatory
response, associated complications are often clinically
masked, promoting delays in diagnosis that result in wors­
ened outcomes. Surgical issues and complications in this
patient population are often unavoidable, and clinicians

395.e1
37  •  Surgical Management of Complications of Burn Injury
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Burns Incl Therm Inj. 1986;12(7):505-507.

396
Electrical Injuries
EILEEN BERNAL and BRETT D. ARNOLDO
38 
Pathophysiology
Electrical current passing through tissue can cause injury
by multiple distinct mechanisms. These include the direct
action of electrical forces on proteins, cell membranes, and
other biomolecular structures, as well as tissue injury medi­
ated by the generation of heat.12,13 The severity of injury is
multifactorial and determined by voltage, current (amper­
age), type of current (alternating or direct), path of current
flow, duration of contact, resistance at the point of contact,
and individual susceptibility. These burns are somewhat
arbitrarily classified as low (<1000 V) and high voltage
(≥1000 V). Although the low-voltage injuries are generally
more localized to the area of the contact point, the high-
voltage injuries may be associated with both extension into
deep tissue as well as a spreading out phenomenon to sur­
rounding structures. So, although a low-voltage injury may
penetrate deeper structures, the zone of injury is more
limited. In contrast, high-voltage injuries, somewhat resem­
bling crush injuries, tend to demonstrate a “tip of the
iceberg” phenomenon, extending into deep structures
(muscle or bone) as well as spreading out proximally and
distally beneath the contact point.14 The clinical implica­
tions of this will be discussed later, but from the surgeon’s
point of view, these injuries are potentially more urgent and
occasionally emergent, but low-voltage injuries are not.
Domestic wiring in the United States operates on alter­
nating current (AC) at 120 V. Therefore, nearly all burns
occurring indoors are of the low-voltage type. Coworkers
typically witness high-voltage injuries occurring indoors
because these are more common in industrial or factory
settings.
Unlike voltage, the actual amount of current is unknown.
Current flow is related to the voltage by Ohm’s law where:
Current I
Voltage E Resistance R
( )
( )
( )
=
Animal experiments have demonstrated that resistance
varies continuously with time, initially dropping slowly
then much more rapidly until arcing occurs at the contact
sites. Resistance then rises to infinity and current flow
ceases.15 Temperature measurements taken simultaneously
showed that the rate of temperature rise parallels changes
in amperage. Interestingly, tissue temperature, a critical
factor in the magnitude of tissue injury, does not increase
distal to the contact points. Clinically, it is common to see
relatively normal and intact digits in association with dev­
astating tissue damage at the wrist and forearm that
Introduction
The harnessing of electricity may be the technical advance
with the greatest impact on human life and culture in
recorded history. The tools of modern life are increasingly
powered by electricity, and life without it would be unrec­
ognizable. There is, however, a price to be paid for this
advancement. Electrical burn injuries are estimated to
make up several thousand admissions to burn centers each
year in the United States. The American Burn Association
(ABA) 2016 Burn Incidence Fact Sheet, which is composed
of registry statistics compiled by ongoing national health
care and fire casualty surveys and the National Burn Repos­
itory, estimated 40,000 burn admissions of which 4% had
a reported electrical etiology.1 These injuries are the most
devastating of all thermal injuries on a size-for-size basis
and are the most frequent cause of amputations on the
burn service.2 These injuries are distributed in a bimodal
fashion in regards to age. Work-related injuries are seen
most commonly in adults. Together, electricians, power
company linemen, and crane operators are especially at
risk. Exposure to electricity made up 3% of all work-related
deaths in 2013–2014 according to the United States
Department of Labor; Bureau of Labor Statistics.3 There is
a 2 : 1 male-to-female ratio in childhood, but more than
90% of electrical injuries in adults are in men.4-8 Children
are more commonly injured in accidents in and around the
home. Children younger than 6 years are more likely to
encounter low-voltage outlets or electric cords. Older chil­
dren have an increased incidence of high-voltage injuries
by comparison because of their increased mobility and
adventurousness.9–11
Electrical burn injuries have several unique acute mani­
festations that differ from other thermal injuries and require
expertise in management. Decisions must be made early
regarding cardiac monitoring and emergent or urgent
exploration and decompression for compartment syn­
drome, as well as a more complex fluid management strat­
egy to avoid the complications of acute kidney injury
associated with myoglobinuria. These patients may need
access to other specialty services such as plastic surgery
consultation for possible early flap coverage to protect
potentially viable tissue. In addition, physical medicine and
rehabilitation services, with experience caring for patients
with electrical injuries, are simply not available in nonburn
centers. These injuries benefit from the multidisciplinary
team approach and vast experience typically seen at ABA-
verified burn centers.

38  •  Electrical Injuries
397
ultimately results in amputation at the forearm level. Early
and detailed discussion between the surgeon and patient
and family can avoid confusion if the patient progresses to
amputation.
In North America, the majority of all electricity used and
the burn injuries it causes are the result of 60 cycle-per-
second commercial AC, which reverses polarity 120 times
per second. Exceptions where direct current (DC) is used for
power are seen in industrial settings, as well as computers,
light-emitting diodes (LEDs), solar cells, and electric vehi­
cles. A series of events in American history, known as the
War of the Currents, explains the dominance of AC over
DC. Contributions from notables such as Thomas Edison,
Nikola Tesla, and George Westinghouse led to concerns over
commercial competition, electrical safety, and debates asso­
ciated with the introduction of the electric chair. The degree
of sordid detail surrounding these events can make for
interesting tangential information during resident and
medical student teaching sessions.16,17
Given the nature of AC and its rapid reversal of polarity
and the relative inability to reconstruct the history with
accuracy, the terms entrance and exit wounds are inaccurate
and should be used with caution if at all. The term contact
point is more appropriate. A thorough search for contact
points should occur in all patients with electrical injuries
because they may be few or many, obvious or well hidden
(e.g., in the hair line).
The path of current, although often imprecise, can
make a significant difference in outcome. Current poten­
tially traversing the conduction system of the heart or a
pathway including the central nervous system can alert
the clinician to potential complications. AC causes tetanic
muscle contractions, which may either throw the victim
away from the source or draw him or her into a continued
contact known as the “no-let-go” phenomenon. This occurs
because both forearm flexors and extensors are stimulated
by the current flow, but the flexors overpower the extensors,
making the person unable to let go voluntarily. Given that
humans most often explore their environment by grasping
rather than tapping with the back of the hand, contact is
usually prolonged. Altered levels of consciousness reported
in about half of high-voltage victims also contributes to
prolonged periods of contact.18 Resistance, measured in
ohms, at the point of contact varies from approximately
100,000 ohms for heavily calloused hands or feet during
very dry winter weather to less than 2500 ohms when skin
is damp.11
The classification of electrical injuries from a clinical
point of view comes in four varieties: (1) the true electrical
injury caused by the flow of current, (2) an arc injury
resulting from the electric arc generated as the current
passes from the source to an object, (3) flame injury caused
by the ignition of clothing or surroundings, and (4) light­
ning strikes.
Electricity arcs at temperatures up to 4000°C and causes
a flash-type injury without actual current flow through the
body.19 This is most commonly seen in electricians working
with metal objects in close proximity to an electrical source.
The victim may be thrown by the force and sustain trauma,
including ruptured eardrums and any other variety of
blunt force injuries. These injuries that occur without
actual current flow may be classified like any other flame
injury. However, the potential problem that arises is in the
difficulty in ascertaining whether there was actual flow of
current. As a result, most of these patients will be treated
as having true electrical injuries.
The mechanism of electrical injury appears to be a mul­
tifactorial combination of thermal and nonthermal causes.
Electricity flowing through tissue generates heat. Electrical
current via ohmic conduction leads to Joule heating that
can cause severe burn injury to the victim.13 The burn
injury is the result of damaging supraphysiological tem­
peratures, which affect all proteins and cell membranes
with Joule’s law defining the amount of power (heat) deliv­
ered to an object:
Power J Joules
I
Current
R Resistance
(
)
[
]
(
)
(
)
=
×
2
In increasing magnitude, tissue resistance is lowest from
nerves, blood vessels, muscle, skin, and bone. Theoretically,
current flow would be distributed in proportion to resis­
tance, with tissues having the highest resistance generating
the most heat. However, in animal models, the body tends
to act as a single uniform resistance rather than a collection
of different resistances. In other words, the body acts as a
volume conductor, with the severity of injury being
inversely proportional to the cross-sectional area of the
involved body part.15 Clinically, this is observed in particu­
larly severe injuries at the level of the wrist and ankle. Deep
tissue does appear to retain heat such that periosseous
tissue, especially between two bones, will often have a more
severe injury pattern than more superficial tissue. Clini­
cally, this may be seen during exploration of the forearm
wherein the superficial flexors are clearly involved and
injured but the deeper pronator quadratus muscle appears
to have a more severe injury. The associated macro- and
microvascular injury appears to occur at the time of injury
and is irreversible.20 This vascular injury has been studied
in a rabbit model in which optical microscopy demonstrated
severe injury to blood vessels. Necrosis of vascular walls
and thrombosis with destruction of arterial endothelium,
pyknosis of vascular smooth muscle, and fibrinous exu­
dates accompanying the thrombotic changes were noted.
Progressive muscle necrosis over the first 72 hours after
injury was also observed and thought attributable to vas­
cular injury.21 The study period followed the injury pattern
for only 72 hours, but experienced clinicians can attest to
a longer period of progression that may extend more than
a week. These findings as well as clinical experience argue
in favor of serial debridement and a conservative approach
to definitive grafting. The pathophysiology, although not
completely understood, also includes electroporation and
electrochemical interactions in addition to thermal
interactions.22–24 These affect all tissue components, but the
cell’s plasma membrane appears to be the most important
structure in determining the rate and quantity of tissue
injury accumulation.13 Electroporation is the formation of
aqueous pores in lipid bilayers exposed to a supraphysio­
logic electrical field. The formation of these pores allows
calcium influx into the cytoplasm and triggers a subsequent
cascade leading to apoptosis. Particularly interesting, owing
to characteristics of electric fields, it has been shown that
cells of long length (skeletal muscle and nerve) are more
vulnerable to electroporation.13 Further experimental work

38  •  Electrical Injuries
398
Orak et al. have found an additional biomarker, pro-B-type
natriuretic peptide (pro-BNP), to be elevated in high-voltage
electrical injury with use as a marker for both morbidity
and mortality.27 However, the interpretation of cardiac bio­
markers is problematic and needs to be correlated with
other clinical findings. All patients should be monitored
during transport and in the ED. Rather than a policy of
more prolonged cardiac monitoring for all patients, a selec­
tive policy makes most efficient use of expensive medical
resources, without patient risk.2,35
Indications for cardiac monitoring include (1) loss
of consciousness, (2) ECG abnormality or evidence of
ischemia, (3) documented dysrhythmia either before or
after admission to the ED, (4) cardiopulmonary resuscita­
tion (CPR) in the field, and (5) patients with other stan­
dard indications.30 Therefore, asymptomatic and stable
patients who have normal initial ECG findings and are
without any risk factors do not need inpatient cardiac
monitoring.37
No published studies have directly studied the appropri­
ate duration of telemetry monitoring, but most series indi­
cate 24–48 hours.38–40 Our institutional bias is to monitor
for approximately 24 hours after injury in patients with an
indication. Low-voltage injuries not meeting the criteria for
cardiac monitoring and no other indication for admission
can be safely discharged from the ED. This is not applicable
to high-voltage injuries, although retrospective evidence
indicates that dysrhythmias will occur early, if at all, in
these patients.35
Myoglobinuria
The presence of pigmented (darker than light pink) urine in
a patient with an electrical burn indicates significant muscle
damage with potentially ongoing ischemia. Myoglobinuria
and hemoglobinuria secondary to rhabdomyolysis present a
risk of acute renal failure and must be cleared promptly.41,42
Whereas low levels are of little clinical concern, grossly
visible urinary pigmentation requires a rapid response to
minimize tubular obstruction. Titrating resuscitation fluid
(Ringer’s lactate) to maintain urine output double the
goal rate of the standard burn patient, or approximately
100 mL/h in an adult, is the goal of therapy. The required
urinary output is generally very high for several hours after
injury followed by a significant reduction in urine require­
ments, as venous return from the injured part to the central
circulation is thrombosed. Therapy continues until the
urine appears clear. Other therapeutic options include the
prevention of oliguria using loop diuretics, alkalinization
of the urine with either a bolus or continuous infusion of
sodium bicarbonate, normalization of serum electrolytes,
and decompression of compartment syndromes.43 Alka­
linization and osmotic diuresis are not supported by level I
evidence, but many burn centers have successfully adopted
their use in various forms. Failure to clear pigment from the
urine is generally an indication of significant muscle necro­
sis or ongoing ischemia. This should prompt a thorough
evaluation of the likely current path and underlying muscle
damage because failure of therapy can often be taken as
an indication for operative intervention for decompression
versus debridement or amputation.
by Block et al.23 in a Sprague-Dawley rat model confirmed
that nonthermal effects alone could induce cellular necro­
sis. Electroconformational denaturation of transmembrane pro­
teins refers to the changes in polarity of amino acids in
response to exposure to electrical fields. Experimentally,
voltage-gated channel proteins were found to change their
conductance and ion specificity after exposure to a powerful
pulsed field.25
Acute Care
Electrically burn-injured patients present some unique
challenges in the acute setting. There are essentially three
acute management concerns differentiating these patients
from patients who were thermally injured without flow
of electric current. In addition to the application of the
basic principles of Advanced Trauma Life Support (ATLS),
the three issues that need to be addressed in the “golden
hour” are (1) which patients require electrocardiographic
monitoring and for how long; (2) which patients are at
risk for compartment syndrome and may need emer­
gency surgical intervention (sometimes directly from the
emergency department [ED]); and (3) how fluid resus­
citation should proceed in the light of the preponder­
ance of deep tissue injury that may not be appreciated
on physical examination, particularly in the presence of
pigmented urine.
Electrocardiographic Monitoring
All studies reviewed in a recent ABA guidelines paper
confirmed that cardiac abnormalities, including dysrhyth­
mias and myocardial damage, occur after both low- and
high-voltage injuries, thus reinforcing the need for elec­
trocardiography (ECG) as part of the initial evaluation
in all patients.26 The most frequent reason for death after
electrical injury is cardiac.27 Nonspecific ST changes are
the most common ECG abnormality, and atrial fibrilla­
tion the most common dysrhythmia,28,29 but ventricular
fibrillation is the most common case of death at the scene
of injury.30
Direct myocardial injury may also result. This injury
behaves more similar to a traumatic myocardial contusion
than a true myocardial infarction, not having the hemody­
namic or recurrence consequences of atherosclerotic myo­
cardial infarctions. Housinger et al. have shown that
creatine kinase (CK) and MB creatine kinase (MB-CK) levels
are poor indicators of myocardial injury in the absence of
ECG findings of myocardial damage, especially in the pres­
ence of significant skeletal muscle injury.31–33 In contrast,
Saracoglu et al. have shown that elevated levels of both are
related to an increased mortality rate.34 Myocardial damage
and dysrhythmias are manifested very soon after injury.35
Although cardiac troponins are the preferred biomarkers
for detecting myocardial injury in most clinical settings, this
has not been adequately studied in the setting of electrical
injuries. A recent study using serum troponin levels and
serial echocardiography in 20 patients surviving high-
voltage injury concluded that this was not a useful diagnos­
tic test for predicting impaired left ventricular contractility.36

38  •  Electrical Injuries
399
significant injury is often at the wrist with variable degree
of spread. Beginning the skin incision distally and extend­
ing it as indicated is a reasonable approach. On occasion,
all that may be required is a carpal tunnel release with a
short proximal extension (Figs. 38.1 and 38.2).
Coverage of the wound may include wet to moist mafenide
acetate 5% solution or a biologic such as porcine hetero­
graft. The initial operation is followed by a second look in
24 to 48 hours, and depending on the degree of injury,
serial debridement may follow. Fasciotomy wound closure
is often not possible and skin grafting for wound coverage
is common. Rarely will any amputation be indicated as the
first operative procedure, and a more conservative approach
is usually indicated. The clearly mummified, contracted
extremity is one exception, however.
Further Surgical and Wound
Considerations
For high-voltage injuries that do not require urgent surgical
intervention, initial wound care and observation are
Compartment Syndrome and
Initial Operative Intervention
Patients with low-voltage electrical injuries are at low risk
of compartment syndrome. The authors have not had to
decompress any patients with low-voltage injuries for com­
partment syndrome in their combined burn experience. In
contrast, high-voltage injuries require vigilance in regards
to clinical decision making. Treatment may include ED to
operative suite urgency, underscoring the need for these to
be seen in centers with 24-hour surgical capability.
Multiple explanations for the pathophysiology of acute
compartment syndrome exist, but in all cases, the final
common pathway is cellular anoxia.44 Damaged muscle and
swelling in the investing fascia of the extremity may cause
increased pressure compromising blood flow such that met­
abolic demand exceeds delivery. Venous outflow is jeopar­
dized, leading to a decreased arteriovenous pressure gradient
that ultimately can cause arteriolar collapse.45,46 Loss of
pulses is one of the last signs in true compartment syn­
drome, which is different from the early loss of pulses seen in
a circumferentially burned extremity requiring escharot­
omy. Compartment pressure measurement is generally con­
sidered an adjunct in electrical injuries and is often an extra
step that may not add to what is generally an obvious diag­
nosis. These injuries are rarely subtle. In the past, a very
aggressive approach to fasciotomy was recommended, but
significant morbidity may accompany this approach. Ampu­
tation rates in the early literature were generally reported in
the range of 35% to 40%.47–51 Mann et al. argued for a con­
servative course of management calling for fasciotomy in
the patient with the usual clinical signs of compartment
syndrome—progressive nerve dysfunction or failure of
resuscitation.52 The ABA guidelines paper indications for
surgical decompression were in agreement with this man­
agement strategy.26 In a review of the National Burn Reposi­
tory, Pannucci et al. found early fasciotomy to be a marker
for increased disease severity. Among patients who under­
went early fasciotomy after electrical injury, 7.5% developed
deep vein thrombosis, and 49% required amputation during
their initial hospitalization.53 Elevated CK levels have been
correlated to the extent of muscle damage with some authors
advocating early decompression and aggressive surgical
management in patients with markedly elevated CK levels.17
In the experience of the authors, high-voltage electrical
injuries requiring decompression have significant clinical
findings, making adjuncts such as CK levels and compart­
ment pressures moot. They add little to the diagnostic evalu­
ation other than for educational purposes in a training
environment. Again, these injuries are generally dramatic.
This tends to alleviate consternation regarding the decision
to perform urgent exploration or fasciotomy; vigilance,
however, must be maintained for the first 24 to 48 hours.
Fasciotomies are best performed in the operating room
under general anesthesia.54 Lower leg fasciotomy is a
common procedure and should be within the skill set of all
general surgeons. The upper extremity fasciotomy is less
common and yet another reason to refer patients with these
injuries to a specialized burn center. We favor a lazy-S inci­
sion with the caveat that formal forearm fasciotomy from
elbow to wrist may not be needed given that the most
Fig. 38.1  High-voltage injury with neurologic deficit on examination.
Fig. 38.2  Carpal tunnel release.

38  •  Electrical Injuries
400
holes deep enough to cause bleeding from viable cancellous
bone is a method to encourage granulation tissue, which
eventually can be skin grafted. This is a prolonged process,
and methods such as the use of wound VAC or Integra may
accelerate the process. The best and most expedient option
may be a rotational scalp flap over the burned area followed
by a split-thickness skin graft to cover the adjacent defect61
(Figs. 38.3–38.5). Larger scalp defects are approached with
free flaps anastomosed to appropriate vessels outside the
zone of injury.62
Although significant electrical burn to the torso is seen
less commonly than extremity wounds in both the high-
and low-voltage categories, they can present special prob­
lems. Chest wall injuries may be particularly difficult to
close, and early consultation with plastic surgery services
may be helpful. Costal chondritis can be a long-term com­
plication of these wounds. Visceral injuries are reportedly
very rare and range from 0.4% to 1.7%.63,64 The colon and
small intestine are the most frequently affected, but gall­
bladder, liver, pancreas, stomach, and urinary bladder inju­
ries have been described.65 Vigilance for these potential
appropriate. Patients with small surface area low-voltage
injuries that do not meet criteria for cardiac monitoring and
do not have excessive pain control needs can either be dis­
charged or observed depending on local capabilities such as
ease of follow up or distance traveled to the burn center.
Local wound care can be performed with 11.1% mafenide
acetate cream (Sulfamylon) on thick contact points, given
the excellent penetration and spectrum of coverage. Other
involved areas may be treated by any number of topical
agents, including silver sulfadiazine, bacitracin, or one of
the silver-containing dressings. Surgical excision is begun 2
to 3 days postburn, either as a second-look operation after
fasciotomy or as a first procedure in patients not requiring
an urgent procedure. Obviously, necrotic tissue is removed,
and tissue of questionable viability retained for reevalua­
tion every several days until all nonviable tissue is ultimately
removed. A very conservative course of tissue removal and
wound closure with a combination of skin grafts or flaps for
soft tissue coverage gives the best functional result. The
addition of the vacuum-assisted closure (VAC) device has
greatly simplified the management of these wounds. Apply­
ing a VAC device over a wound that has questionable tissue
remaining loses nothing. If there is a suspicion of infection,
the VAC device can simply be removed; otherwise, it can be
exchanged at scheduled intervals at the bedside or in the
operating room. For extremity injuries, particularly the
hand, early involvement of a plastic surgeon with experi­
ence in burn reconstruction can provide an important con­
tribution to long-term function. However, surgical options
such as local or regional flaps may be unavailable because
of the large zone of injury, and a free flap may not be toler­
ated by a sick patient given the prolonged operative time
required. In these cases, a distant pedicle flap may be appro­
priate.55 These may include older techniques such as the
Crane principle as described by Barrilo et al. or the use of
random abdominal wall flap, groin flap, tensor fascia lata
flap, or a cross-arm flap.
Multiple diagnostic modalities have been investigated in
an attempt to speed up the process of identifying the extent
of deep tissue necrosis. These include xenon-133 and tech­
netium pyrophosphate scans as well as gadolinium-
enhanced magnetic resonance imaging.56–60 Albeit very
sensitive and specific, diagnostic scans add little to direct
clinical evaluation and are ultimately expensive and unnec­
essary. An ongoing program of physical therapy and func­
tional splinting is begun the day of admission if practical
and continued throughout the hospital stay. Serial neuro­
logic examinations are performed and documented.
Regional anesthesia is avoided to minimize medical legal
complications if late neurologic dysfunction arises.
Problem Areas
Contact points on areas such as the scalp and torso add
complexity to management. Scalp burns that spare the
galea are managed by excision and grafting directly onto
the galea. Wounds that penetrate or expose the outer table
of the skull or deeper require a different approach. Exposure
of nonviable calvarium has historically been approached by
providing a viable wound bed after debridement of dead
bone with an osteotome or a dental burr. Drilling multiple
Fig. 38.3  Rotational flap planning.
Fig. 38.4  Rotational flap creation.

38  •  Electrical Injuries
401
a predictor of outcome.80–82 The ears should be carefully
examined because injuries are frequent, ranging from
ruptured tympanic membranes (most common) to middle
and inner ear destruction.83 Electrical current injuries pre­
dominantly cause pure sensorineural hearing loss and may
significantly increase a patient’s lifetime risk of vertigo.84
Associated ophthalmic injuries are varied; can be bilateral;
and include the formation of thermal keratopathy, ante­
rior uveitis, subcapsular cataract, vitreous hemorrhage,
retinal detachment, central retinal artery and vein occlu­
sion, cystoid macular edema, macular hole, and optic
neuropathy.81,85,86
Neurologic complications are relatively common and
include unconsciousness, seizures, paresthesias, and paral­
ysis, which may develop over several days after injury. The
term keraunoparalysis (Charcot’s or temporary paralysis)
has been used to describe the latter symptom complex, is
associated with vasomotor disorders, and is characterized
by complete tetraplegia and loss of sensory awareness of
the trunk and all four extremities.87 Fortunately, these are
usually transient. Surgically treatable lesions, including
epidural, subdural, and intracerebral hematomas, may
occur, mandating a high index of suspicion for altered levels
of consciousness.74 The prognosis of many lightning-
caused neurologic injuries is generally better than for other
types of traumatic causes, although subtle neurologic
changes may persist, suggesting a very conservative, watch­
ful waiting and supportive approach with serial neurologi­
cal examinations after an initial CT scan to rule out
correctable causes. A study by Muehlberger et al. with
follow-up to 12.3 years after injury showed that none of
their 10 patients had long-term neurologic or psychological
deficits.88 However, posttraumatic stress disorder is common,
occurring in about 30% of patients after lightning injury.89
Low-Voltage Injuries
Low-voltage (<1000 V) AC injury is usually localized to the
points of contact. With prolonged contact, tissue damage
may extend into deep tissues with little lateral extension, as
seen in high-voltage (≥1000 V) wounds. These wounds are
treated by excision to viable tissue and appropriate coverage
based on wound depth and location.
Burns of the oral cavity are the most common type of
serious electrical burn in young children.90 Most of these
injuries are the result of an unattended small child (com­
monly <4 years of age) chewing on an electrical cord. Inju­
ries involving only the oral commissure are almost never
excised because the extent of injury is difficult to predict.
Simple wound care is performed as an outpatient proce­
dure.91,92 The most serious complication is bleeding from
the labial artery, occurring 10–14 days after injury. Fami­
lies are instructed to compress the labial artery digitally if
bleeding occurs and to return to the ED. After healing, treat­
ment varies according to the severity of injury. Gentle
stretching and the use of oral splints give good cosmetic and
functional results in most patients, with reconstructive
surgery being reserved for the remainder. Severe microsto­
mia is corrected by mucosal advancement flaps. Burns of
the midportion of the mouth heal poorly and may require
a more aggressive surgical approach.93,94
injuries is required because they can occur in the absence
of obvious contact points, and mortality rates are signifi­
cant.66,67 The relatively insensitive finding of feeding intol­
erance or a changing abdominal examination may be the
only findings. Computed tomography (CT) may make the
diagnosis and mandates laparotomy.
Lightning Injury
Lightning is the second leading cause of weather-related
death in much of the world, but underreporting likely influ­
ences the data.68–71 Approximately 100,000 thunderstorms
occur in the United States each year, with lightning killing
more people than any other weather phenomenon—about
80 fatalities per year—with Florida and Texas having the
most deaths.72–74 Although lightning strikes involve mil­
lions of volts of electricity, the spectrum of burn injury is
extremely varied, from minimal cutaneous burns to signifi­
cant burns equal in depth to commercial high-voltage elec­
tricity. Major cutaneous injury is rare unless a nearby object
is turned incandescent, causing a flash and flame type of
injury, as when a bag of golf clubs on the victim’s back is
struck. The pathognomonic sign of a lightning strike is a
dendritic, arborescent or fernlike branching erythematous
pattern on the skin. These Lichtenburg figures (also known
as keraunographic markings) consist of extravasation of
blood in the subcutaneous tissue that appears within an
hour of injury and fades rapidly, much like a wheal-and-
flare reaction.75,76 Full-thickness isolated burns on the tips
of the toes have also been reported as characteristic. Both
findings are useful in determining the cause of injury in a
patient found down under uncertain circumstances.77
Lightning may cause both respiratory and cardiac stand­
still, for which CPR is especially effective when promptly
initiated,78 although approximately 10% of lightning
strikes prove to be fatal.79 Patients may respond to resus­
citation even when they appear dead and even when the
interval between injury and resuscitation is prolonged. It
is important to realize that dilated or nonreactive pupils
are not necessarily a reliable sign of brain death in the
early postinjury period, nor is Glasgow Coma Scale score
Fig. 38.5  Rotational flap with skin grafted defect.

38  •  Electrical Injuries
402
frequent complications than patients with low-voltage inju­
ries.102 Despite this, the low-voltage group experienced
similar rates of neuropsychiatric sequelae, limited return to
work, and delays in return to work. Ko et al. reported on 13
patients with delayed onset of spinal cord injuries, postulat­
ing on a vascular cause of the deficits.103 The most common
peripheral defect is a peripheral neuropathy, with weakness
being the most common clinical finding.104 In general, reso­
lution of early-onset lesions is much better than for late
onset, spasticity is more frequent than flaccidity, and func­
tion is affected more than sensation.
Sympathetic overactivity, with changes in bowel habits
and urinary and sexual function, is the primary autonomic
complex complication. Although the exact mechanism of
nerve injury has not been explained, both direct injury by
electrical current or a vascular cause receive the most
attention. To date, imaging studies, including angiography
and magnetic resonance imaging, have not been helpful in
either predicting or evaluating the extent of deficit. Very
often, the patient’s neuropsychological status is abnormal.
In a study comparing electrical burn patients with non­
burned electricians, Pliskin et al. showed significantly
higher cognitive, physical, and emotional complaints not
related to injury or litigation status.105 A full neurologic
examination must be performed on admission, document­
ing the initial presentation. Early involvement of an experi­
enced, interested physiatrist is important in assessing
long-term needs and participating in the creation of a
therapy plan.
Heterotopic ossification occurring at the cut ends of
amputation sites is unique to electrical burn patients. This
occurs in about 80% of patients with long bone amputa­
tions but not in patients with disarticulations or small bone
amputations. Helm et al. found ossification severe enough
to require surgical revision of the bone end in 28%.106 This
is easily accomplished by opening the incision and using a
bone rongeur to remove the soft heterotopic bone and
reclosing the residual limb.
Although electrical burns comprise only about 4% of all
burn injuries, they consume enormous amounts of
resources, requiring a carefully planned team approach for
optimal care.
Complete references available online at

Complications
The primary early complications of electrical injury include
renal, septic, cardiac, neurologic, and ocular manifesta­
tions. Neurologic deficits may be present on admission or
develop days to weeks after injury.
Cataract formation is the most frequent ocular complica­
tion of electrical injury, although ocular manifestations may
affect all portions of the eye.95,96 The exact pathophysiology
is unknown, but ocular changes may affect as many as
5–20% of patients with true electrical burns. Saffle et al.
reported on seven patients with 13 cataracts, noting a high
rate of bilateral involvement and little association with
voltage or location of contact points, although often thought
of as being more frequently associated with contact points of
the head, neck, and upper trunk.97 Of this series, 77% even­
tually progressed to surgical therapy, the results of which
were uniformly good. Lag time before appearance may be as
short as 3 weeks and as long as 11 years after injury.98
Neurologic complications are protean in their diversity
and may present either early or late (as late as up to two
years after injury). Neuromuscular defects including
paresis, paralysis, Guillain-Barre syndrome, transverse
myelitis, or amyotrophic lateral sclerosis can be caused by
electrical injury.99 Several studies put the incidence of
post-electrical injury sequelae into perspective. Grube et al.
reported on 64 patients with high-voltage burns, 67% of
whom developed immediate central or peripheral neuro­
logic symptoms.18 One third had peripheral neuropathies,
and one third of those were persistent. Furthermore, 12%
had delayed onset of peripheral neuropathy, with 50%
resolving. They reported no late-onset central neuropa­
thies. Singerman et al. reported neurologic and psychologi­
cal complication rates of 81.6% and 71%, respectively.100
The most common neurologic symptoms were numbness
(42%), weakness (32%), memory problems (32%), pares­
thesias (24%), and chronic pain (24%). The most common
psychological symptoms were anxiety (50%), nightmares
(45%), insomnia (37%), and flashbacks to the event (37%).
Interestingly, the low-voltage injuries resulted in more long-
term sequelae than high-voltage injuries. Further studies
from the same center demonstrated only a 30% return to
work after low-voltage electrical injuries.101 In a study by
Chudasama et al., the patients with high-voltage injuries
had longer and more complex hospital stays and more

402.e1
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97. Saffle JR, Crandall A, Warden GD. Cataracts: a long-term complica­
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resonance imaging and histopathology of an amputated forearm
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the scalp and skull. Arch Surg. 1983;118(5):621-625.
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1995;21(7):530-535.
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complication of an electrical burn. Arch Surg. 1972;105(3):494-497.
67. Reilley AF, Rees R, Kelton P, Lynch JB. Abdominal aortic occlusion
following electric injury. J Burn Care Rehabil. 1985;6(3):226-229.
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lightning strike. Surv Ophthalmol. 2001;46(1):19-24.

403
Cold-Induced Injury: Frostbite
AMALIA COCHRAN and STEPHEN E. MORRIS
39 
Frostbite continues to present a tremendous clinical chal­
lenge, with the greatest clinical advance coming only in the
past decade with the use of thrombolytic therapy in early
management.17–19
Pathophysiology and
Classification of Frostbite
The injury associated with frostbite results from two broad
mechanistic categories: the first is that of direct cellular
damage and death due to the cold insult, and the second is
the delayed process mediated by progressive tissue
ischemia.20–23 The immediate effects of frostbite are evi­
denced by formation of extracellular ice crystals that cause
direct injury to the cell membrane, resulting in cellular
dehydration due to a change in the osmotic gradient.24
Rapid cooling results in intracellular freezing, causing more
severe cellular damage and cell death, whereas a slower rate
of cooling produces extracellular ice crystals. This slower
process results in a transmembrane osmotic shift that draws
water from within the cell and produces intracellular dehy­
dration. This dehydration causes changes in protein and
lipid conformation as well as changes in biochemical pro­
cesses that are deleterious to intracellular homeostasis.25–29
As the temperature continues to fall, intracellular crystals
develop, with a loss of the linear relationship of tempera­
ture to metabolism, decreased DNA synthesis, and hista­
mine response with skin flushing and development of a
fluid-filled wheal.13,30–33
Microvascular pathophysiology may be even more impor­
tant than the direct cold injury to the cell, a concept sug­
gested by studies showing the survival of full-thickness skin
subjected to freezing and thawing that progressed to necro­
sis when left in situ but survived when transplanted to a
normal, uninjured recipient site.23 Zacarian identified a
number of processes that may play a role in the microcir­
culatory changes of frostbite. Transient vasoconstriction of
both arterioles and venules with subsequent resumption of
capillary blood flow appears to occur, and microemboli
result from this course.34 With thawing, the capillaries dem­
onstrate restoration of blood flow that diminishes within
minutes. Complete cessation of blood flow is often seen
within 20 minutes of rewarming frozen tissue. Similar
changes have been seen with random skin flap models
after reperfusion, suggesting reactive oxygen species as
mediators of injury.35 Within 72 hours, significant de-
endothelialization and deposition of fibrin in the capillary
bed occurs. Examination of the endothelial ultrastructure
demonstrates swelling, fluid extravasation, endothelial cell
dilation, and significant projection of the cell into the vas­
cular lumen prior to cell lysis.36 There is regional variation
in the extent of injury, with low-flow venules being most
Videos available at
History of Frostbite
Frostbite is a traumatic injury caused by the failure of
normal protective mechanisms against the environment,
resulting in freezing of tissue. Cold-induced injury remains
surprisingly frequent in the United States owing to increas­
ing interest in outdoor winter recreational activities as
well as the common presence of homeless and socio­
economically disadvantaged individuals in large urban
centers.1,2
The incidence of and circumstances surrounding frost­
bite have been documented in numerous military histories.3
Hannibal lost nearly half of his army of 46,000 soldiers
during a 2-week crossing of the Alps due to frostbite injury.
During the Revolutionary War, Dr. James Thatcher recorded
that Washington lost 10% of his army to cold-related casu­
alties during the winter of 1778. Baron Dominique Jean
Larrey produced the first systematic medical observations
of frostbite while serving as Surgeon General of Napoleon’s
forces during the ill-fated invasion of Moscow in the Fall of
1812 and the subsequent retreat in a harsh Russian winter.4
Because of the epidemic nature of frostbite in this cam­
paign, Larrey was able to create seminal descriptions of
frostbite and to identify the debilitating effects of daily
refreezing that occurred with bonfire thawing and subse­
quent marching in frigid conditions; in addition, many sol­
diers burned their insensate frostbitten feet while attempting
to rewarm them over bonfires. Larrey became convinced
that the optimal therapeutic management consisted of fric­
tion massage with snow or ice, resulting in slow rewarm­
ing.4 These recommendations were maintained as the
standard of care for frostbite in military medicine for more
than 100 years.
In the winter of 1941–1942, German troops sustained
an estimated 250,000 frostbite injuries in the attempt to
take Moscow, constituting the largest reported number of
related frostbite injuries in history.5 During World War II
both German and Russian troops moved to a philosophy of
rapid rewarming based on work conducted at the Kirov
Institute in the 1930s.5,6 Following World War II existing
Russian and German works were translated into English
and became the basis for rapid rewarming as the predomi­
nant Western paradigm. In 1960, Mills published the first
major clinical experience with rapid rewarming and
included a philosophy of total care for frostbite with his
report.7 Meryman subsequently edited a seminal text eluci­
dating the scientific bases for frostbite injury.8 Both military
and civilian cold-induced injury data continued to accrue
over the subsequent three decades in the absence of any
significant clinical advances in the care of frostbite.9–16

39  •  Cold-Induced Injury: Frostbite
404
profoundly affected, resulting in the hypothesis that stasis
also plays a role in this pathophysiologic process.32
The pathobiochemistry of frostbite has been closely com­
pared to the inflammatory response in the burn wound.37
Inflammatory mediators such as eicosanoids in burn blister
fluid coupled with bradykinin and histamine release in the
region of injury draw parallels with findings in cold-induced
injury.38–44 This has prompted investigators to hypothesize
a frostbite soft tissue model similar to that of Jackson’s for
burns, including zones of necrosis and stasis.45 Similar to
their burn blister analysis, Robson and Heggers examined
the fluid in frostbite blisters and found high levels of pros­
taglandin F2 and thromboxane B2.37 These agents or their
precursors have been implicated in vasoconstriction and
leukocyte adherence. In addition, when refreezing follows
thawing, the cellular damage caused by ice crystals and the
subsequent inflammatory response are exaggerated.46,47
Clinical Findings and
Classification of Frostbite Injury
In many situations, the patient is unaware that frostbite is
occurring. The presence of hypothermia and the frequent
use of mind-altering substances by frostbite patients may
contribute to this problem. Typical distribution of injury is
acral, with injuries to ears, nose, cheeks, and penis also
being fairly common.9,14,48 The patient may note insensitiv­
ity and clumsiness of the affected part. This complex of
symptoms rapidly reverses upon rewarming. Severe pain
occurs during and immediately after the rewarming process,
is often described as throbbing in character, and typically
requires parenteral opioids for relief.49
Because of the nature of freezing injury, classification
has traditionally been based on physical examination find­
ings that occur after rewarming. The most common presen­
tation of frostnip is numbness and pallor of exposed skin.
Frostnip does not include injury to the underlying dermis
or soft tissues, so rewarming results in near-complete reso­
lution of symptoms and physical findings. In contrast, true
frostbite involves some degree of dermal and soft-tissue
injury. Clinical appearance evolves over a period of time
after rewarming, although the initial appearance may be
deceptive because hyperemia is present in both frostbite and
frostnip.9,50 The development of skin blebs may require
hours to days from the time of injury. After 12–24 hours,
the character of the blebs usually becomes apparent and an
assessment of the severity of involvement can allow for
management planning for the injury.
Traditional classification of frostbite is similar to that of
burn injury. First-degree injury is superficial, with hyper­
emia in the absence of vesicles or blebs. There may initially
be an area of pallor with surrounding erythema that evolves
into general edema and erythema without long-term
sequelae. Second-degree injury has associated light-colored
blisters and subsequent epidermal sloughing. This may cor­
relate with partial dermal involvement but has a generally
favorable prognosis. Third-degree frostbite typically has
hemorrhagic blisters that evolve into thick, black eschar
over 1–2 weeks. Fourth-degree injury involves bone, tendon,
or muscle and uniformly results in tissue loss. Precision in
depth of injury cannot be expected from visual inspection,
and some favor a more general classification of superficial
(first- and second-degree injury, see Fig. 39.1) or deep
(third- and fourth-degree, see Fig. 39.2) frostbite injury;51,52
clinically, these can be delineated by clear vesicles, present
with superficial injury or hemorrhagic blisters indicative of
structural damage to the subdermal tissues.52,53 Cauchy
most recently proposed an alternative classification system
based on risk of amputation that includes the extent of the
lesion immediately after rewarming, findings from bone
scan on day 2, and the presence of blisters on day 2.54
Although this system has not come into widespread use, the
relationship of objective findings to prognosis may prove
helpful for future therapeutic trials in the management of
frostbite.
Fig. 39.1  Superficial frostbite injury with clear vesicles.
Fig. 39.2  Deep frostbite injury with hemorrhagic vesicles.

39  •  Cold-Induced Injury: Frostbite
405
with marked edema because of loss of the protective prop­
erties of the skin against skin flora when significant edema
is present.47,53,57,61,65–67
Post-Thaw Evaluation and
Management
Following rewarming, local care of the involved tissue is the
first priority. Unroofing of blisters remains a matter of con­
troversy.67 Alteration in local chemokines through the pres­
ence of blister fluid, including high levels of PGF2α and TXB2
and diminished levels of PGE2, result in vasoconstriction of
the involved area, increased leukocyte adherence, and
increased platelet aggregation, all of which cause progres­
sive dermal ischemia.13,37,41,44 However, concern also exists
about removal of hemorrhagic blisters because of the
damage to subdermal structures associated with these blis­
ters, indicating that debridement may extend the soft-tissue
damage in these areas.52,53 A more practical justification for
debridement of blisters is that it improves the visualization
of underlying tissue, allowing the clinician to better assess
the status of the wounds.66
Aloe vera has properties that counter the arachidonic
acid cascade and therefore benefit the local care of frostbit­
ten areas. Heggers demonstrated that the use of systemic
NSAIDs and local aloe vera to address the inflammatory
chemokines, coupled with systemic penicillin as prophy­
laxis against Gram-positive infection, resulted in demon­
strably less tissue loss, a lower amputation rate, and shorter
hospital stay versus patients managed with traditional
topical antimicrobials.13 Topical aloe vera alone was cred­
ited with clinically significant tissue salvage in these
patients, resulting in preferential management with aloe
vera rather than topical antimicrobials such as silver sulfa­
diazine or sulfamylon.13,57,61,67 Topical wound care also
should address mechanical protection of the affected areas,
with careful padding, splinting, and elevation and/or com­
pression to manage edema formation.51,53,61,67
NONSURGICAL THERAPIES
Pharmacologic management of the frostbite patient also
includes systemic blockade of the arachidonic acid pathway
to ameliorate the inflammatory response to the local cold
injury. Historically aspirin was used and did demonstrate
tissue survival improvement of greater than 20% in a
rabbit ear model.13 However aspirin blocks all arachido­
nate metabolites, including those that are beneficial for
wound healing. Therefore, more recent recommendations
center on the use of ibuprofen and specific blockade of
TXA2.1,61,65,68
Pentoxifylline, a phosphodiesterase inhibitor that is pri­
marily used in claudication, has been shown to synergisti­
cally improve tissue viability in conjunction with topical
aloe vera.69 Pentoxifylline improves red blood cell flexibility,
which may limit microvascular sludging and thereby dimin­
ish thrombus formation in small vessels. In addition, pent­
oxifylline may reduce blood viscosity, again contributing to
improved tissue survival.70 When pentoxifylline is used for
post-thaw pharmacologic management, the current rec­
ommendation, based on a study of pedal frostbite, is 400 mg
Initial Management of Freezing
Cold Injury
Prevention is obviously the ideal means of treatment for
frostbite. Alcohol and drug intoxication heighten the risk
for frostbite, most notably in urban populations and the
mentally ill.55,56 Although the cases of frostbite that occur
in intoxicated, mentally ill, and homeless individuals are
truly preventable only through broader social interven­
tions, simple techniques exist for those who sustain frostbite
secondary to involvement in cold-weather wilderness activ­
ities. Frostbite prevention measures in planned cold-weather
wilderness activity include, but are not limited to, wearing
appropriate clothing, which may include layers and wicking
fabrics; keeping that clothing dry; responding appropriately
to changing environmental conditions; and performing
“cold checks” of at-risk or suspect areas.57
If frostbite is identified in the field, the greatest manage­
ment priority is to not incur further injury. Jewelry should
be removed if present in the affected area; rubbing the area
with ice or snow is now known to incur further damage to
fragile, injured tissue.4,49,51,58,59 Injured areas should be
mechanically protected from trauma because they are typi­
cally insensate and are at high risk for further injury.49,51,58,60
The key decision that must be made in the field is whether
thawing should be pursued prior to transfer to definitive
care for the frostbite injury.61 Based on the work of Mills at
the Arctic Aeromedical Laboratory demonstrating the del­
eterious effects of thawing and refreezing on clinical out­
comes from frostbite, rewarming in the field should not be
pursued unless the ability to maintain the affected tissue in
a thawed state is certain.7,58,62 Systemic cold injury in the
form of hypothermia often accompanies local frostbite
injury, thus mandating that patients be carefully evaluated
to verify that they are normothermic prior to initiating
definitive frostbite management. Hypothermia causes
peripheral vasoconstriction and diminished blood flow, pro­
cesses that are exacerbated by the local cold injury. Most
importantly, hypothermia can be life-threatening, as
opposed to the digit or limb threat posed by frostbite.63,64
Moderate to severe hypothermia, defined as a core tempera­
ture of less than 32°C, must be addressed prior to initiation
of frostbite treatment.48,50,57,62
The traditional recommendations for rapid rewarming
favor a water bath temperature of 40–42°C.49,53,58,62 The
State of Alaska guidelines recently changed the water bath
recommendation to a temperature of 37–39°C because
this does not substantially increase the time to rewarm­
ing but causes less pain for the patient.51,57 The water bath
for thawing should be maintained in this range with the
water circulating around the involved tissue. The duration
of rewarming is approximately 30 min, although clinical
findings to determine the length of time for rewarming
include the return of sensation and presence of flushing
at the most distal aspect of the involved tissue.51,61 Admin­
istration of narcotics is appropriate at the time of defini­
tive rewarming because of the pain associated with the
thawing process.49 In addition, because these are tetanus-
prone wounds, the patient’s tetanus immunization should
be verified and updated as appropriate. Finally, systemic
antibiotics are recommended by some authors in patients

39  •  Cold-Induced Injury: Frostbite
406
neuropathic pain and paresthesias that often present one of
the greatest clinical challenges following freezing cold
injury.78,80 Therefore, the best use of sympathectomy may
be in the longer-term management of otherwise disabling
complications of frostbite.
Studies of hyperbaric oxygen (HBO) are limited but have
some of the most promising functional results of an adjunc­
tive therapy for frostbite. An early documented use of HBO
for therapy in frostbite involved four Alpine mountaineers,
all of whom presented 10 or more days following injury and
all of whom demonstrated good tissue preservation with
HBO.81 Several subsequent case reports have demonstrated
improved nutritive blood flow and/or complete mainte­
nance of frostbitten areas following HBO therapy, even with
delayed presentations.82–85 The utility in delayed presenta­
tion combined with the potential for improved functional
outcomes make HBO an extremely attractive therapy in
frostbite. Multicenter trials of HBO would provide substan­
tial progress toward understanding the role for this therapy
in frostbite management.
IMAGING AND SURGICAL MANAGEMENT
Both scintigraphy and magnetic resonance imaging/
angiography (MRI/MRA) have been recommended as diag­
nostic aids to improve the process of surgical management
of frostbite. More than 20 years ago, Mehta identified three
different patterns in triple-phase bone scanning that were
useful indicators of outcome within 48 hours of injury.86
Specifically, he found that perfusion and blood pooling
t.i.d. for 2–6 weeks following injury.70 Iloprost, a prostacy­
clin analog that also serves as a vasodilator, has interesting
features that may be of benefit, although all data on its use
are preliminary.57,71 Although studies of pentoxifylline and
iloprost are ongoing in Europe, current data are inadequate
to recommend their use.
Thrombolytics have demonstrated the most notable clini­
cal advance in the management of frostbite in the past 50
or more years. The first demonstration of possible utility for
thrombolytics in frostbite management was an animal
model using IV urokinase.72 In 1992, a preliminary account
indicated that thrombolytics were potentially better than
slow rewarming for reducing amputation following frost­
bite injury.73 Subsequent publications have shown improved
digit salvage with the use of tissue plasminogen activator
(t-PA) (see Fig. 39.3).17,19,74–77 Unfortunately, t-PA only
appears to be efficacious within 24 hours of thaw, meaning
that this may not be an option for patients who are injured
in extremely remote environments. Additionally, although
digit salvage has been improved with thrombolytics, the
long-term functional results of this salvage remain unclear,
particularly the impact on neuropathic complications of
freezing cold injury.
Surgical and chemical sympathectomy has largely fallen
out of favor owing to clinical results that are mixed at best.
Sympathectomy has not shown any improvement in tissue
preservation in frostbite and may ultimately result in more
proximal injury demarcation.78,79 The two best-documented
benefits of sympathectomy relate to long-term function,
with improved cold tolerance and amelioration of the
A
B
Fig. 39.3  (A) Angiogram of foot with deep frostbite prior to tissue plasminogen activator (t-PA). (B) Angiogram of foot with deep frostbite following
19 hours of t-PA.

39  •  Cold-Induced Injury: Frostbite
407
management approach have occurred. Thrombolytic
therapy has shown benefit in digital salvage but requires
early use and has unclear long-term functional outcomes.
HBO has shown promise in terms of salvage and functional
outcomes but so far has only been evaluated in case series.
Vasodilation with pentoxifylline or iloprost merits ongoing
study as a potential therapy for frostbite. Scintigraphy may
provide a means to expedite the surgical management of
frostbitten digits and extremities, but again has only been
studied in limited settings. Large-scale multicenter evalua­
tion of these varied evaluation and management tech­
niques is required to demonstrate whether any of these
practices will ultimately improve tissue salvage and func­
tional outcomes.
Complete references available online at

Further Reading
Bruen KJ, Ballard JR, Morris SE, et al. Reduction of the incidence of ampu­
tation in frostbite injury with thrombolytic therapy. Arch Surg.
2007;142(6):546-551, discussion 551-553.
This retrospective, single-center review presented the largest series of frost­
bite patients managed with thrombolytic therapy. A reduction in incidence of
digital amputation rates ranges from 41% to 10%.
Cauchy E, Marsigny B, Allamel G, et al. The value of technetium 99 scin­
tigraphy in the prognosis of amputation in severe frostbite injuries of
the extremities: a retrospective study of 92 severe frostbite injuries. J
Hand Surg Am. 2000;25(5):969-978.
The Chamonix group provides a 12-year review including 92 patients,
demonstrating the value of 99Tc scanning in frostbite evaluation and manage­
ment. They use their experience to delineate an algorithm with potential use
in future research on medical and surgical management of frostbite.
McCauley RL, Hing DN, Robson MC, et al. Frostbite injuries: a rational
approach based on the pathophysiology. J Trauma. 1983;23(2):143-147.
This seminal article describes a limited single-center experience with frost­
bite. The University of Chicago Frostbite Protocol that is included is the
foundation for multiple protocols that have been published subsequently.
State of Alaska. State of Alaska Cold Injury Guidelines. Juneau: State of
Alaska; 2005.
These represent the most comprehensive guidelines for the management of
all forms of cold injury. Frostbite guidelines include the spectrum of care, from
management in the field through arrival at a hospital that can provide defini­
tive care.
phases demonstrated at-risk tissue, and the bone phase
showed deep tissue and bone infarction. Several studies
have demonstrated excellent correlation between scinti­
graphic findings and surgical outcomes, although some
authors claim that bone scan findings best correlate with
surgical findings at 7–10 days following injury.66,87,88 Con­
fidence in scintigraphic findings by some practitioners has
been adequate for them to derive a protocol using the find­
ings to direct early surgery.54,89 The use of MRI/ MRA ini­
tially seemed promising, allowing direct visualization of
occluded vessels and possible better delineation of viable
tissue than 99Tc scanning.90 However a subsequent study
demonstrated that MRI was no better than bone scanning
to identify anatomic sites for amputation and that the
limited soft tissue present in digits hampered the utility of
MRI.65
Because of a historical bias based on data showing that
early surgery was potentially associated with worse out­
comes, the adoption of scintigraphy with early operative
intervention has been limited.79 However, Greenwald devel­
oped a protocol with early scintigraphy followed by opera­
tive intervention at 7–10 days following injury.89 Cauchy
makes a plausible argument for intervention at 10–15 days
post injury with a bone scan based on a shorter waiting
time for the patient, lower infection risk, and earlier pro­
gression to rehabilitation; of note, Cauchy advocates repeat
scanning at 7–10 days post injury if the injury is not clearly
delineated on early (<48 hours) bone scan.66 Nevertheless
the prevalent clinical practice remains to time surgery any­
where from 4 weeks to 3 months following injury, once
tissues have clearly demarcated to an experienced clinical
eye.49,67
Conclusion
Frostbite has a long clinical history and remains a modern
clinical challenge. Although the pathophysiology of freez­
ing cold injury is well delineated, few advances from the
traditional “frostbite in January, amputation in July”

407.e1
39  •  Cold-Induced Injury: Frostbite
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35. Bulkley GB. The role of oxygen free radicals in human disease pro­
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53. McCauley RL, Hing DN, Robson MC, Heggers JP. Frostbite inju­
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54. Cauchy E, Chetaille E, Marchand V, Marsigny B. Retrospective study
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55. Kowal-Vern A, Latenser BA. Demographics of the homeless in an
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56. Pinzur MS, Weaver FM. Is urban frostbite a psychiatric disorder?
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57. Imray C, Grieve A, Dhillon S. Cold damage to the extremities: frostbite
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59. Syme D. Position paper: on-site treatment of frostbite for mountain­
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77. Ibrahim AE, Goverman J, Sarhane KA, et al. The emerging role of
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with triple-phase bone scanning. Radiology. 1989;170(2):511-514.
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89. Greenwald D, Cooper B, Gottlieb L. An algorithm for early aggressive
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pathogenesis and treatment. J Trauma. 2000;48(1):171-178.
66. Cauchy E, Marsigny B, Allamel G, Verhellen R, Chetaille E. The value
of technetium 99 scintigraphy in the prognosis of amputation in
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75. Johnson AR, Jensen HL, Peltier G, DelaCruz E. Efficacy of intrave­
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thrombolytic therapy for acute treatment of frostbite in 62 patients
with review of thrombolytic therapy in frostbite. J Burn Care Res.
2015.

408
Chemical Burns
FELICIA N. WILLIAMS and JONG O. LEE
40 
■ Mechanism of action of the chemical
■ Physical state of agent (liquid, solid, gas).
There are six mechanisms of action for chemical agents
in biological systems, classified by how they denature and
damage proteins:5,6
1. Reduction: Reducing agents act by binding free electrons
in tissue proteins, causing denaturation. In general, they
do so by reducing the amide link. Examples include
hydrochloric acid, nitric acid, alkyl mercuric com­
pounds, ferrous iron, and sulfite compounds.5,7
2. Oxidation: Oxidizing agents are oxidized on contact with
tissue proteins. These agents cause destruction by insert­
ing oxygen, sulfur, or halogen atoms to structural and
functional proteins. Byproducts are often toxic and con­
tinue to react with the surrounding tissue. Examples of
oxidizing agents are sodium hypochlorite, potassium
permanganate, chromic acid, and peroxide.5
3. Corrosive agents: Corrosive substances denature tissue
proteins on contact and form eschar and a shallow ulcer.
Examples of corrosive agents include phenols, cresols,
white phosphorus, dichromate salts, sodium metals,
lyes, sulfuric acid, and hydrochloric acid.
4. Protoplasmic poisons: These agents produce their effects
by binding or inhibiting calcium or other organic ions
necessary for tissue viability and function. These agents
form esters with proteins and/or chelate calcium or
other ions. Examples of protoplasmic poisons include
“alkaloidal” acids; acetic acid; formic acid; and meta­
bolic competitors and inhibitors such as oxalic acid,
hydrofluoric acid, and hydrazoic acid.
5. Vesicants: Vesicant agents produce ischemia with necro­
sis at the site of contact. There is associated tissue cyto­
kine release and blister formation. Examples include
cantharides, dimethyl sulfoxide (DMSO), mustard gas
(sulfur and nitrogen), and Lewisite.
6. Desiccants: These substances cause damage by dehydrat­
ing tissues and exothermic reactions, causing the release
of heat into the tissue. Examples include sulfuric acid,
muriatic acid, calcium sulfate, and silica gel.
Chemical burns are often described as acidic or alkali.8
Acids act as proton donors in the biological system, and
strong acids have a pH less than 2. Alkali, or basic, materi­
als capable of producing injury typically have a pH greater
than 11.5.8 In general, alkaline materials cause more injury
than acidic compounds. Whereas acids cause coagulation
necrosis with precipitation of protein, the reaction to alkali
is “liquefaction” necrosis, allowing the alkali to penetrate
deeper into the injured tissue.9 The presence of hydroxyl
ions within these tissues increases their solubility, allowing
alkaline proteinases to form when the alkalis dissolve the
proteins of the tissues.1 Organic solutions tend to dissolve
Introduction
Chemical burns represent a small percentage of burn inju­
ries yet up to one third of burn-related deaths.1 Many
common household and industrial compounds have the
potential to induce severe chemical burns. The American
Association of Poison Control Centers’ National Poison
Data System 2014 annual report demonstrated 199,291
cases of exposure to cosmetic or personal care products;
198,018 household cleaning substances; 83,005 pesti­
cides; 31,903 hydrocarbons; and 38,975 unspecified
chemicals.2 Exposure to specific chemicals, including acids,
alkalines, peroxides, bleaches, and phenols, in 2014 totaled
38,594, which was up from the 38,552 cases of exposures
in 2013.3 The unfortunate reality concerning the ease of
access to toxic products is evident in the presence of a rising
number of pediatric exposures to chemical injuries. Most
chemical burns involving children are secondary to
common household products. Domestic chemical burn
injuries are often due to poor labeling and storage, as well
as secondary to intentional assault and suicide attempts.
The most commonly affected areas of the body are the face,
eyes, and arms and legs. As a result, the length of hospital
stay and duration of healing tend to be greater with chemi­
cal burns. The majority of these deaths are related to the
ingestion of chemical substances.4 This chapter provides
general principles for the treatment of chemical injuries.
Pathophysiology
All burn wounds, whether caused by chemical or thermal
sources, have in common the denaturation of key struc­
tural and functional proteins. The structure of biological
proteins involves not only a specific amino acid sequence
but also a three-dimensional structure depending on weak
forces, such as hydrogen bonding or van der Waals’ forces.
These three-dimensional structures impart biological activ­
ity to the proteins and are easily disrupted by outside influ­
ences, specifically chemical and thermal energy sources.
Weak bonds are impaired by heat energy sources degrading
and denaturing proteins. Moreover, any variations in pH or
dissolution of surrounding lipids may neutralize a protein
and disrupt its function. Direct chemical effects on a reac­
tive group in a protein will similarly render it inactive.
The severity of a chemical burn injury is determined by
several factors:5
■ Concentration of chemical in contact or ingested
■ Quantity of chemical agent
■ Manner and duration of contact (skin or ingestion)
■ Extent of penetration

40  •  Chemical Burns
409
the lipid membrane of cell walls and cause disruption of
cellular architecture as their mechanism of action. Inor­
ganic solutions tend more to remain on the exterior of cells
but may act as transporters to carry the above-mentioned
agents that denature proteins or form salts with proteins
themselves.5
General Principles of
Management
The most important aspects of first aid for patients with
chemical burns involve removal of the offending agent from
contact with the patient—stop the burn. This requires
removal of all potentially contaminated clothing and
copious irrigation. Irrigation of chemical burns requires
protection of healthcare providers to prevent additional
injuries and additional patients. In addition, the wounds
should not be irrigated by placing the patient into a tub,
thereby containing the chemical and spreading the injuri­
ous material. Irrigation should be a large-volume shower or
decontamination station and drained out of an appropriate
drain. Immediate copious irrigation has been shown to
reduce the extent and depth of injury, especially to eyes.10
No measure of adequacy of lavage has been developed, but
monitoring the pH from the effluent can provide quantifi­
able information as to adequacy of lavage. Thirty minutes
to 2 hours of lavage is often necessary.
Safety data sheets (SDS) are mandated to be available for
all chemicals present in the workplace. These can be valu­
able resources for potential systemic toxicity and adverse
effects of an agent. Further assistance is available from
regional poison control centers for household chemicals or
unidentified agents.
The use of neutralizing agents is generally contraindi­
cated. Neutralizing agents cause exothermic reactions, pro­
ducing a thermal component along with a chemical injury.
When the chemical agent is known and an appropriate
antidote to support the physiologic changes incited by the
original agent is known, some benefit to its use has been
documented but has not been found to be superior to water
for irrigation.11–13 An example is calcium gluconate for
hydrofluoric acid burns (discussed later in the chapter).
Treatment paradigms remain unchanged for burn and
trauma patients with strict adherence to Advanced Trauma
Life Support (ATLS)and Advanced Burn Life Support (ABLS)
guidelines. After airway patency is assured, adequate air
movement and hemodynamics should be maintained. Con­
ventional thermal burn formulas are used for resuscitation
at maintaining end-organ perfusion. Monitoring of urine
output remains paramount to assessment of adequacy of
end-organ perfusion and hence resuscitation. Systemic dis­
turbances of pH are potential complications and must be
monitored until acid–base disorder and electrolyte abnor­
malities are corrected.
The typical large-volume lavage required to adequately
dilute chemical exposures puts the patient at potential risk
for hypothermia, both from evaporative cooling losses and
from the use of unwarmed lavage fluid. Principles of wound
care for chemical burns are typically the same as for thermal
burns. Early excision and grafting of obviously nonviable
tissue is advocated, particularly in light of the observation
that chemical burns tend to be deeper than they initially
appear. As a result, they tend to heal more slowly.
Specific Agents
ACIDS
Acetic Acid
Acetic acid, also known as ethanoic acid, ethylic acid, and
methane carboxylic acid, is a mild chelating agent. Solu­
tions diluted to less than 40% concentrations, such as table
vinegar and hair-wave neutralizing products, are usually
harmless, but if used inappropriately, they may cause inju­
ries. Chemical exposures may cause symptoms of upper and
lower airway irritation, including cough, tachypnea,
wheezing, nose and throat irritation, and pharyngeal and
pulmonary edema. Other symptoms found are tooth
erosion, conjunctivitis, headache, nausea, vomiting,
impaired vision, abdominal pain, eye pain, and whitish dis­
coloration of the skin.5 In such cases, initial treatment
involves irrigation.14
Carbolic Acid (Phenol)
Carbolic acid is a hydrocarbon derived from coal tar, which
acts to cause damage secondary to its ability to induce
denaturation and necrosis.15,16 The most common adverse
effects are dermatitis, abnormal pigmentation, and burns to
the skin.17 Concentrated amounts of phenol are caustic;
therefore, prolonged skin contact causes partial- or full-
thickness burns. These burns tend to become extensive
before detection, secondary to the local anesthetic proper­
ties of phenol. Ingestion of as little as 1000 mg may be
fatal. Systemic effects include ventricular arrhythmias,18
pulmonary edema, stridor, and tachypnea. Locally, con­
junctivitis, corneal edema or necrosis, and skin necrosis
result.16
Acute poisonings are potentially fatal; hence, prompt
action is necessary with copious irrigation. Polyethylene
glycol (PEG; molecular weight 300 or 400 Da) has been
shown to be of potential benefit, but large-volume lavage
should not be delayed while PEG application is begun.
Reports in the literature indicate that intravenous (IV)
sodium bicarbonate may be of use to prevent some of the
systemic effects of phenol.19–26
Chromic Acid
This acid causes nonpainful but corrosive ulcers upon
contact with the skin.27 Ulceration of the nasal septum and
bronchospasm can occur with inhalation. This agent causes
protein coagulation. Peak blood levels are thought to be
achieved within 5 hours of exposure. Symptoms may occur
with just 1% total body surface area (TBSA) burn, but a
10% burn or greater is often fatal owing to its systemic
effects. Irrigation is the primary treatment for exposure, but
in an industrial setting, washing with a dilute solution of
sodium hyposulfite or water followed by rinsing in a buff­
ered phosphate solution may be a more specific antidote.
Dimercaprol may be used at 4 mg/kg intramuscularly every
4 hours for 2 days followed by 2–4 mg/kg/day for 7 days in
total to treat the systemic effects. Dialysis in the first 24

40  •  Chemical Burns
410
cleaners contain dilute hydrochloric acid (3–6%) and sulfu­
ric acid and its desiccant precursor (sulfur trioxide) in con­
centrations up to 80–99%. Muriatic acid is the commercial
grade of concentrated hydrochloric acid. When in contact
with the skin, it denatures proteins into their chloride salts.
Copious irrigation and early excision are the treatments of
choice. Hydrochloric acid fumes can cause inhalation
injury with acute pulmonary edema (Figs. 40.2 and 40.3).
Other symptoms found to occur are white or grayish discol­
oration of the skin and exposed mucosa. Patients may have
eye, mouth, throat, and abdominal pain and injuries. They
may experience hematemesis, vomiting, dizziness, head­
ache, dyspnea, cough, tachypnea, pneumonia, laryngo­
spasm, and ultimately respiratory failure.5
hours is a reasonable means to remove circulating chro­
mium and to address existing electrolyte imbalances.
Exchange transfusion may be necessary. Various ointments
containing products such as 10% calcium ethylenediami­
netetraacetic acid (EDTA) or ascorbic acid are available for
small superficial burns.28,29 There have been case reports
supporting the early excision of chromic acid burn to assist
in preventing systemic toxicity.28,30
Epichlorohydrin Acid
Epichlorohydrin is a rare, corrosive carcinogen that is color­
less and exudes a garlic-like odor. It is used in the production
of glues, plastic, glycerols, and resins, as well as in paper
reinforcement and water purification. It can also be con­
verted into a binder used in the production of explosives.
These burns may demonstrate a rapid progression to a full-
thickness wound within hours. Management commences
with copious irrigation and hemodynamic monitoring
(Fig. 40.1).
Formic Acid
Formic acid is a strong inorganic acid used by glue makers
and tanning workers. After contact, it creates an eschar,
which does not prevent systemic absorption. After it is
absorbed, metabolic acidosis, intravascular hemolysis with
hemoglobinuria, renal failure, pulmonary complications,
and abdominal pain with necrotizing pancreatitis usually
occur.31 All patients injured by formic acid should be hospi­
talized because of this multitude of potential systemic
effects. Formic acid is the acid most commonly used in
assaults, especially in developing countries, because of its
easy availability.32
Hydrochloric Acid, Muriatic Acid, and Sulfuric Acid
Hydrochloric acid is one of the most commonly treated
chemical burns. Hydrochloric acid and sulfuric acid are
proton donors, which cause the pH in local tissues to drop
to zero as hydrogen ions disassociate.33 Coagulation necro­
sis and tissue ulceration occur, leading to consolidation of
connective tissue and thrombosis of intramural vessels,
ulceration, fibrosis, and hemolysis.7 Many household
Fig. 40.1  Epichlorohydrin acid burn 3 days after admission.
Fig. 40.2  Hydrochloric acid burn to the hand before blister removal.
Fig. 40.3  Hydrochloric acid burn to the hand after blister removal.

40  •  Chemical Burns
411
subcutaneously or intradermally) have also been used, with
good results.44 Intraarterial injections into the radial artery
(10 mL of 10% calcium gluconate and 40 mL of 5% dex­
trose in water infused over 2–4 hours) can be used for man­
agement of burns to the hand, but in severe cases, palmar
fasciotomy may be needed.45,46 This injection should be per­
formed within 6 hours of exposure to prevent tissue necro­
sis and minimize pain. It should continue until the patient
is symptom free.
Nitric Acid
This is a strong oxidizing agent that can combine with
organic proteins to produce organonitrates, which act as
metabolic poisons. It is used in fertilizer management,
casting iron and steel, and engraving. Upon skin contact, a
yellow-brown stain develops on the skin and mucosa, with
an eschar. Demarcation tends to occur slowly, causing dif­
ficulty in discerning burn depth. Initial treatment involves
irrigation and the use of topical treatment.47 In addition,
patients may present with whitish tinge of the teeth, eye
pain, oropharyngeal pain, or abdominal pain. Patients may
have dyspnea, hematemesis, dizziness, cough, tachypnea,
and even develop pneumonia and laryngospasm.5
Oxalic Acid
This is a potent metabolic poison that combines with
calcium to limit its bioavailability, thereby limiting muscle
contraction.48 It is used industrially to remove rust and in
bleaching products. Treatment consists of water irrigation
and IV calcium, with continuous cardiopulmonary moni­
toring, as well as measurements of serum electrolytes and
renal function.48
Phosphoric Acid
Phosphorus is an incendiary agent found in hand grenades,
artillery shells, fireworks, and fertilizers.18,49 White phos­
phorus ignites in the presence of air and burns until the
entire agent is oxidized or the oxygen source is removed. The
wounds are irrigated with water, and easily identifiable
pieces of phosphorus are removed. Ultraviolet light can be
used to identify embedded particles through phosphores­
cence. In addition, a solution of 0.5% copper sulfate can be
applied, which will impede oxidation and turn the particles
black to aid in their identification and removal. Hypocalce­
mia, hyperphosphatemia, and cardiac arrhythmias have
been reported with phosphorus burns.18,49 Patients may
present with eye and respiratory tract irritation, blepharo­
spasm, endophthalmitis, a sensation of a foreign body in
the eye, lacrimation, photophobia, cornea perforation, and
even ultimately blindness.5
ALKALIS
Strong alkalis have a pH of 12 or greater. Wounds caused
by alkalis initially appear superficial but may often become
full thickness in 2–3 days. This chemical creates a soluble
protein by binding with lipids and proteins, thus allowing
passage of hydroxyl ions into the tissue. Eventually, a soft,
brownish, gelatinous eschar is created. Alkalis are very cor­
rosive in nature and penetrate deeply. Examples of strong
alkalis (lyes) include barium, sodium, ammonium, calcium,
lithium, and potassium hydroxides. They are present in
Hydrofluoric Acid
Hydrofluoric acid is a corrosive that is commonly used in
industrial applications and computer processing. It is used
as a cleaning agent in the petroleum industry, in the produc­
tion of high-octane fuel, glass etching, germicides, dyes,
tanning, and fireproofing material, as well as in rust removal.
Hydrofluoric acid is particularly lethal owing to its proper­
ties both as an acid and as a metabolic poison. The acid
component causes coagulation necrosis and cellular death.
Fluoride ions then gain a portal of entry that chelates posi­
tively charged ions such as calcium and magnesium, result­
ing in hypocalcemia and hypomagnesemia.34 This causes an
efflux of intracellular calcium with resultant cell death. The
fluoride ion remains active until it is completely neutralized
by the bivalent cations. This may exceed the body’s ability to
mobilize calcium and magnesium rapidly enough, causing
muscle contraction and cellular dysfunction. Fluoride ion
also acts as a metabolic poison by inhibiting Na-K ATPase,
allowing efflux of potassium.35 Excess potassium subse­
quently causes shifts at nerve endings and is thought to be
the cause of the extreme pain associated with hydrofluoric
acid burns.36–38 Patients may present with self-limiting
symptoms such as nausea, vomiting, fever, whitish tissue
with surrounding erythema, immediate profound abdomi­
nal, mouth and throat pain, skin edema, ulcers and necrosis
or stridor, laryngeal edema, wheezing, tachypnea, tetany,
and potentially fatal cardiac arrhythmias.5
Hydrofluoric acid burns are classified based on the con­
centration of the exposure.39 Concentrations greater than
50% cause immediate tissue destruction and pain. Concen­
trations of 20–50% result in a burn becoming apparent
within several hours of exposure. Injuries from concentra­
tions less than 20% may take up to 24 hours to become
apparent.
Death from hydrofluoric acid exposure is usually second­
ary to systemic toxicity. Systemic symptoms are secondary
to acidosis, hypocalcemia, hypomagnesemia, and hyperka­
lemia, which can lead to ventricular fibrillation. Thus, elec­
trolytes and cardiac rhythm should be monitored closely.40
When cardiac dysrhythmias develop, it is difficult to restore
a normal rhythm.41 Compounding the problem of hypocal­
cemia, the fluoride ion may act as a metabolic poison in the
myocardium to promote the irritability. The typical electro­
cardiographic change seen is Q–T interval prolongation.
The fluoride ions can be removed by hemodialysis or cation
exchange resins.42
Treatments for hydrofluoric acid exposure are designed
to neutralize the fluoride ion and prevent systemic toxicity.
Primarily, the wound should be copiously irrigated for 30
minutes. If the concentration of exposure is less than 20%
or the duration of exposure is minimal, this may serve as
the extent of treatment. For more serious exposures, topical,
subcutaneous, or intraarterial mixtures of calcium gluco­
nate can be used as a first option. The topical gel is a mixture
of 3.5 g of 2.5% calcium gluconate and 5 oz of water-
soluble lubricant. It should be applied to the wound four to
six times each day for 3 to 4 days.43 The mixture’s penetra­
tion into the dermis is limited by its calcium component.
This is improved with the use of DMSO, which has its own
associated toxicity. Calcium gluconate injections into the
area of the wound (0.5 mL/cm2 of 10% calcium gluconate

40  •  Chemical Burns
412
HYPOCHLORITE SOLUTIONS
These are potent oxidizers delivered in alkaline solution
used as bleaches and household cleaners. Exposure to
30 mL of 15% solution is potentially fatal. Systemic mani­
festations of toxicity include vomiting, confusion, dyspnea,
airway edema, cyanosis, cardiovascular collapse, and
coma.49 Treatment consists of copious irrigation.
ALKYL MERCURIC COMPOUNDS
Skin reaction with these substances releases free mercury,
which can be found in blister fluid. With time, mercury is
absorbed, leading subsequently to systemic effects. After
blisters are debrided, repeat washing to lavage the blister
fluid is necessary.
TAR
Tar, crude oil, and asphalt are various names for mineral
products created from long-chain petroleum and coal or
fossil hydrocarbons. This compound should be removed
from the skin immediately. After it has cooled, the tar pro­
duces liquefaction injury and should be debrided from the
skin, especially if obvious burn, blister, or tissue loss is
apparent. Antibiotic ointments and household items such
as baby oil, mineral oil, mayonnaise, and butter have been
found to aid in its removal (Fig. 40.5).52
VESICANT CHEMICAL WARFARE AGENTS
(MUSTARD, LEWISITE, NITROGEN)
These agents affect all epithelial tissues, including the skin,
eyes, and respiratory epithelium. Symptoms described after
exposure to mustard gas include burning eyes, a burning
throat, and a feeling of suffocation.43,46 This is followed by
erythema of the skin within 4 hours and blister develop­
ment within 12 to 48 hours. Severe pruritus develops, par­
ticularly in moist areas such as the axilla and perineum.
When the blisters rupture, they leave painful, shallow
ulcers. Exposure to larger quantities of these agents
many household cleaning solutions and have historically
been ingested in suicide attempts, causing death secondary
to airway occlusion.17 Management of these burns neces­
sitates immediate and copious irrigation.
Dry residues of alkali (e.g., lime) must be brushed away
and then copious irrigation is undertaken. Attempts to neu­
tralize alkali are not recommended. Alkaline injury to the
eye is particularly devastating. These compounds rapidly
penetrate the cornea, causing scarring and opacification,
with associated perforation.17
CEMENT
Cement acts both as a desiccant and an alkali. Cement is
calcium oxide, which becomes calcium hydroxide upon
exposure to water. It usually contains lime, sand, and other
metal oxides. The dry powder is very hygroscopic and will
cause desiccation injury if not hydrated or washed away.
Injury results from the action of the hydroxyl ion.50
METALS
Occupational injuries often occur to workers using molten
metal, such as elemental metals, sodium, lithium, potas­
sium, magnesium, aluminum, or calcium. After exposure,
the use of water is contraindicated because it may result in
an explosive exothermic reaction. Class D fire extinguishers
or sand are ideal for management, but mineral oil is also an
option (Fig. 40.4).
HYDROCARBONS
Hydrocarbons are corrosive agents, often contained within
plants, animal fats, and fuel oils. Prolonged contact with
petroleum distillates results in dissolution of lipid cell mem­
branes, leading to cell death.51 These burns tend to be
superficial. Systemic toxicity usually involves respiratory
depression. Heat loss from rapid evaporation of gasoline can
cause the development of frostbite and dehydration. Early
decontamination is most efficiently achieved with soap and
water.
Fig. 40.4  Sodium hydroxide burn to the face and tongue.
Fig. 40.5  Crude oil burn to the face.

40  •  Chemical Burns
413
Conclusion
Many chemical compounds can cause burn injury. The
principal idea behind the treatment of chemical burns is
early, copious irrigation. Wound care is the same as for
thermal burns. Chemical burns tend to be deeper than
they initially appear, often requiring skin grafting for
management.
Complete references available online at

Further Reading
Chung JY, Kowal-Vern A, Latenser BA, et al. Cement-related injuries:
review of a series, the National Burn Repository, and the prevailing lit­
erature. J Burn Care Res. 2007;28(6):827-834. General overview of
cement burns.
Devereaux A, Amundson DE, Parrish JS, et al. Vesicants and nerve agents
in chemical warfare. Decontamination and treatment strategies for a
changed world. Postgrad Med. 2002;112(4):90-96. General overview of
vesicant chemical warfare agents.
Harchelroad FP, Rottinghaus DM. Chemical Burns. In: Emergency Medicine:
A Comprehensive Study Guide. 6th ed. 2004:200. General review of chemi­
cal burns.
Kuckelkorn R, Schrage N, Keller G, Redbrake C. Emergency treatment of
chemical and thermal eye burns. Acta Ophthalmol Scand. 2002;80(1):4-10.
General review of chemical burns to eyes.
Stuke LE, Arnoldo BD, Hunt JL, et al. Hydrofluoric acid burns: a 15-year
experience. J Burn Care Res. 2008;29(6):893-896. General overview of
hydrofluoric acid burns.
produces coagulative necrosis of the skin, with either no
blistering or “doughnut blisters” surrounding a central
necrotic zone.43,44,46
Lewisite (2-chlorovinyl-dichloroarsine) is the best known
arsine. It is more powerful than the mustards, and the
symptoms occur sooner.
Phosgene oxime is another common agent in chemical
warfare. It is the most widely used halogenated oxime and
has the immediate effect of stinging, likened to contact with
a stinging needle.46 Affected areas quickly become swollen
with blister formation, and eschars develop over the ensuing
week. Wound healing is slow, typically over 2 months. Eye
involvement is extremely painful and can result in perma­
nent blindness. Inhalation leads to hypersecretion and pul­
monary edema.
Clothing must be removed from the victim and large-
volume lavage of the skin is undertaken. Eyes are irrigated
with water or “balanced salt solution.” Blisters are debrided
and dressed with topical antimicrobials. Dimercaprol is a
chelating agent that is an antidote for lewisite poisoning.
There is no specific antidote for nitrogen mustard, but
sodium thiosulfate and N-acetylcysteine may be helpful to
reduce the effects if administered early.46 The blister fluid
from nitrogen mustard injuries does not contain active
agent and is hence harmless.47 Agranulocytosis or aplastic
anemia can result from exposure to these agents.24 In the
appropriate setting, bone marrow transplantation may be
considered.

413.e1
40  •  Chemical Burns
26. Sabourin CL, Danne MM, Buxton KL, Casillas RP, Schlager JJ. Cyto­
kine, chemokine, and matrix metalloproteinase response after
sulfur mustard injury to weanling pig skin. J Biochem Mol Toxicol.
2002;16:263-272.
27. Ogawa M, Nakajima Y, Endo Y. Four cases of chemical burns thought
to be caused by exposure to chromic acid mist. J Occup Health.
2007;49:402-404.
28. Cason JS. Report on three extensive industrial chemical burns. Br Med
J. 1959;1:827-829.
29. Terrill PJ, Gowar JP. Chromic acid burns; beware, be aggressive, be
watchful. Br J Plast Surg. 1990;43:699-701.
30. Matey P, Allison KP, Sheehan TM, Gowar JP. Chromic acid burns: early
aggressive excision is the best method to prevent systemic toxicity. J
Burn Care Rehabil. 2000;21:241-245.
31. Chan TC, Williams SR, Clark RF. Formic acid skin burns resulting in
systemic toxicity. Ann Emerg Med. 1995;26:383-386.
32. Karunadasa KP, Perera C, Kanagaratnum V, et al. Burns due to acid
assaults in Sri Lanka. J Burn Care Res. 2010;31:781-785.
33. Reilly DA, Garner WL. Management of chemical injuries to the upper
extremity. Hand Clin. 2000;16:215-224.
34. Stuke LE, Arnoldo BD, Hunt JL, Purdue GF. Hydrofluoric acid burns:
a 15-year experience. J Burn Care Res. 2008;29:893-896.
35. Mayer TG, Gross PL. Fatal systemic fluorosis due to hydrofluoric acid
burns. Ann Emerg Med. 1985;14:149-153.
36. McIvor ME. Delayed fatal hyperkalemia in a patient with acute fluo­
ride intoxication. Ann Emerg Med. 1987;16:1165-1167.
37. McIvor ME, Cummings CE, Mower MM, et al. Sudden cardiac death
from acute fluoride intoxication: the role of potassium. Ann Emerg
Med. 1987;16:777-781.
38. McIvor ME, Cummings CC, Mower MM, et al. The manipulation of
potassium efflux during fluoride intoxication: implications for therapy.
Toxicology. 1985;37:233-239.
39. Yolken R, Konecny P, McCarthy P. Acute fluoride poisoning. Pediatrics.
1976;58:90-93.
40. Anderson WJ, Anderson JR. Hydrofluoric acid burns of the hand:
mechanism of injury and treatment. J Hand Surg Am. 1988;13:52-57.
41. Vance MV, Curry SC, Kunkel DB, Ryan PJ, Ruggeri SB. Digital hydro­
fluoric acid burns: treatment with intraarterial calcium infusion. Ann
Emerg Med. 1986;15:890-896.
42. Caravati EM. Acute hydrofluoric acid exposure. Am J Emerg Med.
1988;6:143-150.
43. Miller FG. Poisoning by Phenol. Can Med Assoc J. 1942;46:615-616.
44. Saunders A, Geddes L, Elliott P. Are phenolic disinfectants toxic to staff
members? Aust Nurses J. 1988;17:25-26.
45. Lazarus AA, Devereaux A. Potential agents of chemical warfare.
Worst-case scenario protection and decontamination methods. Post­
grad Med. 2002;112:133-140.
46. Devereaux A, Amundson DE, Parrish JS, Lazarus AA. Vesicants and
nerve agents in chemical warfare. Decontamination and treatment
strategies for a changed world. Postgrad Med. 2002;112:90-96, quiz
4.
47. Kolios L, Striepling E, Kolios G, et al. The nitric acid burn trauma of
the skin. J Plast Reconstr Aesthet Surg. 2010;63:e358-e363.
48. Fitzpatrick KT, Moylan JA. Emergency care of chemical burns. Post­
grad Med. 1985;78:189-194.
49. Summerlin WT, Walder AI, Moncrief JA. White phosphorus burns
and massive hemolysis. J Trauma. 1967;7:476-484.
50. Chung JY, Kowal-Vern A, Latenser BA, Lewis RW 2nd. Cement-related
injuries: review of a series, the National Burn Repository, and the
prevailing literature. J Burn Care Res. 2007;28:827-834.
51. Klauder JV, Shelanski L, Gabriel K. Industrial uses of compounds of
fluorine and oxalic acid; cutaneous reaction and calcium therapy.
AMA Arch Ind Health. 1955;12:412-419.
52. Renz BM, Sherman R. Hot tar burns: twenty-seven hospitalized cases.
J Burn Care Rehabil. 1994;15:341-345.
References
1. Palao R, Monge I, Ruiz M, Barret JP. Chemical burns: pathophysiology
and treatment. Burns. 2010;36:295-304.
2. Mowry JB, Spyker DA, Brooks DE, McMillan N, Schauben JL. 2014
Annual Report of the American Association of Poison Control
Centers’ National Poison Data System (NPDS): 32nd Annual Report.
Clin Toxicol (Phila). 2015;53:962-1147.
3. Mowry JB, Spyker DA, Cantilena LR Jr, McMillan N, Ford M. 2013
Annual Report of the American Association of Poison Control
Centers’ National Poison Data System (NPDS): 31st Annual Report.
Clin Toxicol (Phila). 2014;52:1032-1283.
4. Watson WA, Litovitz TL, Rodgers GC Jr, et al. 2004 Annual report of
the American Association of Poison Control Centers Toxic Exposure
Surveillance System. Am J Emerg Med. 2005;23:589-666.
5. Dinis-Oliveira RJ, Carvalho F, Moreira R, et al. Clinical and forensic
signs related to chemical burns: a mechanistic approach. Burns.
2015;41:658-679.
6. Jelenko C 3rd. Chemicals that “burn”. J Trauma. 1974;14:65-72.
7. Matshes EW, Taylor KA, Rao VJ. Sulfuric acid injury. Am J Forensic Med
Pathol. 2008;29:340-345.
8. Leonard LG, Scheulen JJ, Munster AM. Chemical burns: effect of
prompt first aid. J Trauma. 1982;22:420-423.
9. Yano K, Hata Y, Matsuka K, Ito O, Matsuda H. Effects of washing
with a neutralizing agent on alkaline skin injuries in an experimental
model. Burns. 1994;20:36-39.
10. Kuckelkorn R, Schrage N, Keller G, Redbrake C. Emergency treat­
ment of chemical and thermal eye burns. Acta Ophthalmol Scand.
2002;80:4-10.
11. Cope O. The treatment of the surface burns. Ann Surg.
1943;117:885-893.
12. Cope VZ. What we learnt about burns in the war. Clin J.
1949;78:209-213.
13. Pike J, Patterson A Jr, Arons MS. Chemistry of cement burns: patho­
genesis and treatment. J Burn Care Rehabil. 1988;9:258-260.
14. Fischer H, Caurdy-Bess L. Scalp burns from a permanent wave
product. Clin Pediatr (Phila). 1990;29:53.
15. Fisher AA. Irritant and toxic reactions to phenol in topical medica­
tions. Cutis. 1980;26:363-364, 90–92.
16. Lin TM, Lee SS, Lai CS, Lin SD. Phenol burn. Burns. 2006;32:517-521.
17. Sawhney CP, Kaushish R. Acid and alkali burns: considerations in
management. Burns. 1989;15:132-134.
18. Bowen TE, Whelan TJ Jr, Nelson TG. Sudden death after phosphorus
burns: experimental observations of hypocalcemia, hyperphosphate­
mia and electrocardiographic abnormalities following production of
a standard white phosphorus burn. Ann Surg. 1971;174:779-784.
19. Casillas RP, Kiser RC, Truxall JA, et al. Therapeutic approaches to
dermatotoxicity by sulfur mustard. I. Modulaton of sulfur mustard-
induced cutaneous injury in the mouse ear vesicant model. J Appl
Toxicol. 2000;20(suppl 1):S145-S151.
20. Dachir S, Fishbeine E, Meshulam Y, et al. Amelioration of sulfur
mustard skin injury following a topical treatment with a mixture of
a steroid and a NSAID. J Appl Toxicol. 2004;24:107-113.
21. Emami MH, Talaei M, Panahi Y, Saburi A, Ghanei M. Efficacy of
omeprazole on cough, pulmonary function and quality of life of
patients with sulfur mustard lung injury: A placebo-control, cross-
over clinical trial study. J Res Med Sci. 2014;19:1027-1033.
22. Gu TY. Mechanism and treatment of sulfur mustard-induced cutane­
ous injury. Chin J Traumatol. 2014;17:345-350.
23. Kehe K, Thiermann H, Balszuweit F, et al. Acute effects of sulfur
mustard injury – Munich experiences. Toxicology. 2009;263:3-8.
24. Laskin JD, Black AT, Jan YH, et al. Oxidants and antioxidants in sulfur
mustard-induced injury. Ann N Y Acad Sci. 2010;1203:92-100.
25. Ruff AL, Dillman JF. Signaling molecules in sulfur mustard-induced
cutaneous injury. Eplasty. 2007;8:e2.

414
Radiation Injuries and Vesicant
Burns
GABRIEL HUNDESHAGEN and STEPHEN M. MILNER
41 
Terminology
Damage to biological tissue by ionizing radiation is medi­
ated by energy transference. This can be the result of expo­
sure to electromagnetic radiation (e.g., X-rays and gamma
rays) or particulate radiation (e.g., alpha and beta particles
or neutrons). The severity of tissue damage is determined by
the energy deposited per unit track length, known as linear
energy transfer (LET). Electromagnetic radiation passes
through tissue almost unimpeded by the skin and is called
low LET because little energy is left behind. In contrast,
neutron exposure has high LET, resulting in significant
energy absorption within the first few centimeters of the
body. Alpha and low-energy beta particles do not penetrate
the skin and represent a hazard only when internalized by
inhalation, ingestion, or absorption through a wound.
The biological effect of ionizing radiation is measured by
the radiation absorbed dose (rad). The newer SI unit of
absorbed dose is the gray (1 Gy = 100 rad). Not all radiation
is equally effective in causing biological damage, although
it may cause the same energy deposition in tissue. For
example, 1 Gy of neutron radiation will not have the same
effect as 1 Gy of gamma or X-radiation. For this reason, a
unit of dose equivalence was derived that allows radiations
with different LET values to be compared. One such unit is
the rem (acronym of roentgen equivalent man). The dose
in rem is equal to the dose in rads multiplied by a quality
factor (QF).5 The QF takes into account the LET and has a
different value for different radiations; for X-rays, it is 1.0,
and for neutrons, it is 10. The international unit, now more
widely in use, is the sievert (Sv). One sievert equals 100 rem;
1 rem equals 10 mSv. This allows radiations with different
LET values to be compared because 1 Sv of neutron radia­
tion has the same biological effect as 1 Sv of low LET gamma
or X-radiation.
Incidence
The source of the most abundant type of biologically rel­
evant electromagnetic radiation is the sun. Ultraviolet
(UV) light with a wavelength of 315–400 nm (UVA), 280
to 315 nm (UVB), and 10–280 nm (UVC) would normally
be absorbed by 98% in the atmosphere’s so-called ozone
layer, which extends at about 20 miles above sea level.6
However, mostly because of human-made pollution and
the resulting increase in local permeability of this protec­
tive layer, UV radiation can reach the surface of the skin
and unfold its hazardous effects. Although not technically
ionizing, UV light can severely irritate dermal structures in
terms of first- and second-degree burns. Simultaneously,
Radiation Injury: Introduction
In the aftermath of 9/11 and more recent acts of unrelent­
ing terrorism, such as the mass killings in Paris, Brussels,
and Orlando, the possibility of the use of nuclear weapons
or crude nuclear devices in attacks on nuclear facilities and
use of chemical agents cannot be ignored. Given the devas­
tating medical consequences that would follow the use of
such weapons, the training of medical personnel will be a
crucial factor in the effective management of such casual­
ties if the unthinkable ever occurs.
Only 4 months after Roentgen reported the discovery of
X-rays, Dr. John Daniel observed that irradiation of his col­
league’s skull caused hair loss. Since this finding was
reported in 1896, many biomedical effects of radiation
have been described.1 Knowledge of nuclear physics was
rapidly amassed in the early part of the 20th century,
leading eventually to the Manhattan project and the devel­
opment of the atomic bomb. The use of this weapon over
Japanese cities Hiroshima and Nagasaki in 1945 with at
least 129,000 direct casualties and an extended amount of
long-term sequelae stands as the most gruesome demon­
stration of the impact and threat that nuclear weapons
hold. The past 50 years has also seen widespread deploy­
ment of energy-generating nuclear reactors and the
expanding use of radioactive isotopes in industry, science,
and health care.2 In 2011, a tsunami following an earth­
quake near the Fukushima 1 power plant in Japan led to
severe equipment failures and three nuclear meltdowns and
the release of radioactive material with contaminative con­
sequences.3 This incidence was preceded by other major
industrial accidents of note at Three Mile Island in Pennsyl­
vania, Chernobyl in the Ukraine, and Goiania, Brazil, all of
which have resulted in potential or real radiation injuries to
hundreds of people. According to the latest National Council
on Radiation Protection & Measurements report on radia­
tion exposure to United States citizens, the most significant
increase in ionizing radiation exposure, over the past 20
years, has been through medical imaging.4
Exposure to ionizing radiation can follow one of three
patterns:
1. Small-scale accidents, or cumulative exposures, as might
occur in a laboratory or from an X-ray device in a hos­
pital setting
2. Large industrial accidents (such as those mentioned
above), stretching the need for treatment beyond avail­
able resources
3. Detonation of a nuclear device in a military conflict in
which resources are totally overwhelmed or unavailable
and associated multiple and combined injuries also exist.

41  •  Radiation Injuries and Vesicant Burns
415
the formation of pyrimidine dimers in the DNA of dermal
cells can be induced, which in the long term can result in
malignancies.6,7
A significant radiation accident is one in which an indi­
vidual exceeds at least one of the following criteria:8
■ Whole-body doses equal to or exceeding 25 rem (0.25 Sv)
■ Skin doses equal to or exceeding 600 rem (6 Sv)
■ Absorbed dose equal to or greater than 75 rem (0.75 Sv)
to other tissues or organs from an external source
■ Internal contamination equal to or exceeding one-half
the maximum permissible body burden (MPBB) as defined
by the International Commission on Radiological Protec­
tion (this number is different for each radionuclide)
■ Medical misadministration provided it results in a dose or
burden equal to or greater than the criteria listed above.
Radiation accidents within the United States should be
reported to the federally funded Radiation Emergency Assis­
tance Center/Training Site (REAC/TS), where a Radiation
Accident Registry System is maintained. It is operated by
Oak Ridge Institute for Science and Education (ORISE) at
Oak Ridge, Tennessee, and can be contacted by calling
865-576-1005 (website: ). An
emergency response team of physicians, nurses, health
physicists, and support personnel provides consultative
assistance on a 24-hour basis and has the capability of
providing medical advice or treatment whenever a radia­
tion accident occurs. If an accident involving radiation
occurs outside the United States and local resources fall
short in providing immediate advice, the REAC/TS hotline
can be consulted internationally as well. The International
Atomic Energy Agency (IAEA) provides a detailed publica­
tion concerning the immediate actions that should be taken
in the event of large-scale radiation accidents, which can
be found at
iec/frg/default.asp.
The number of accidents, the number of persons involved,
and the number of fatalities, in the United States and world­
wide are shown in Table 41.1. There have been a total of
128 fatalities recorded by the Registry worldwide (Dainiak
N, personal communication and unpublished data, 2010).8
The majority of the radiation deaths occurred as a result of
the Chernobyl accident in 1986 (>40). The classification of
radiation accident by device for the period 1944 until 2016
is shown in Table 41.2.
The majority of radiation accidents involve radioactive
sources used for industrial radiography. The next most
frequent accidents are radioisotope accidents involving
unsealed radioactive materials, such as tritium, fission
products, radium, and free isotopes used for diagnosis and
therapy. Uncommon criticality accidents occur when
enough fissionable material, such as enriched uranium, is
brought together to produce a neutron flux so high that the
material undergoes a nuclear reaction.
The most devastating radiation injuries and fatalities yet
seen, however, resulted from detonation of nuclear weapons
at Hiroshima and Nagasaki during World War II. Since
1945, nuclear weapon technology has developed enor­
mously, and current strategic thermonuclear warheads
dwarf the weapons used in Japan.9 The majority of radia­
tion exposure occurred within the first minute of the explo­
sion. There were no deaths attributed to the products left
behind by the atomic explosions. As detailed by Kucan in
2004, the majority of radioactive fallout from these
weapons was dispersed into the atmosphere because both
were detonated several thousand feet in the air.10
Perhaps a more likely weapon of terrorism will involve
the use of a radiological dispersal device (RDD). The term
“dirty bomb” generally refers to a conventional explosive
packaged with radioactive material that is scattered over a
wide area when detonated. It is believed that these devices
would probably elicit more harm by public fear and panic
than by serious injury.11
In clinical practice, there are concerns that relatively low
levels of radiation delivered over a long period of time might
induce cancer or exert genetic or teratogenetic effects.
Table 41.1  Major Radiation Accidents: Human
Experience (1944–2016)
Location
Accidents
(n)
Persons
Involved (n)
Significant
Exposures*
Fatalities
United States
271
1405
802
26
Non-United
States
191
132,467
2183
102
Former Soviet
Union†
(137)
(507)
(278)
(35)
Total
462
133,872
2985
128
*DOE/NRC dose criteria.
†Former Soviet Union Registry Data (not included in totals; data incomplete).
Source: REAC/TS Registry, 2016.
Source: REAC/TS Registries, 2016.
Table 41.2  Major Radiation Accidents Worldwide
(1944–2016): Classification by Device
Type
Accidents (n)
Radiation devices
347
Sealed sources
222
X-ray devices
87
Accelerators
8
Radar generators
1
Radioisotopes
95
Diagnosis and therapy
50
Transuranics
25
Fission products
11
Tritium
2
Radium spills
1
Other
18
Criticalities
20
Critical assemblies
8
Reactors
6
Chemical operations
6
Total
462

41  •  Radiation Injuries and Vesicant Burns
416
flame burns may be present after the ignition of the victim’s
clothing or environment. The physicians at Hiroshima and
Nagasaki observed that the “flame” burn wound seemed to
heal at first. However, between 1 and 2 weeks later, a serious
relapse occurred. Wound infection set in; there was disorder
in granulation tissue formation; and a gray, greasy coating
would form on the wounds. Thrombocytopenia resulted in
spontaneous bleeding both into the wound and elsewhere.
Histologically, the normal collection of leukocytes delineat­
ing a necrotic area was found to be absent because of
agranulocytosis, and gross bacterial invasion was evident;
both of these changes obviously affected the prognosis of
these otherwise relatively small injuries.17
RADIATION EFFECT
The transference of radiation energy can damage critical
parts of the cell directly or indirectly by formation of free
radicals. The primary targets are cellular and nuclear mem­
branes as well as DNA.18
The morbidity of radiation depends on its dose, the dose
rate, and the sensitivity of the cell exposed. Cells are most
sensitive when undergoing mitosis so that those that divide
rapidly such as bone marrow, skin, and the gastrointestinal
(GI) tract are more susceptible to radiation damage. Radia­
tion to an organ such as brain or liver, which has parenchy­
mal cells with a slow turnover rate, results in damage to the
more sensitive connective tissue and microcirculation.
The overall effect on the organism depends on the extent
of the body surface involved, duration of exposure, and
homogeneity of the radiation field. It is convenient to con­
sider radiation injuries as localized or whole body (acute
radiation syndrome).
Long-term effects of radiation exposure include the for­
mation of cancer and wound-healing deficits. These have
been studied in various venues including exposure to
tanning beds, which have been linked to an increase in
melanoma in young women of up to 75%. These changes
are thought to be due to a defect in the p53 tumor suppres­
sor pathway. Children are particularly at risk for radiation-
induced injuries because they have a proportionally larger
amount of replicating cells and will live long enough to see
the effects of radiation, which can have upwards of a
30-year latency period.19
LOCALIZED INJURY
In a localized injury, a relatively small part of the body is
affected without significant systemic effects.20 The skin and
subcutaneous tissue alone may be involved after exposure
to low-energy radiation. Exposure to high-energy radiation
may injure deeper structures.
Radiation damage depends on the dose of exposure and
several progressive features are observed in skin: Erythema
is equivalent to a first-degree thermal burn and occurs in
two stages. Mild erythema appears within minutes or hours
after the initial exposure and subsides in 2–3 days. The
second onset of erythema occurs 2–3 weeks after exposure
and is accompanied by dry desquamation of the epidermal
keratinocytes. Epilation (loss of hair) may occur as soon as
7 days after injury. It is usually temporary with doses less
than 5 Gy but may be permanent with higher doses.
Although most of the literature that explores this issue
refers to case studies, it confirms that exposure at a younger
age increases the risk of cancer. Even more important, this
risk is not reduced with time.12 Exposure to radiation
through computed tomography imaging is now common­
place, and healthcare personnel should not disregard the
cumulative effects of these examinations, which can
approximate levels seen in atomic bomb survivors
(30 mSv).13 Because distance and radiation intensity obey
the inverse square law, radiation dose can be limited most
effectively by increasing the distance from the source of
radiation. Although the efficacy of shielding devices will be
determined by the type and thickness of the material and
the energy and type of radiation, Table 41.3 illustrates the
effectiveness of these devices when used at diagnostic X-ray
energies.
Cumulative doses of radiation can be recorded on radia­
tion badges containing photographic emulsion. The per­
sonnel dosimeter is relatively cheap and accurate but has
limitations. The smallest exposure that can be measured is
10 millirem; film badges can be exposed by heat, giving false
readings, and they are analyzed only at monthly intervals.
Pathophysiology
The detonation of a nuclear device over a population center
will produce an extremely hot, luminous fireball, which
emits intense thermal radiation capable of causing burns
and starting fires at considerable distance. This is accompa­
nied by a destructive blast wave moving away from the fire­
ball at supersonic speed and the emission of irradiation,
mainly gamma rays and neutrons.14 The result of a combi­
nation of thermal and radiation injuries can have a syner­
gistic effect on the outcome. Several animal experiments
have demonstrated a significant increase in mortality rate
when a standard burn wound model is irradiated, over and
above that expected from either injury alone.15
THERMAL EFFECTS
Exact information about the cause of fatalities in a nuclear
blast is not available, but from the nuclear attack on Japan,
it has been estimated that 50% of deaths were due to burns,
and some 20% to 30% were flash burns.16 The clinical
picture may range from an erythema of exposed areas to a
charring of the superficial layers of the skin. Secondary
Table 41.3  The Effectiveness of Shielding Devices
Device
Transmission (%)
Lead apron
<10
Thyroid shield
<10
Leaded glasses
<10
Unleaded glasses
50
Human body
1
Human body wearing lead apron
0.1
Portable lead shields
<1

41  •  Radiation Injuries and Vesicant Burns
417
TRIAGE
Triage is the initial classification of casualties into priority
groups for treatment and is essential in the management of
large numbers of casualties. All first responders should take
into account their own safety and remember that exposure
to radiation is reduced by distance and shielding. Therefore,
a perimeter should be established beyond which those
without shielding should remain until the donning of per­
sonal protection equipment is complete. In most circum­
stances, ionizing radiation is not immediately life
threatening, and after life-saving measures have been
carried out and the patient stabilized, assessment of radia­
tion exposure can proceed.23
If large-scale casualties are encountered, triage may, of
necessity, seem to be draconian. Patients who are unlikely
to survive should not be allowed to overwhelm available
resources, so that adequate treatment reaches those most
likely to survive. In conventional warfare with limited
medical resources, 50% of soldiers with thermal injuries of
up to 70% total body surface area (TBSA) are expected to
survive (Table 41.4).
This survival rate should be bettered in a smaller civilian
accident. Thus, patients with burns alone over 70% TBSA
should receive expectant treatment, and those with burns
under 20% can have their treatment delayed. If there has
been a significant exposure to radiation as well as a thermal
injury, individuals with over 30% TBSA burns are unlikely
to survive without the use of major resources.24
Treatment
The treatment of any burn requires massive support from
a dedicated team. This will be available for small accidents.
With larger accidents or a nuclear attack, the number of
victims could swamp the services; treatment facilities may
be destroyed; normal supply channels would be drastically
reduced, if present at all; production, distribution, and
transportation of supplies may be greatly impaired; and
local care workers may also be the victims.2
FIRST AID
The victims must be evacuated from the source of radiation
to limit exposure. Normal resuscitation procedures must be
followed. Contaminated clothing must be removed, and the
skin wounds must be decontaminated by copious but gentle
irrigation with water or saline. The goal of decontamina­
tion is to dilute and neutralize particles without spreading
Moist desquamation is equivalent to a second-degree
thermal burn and develops after a latent period of about 3
weeks with a dose of 12–20 Gy. The latency period may be
shorter with higher doses. Blisters form, which are suscep­
tible to infection if not treated.
Full-thickness skin ulceration and necrosis are caused by
doses in excess of about 25 Gy. Onset varies from a few
weeks to a few months after exposure. Blood vessels become
telangiectatic, and deeper vessels occlude. Obliterating end­
arteritis results in fibrosis, atrophy, and necrosis. Skin
cancers may be evident after months or years.
One of the most closely studied local effects of radiation
injury involves the treatment of breast cancer. It is well
known that radiation therapy improves postmastectomy
outcomes in women with multiple nodal involvement. This
outcome comes at a cost as significantly increased rates of
tissue contracture, hyperpigmentation, and asymmetry
after all types of reconstruction paired with radiation.20
THE ACUTE RADIATION SYNDROME
The physiological effects of whole-body radiation are
described as the acute radiation syndrome (ARS). The clini­
cal course usually begins within hours of exposure. Prodro­
mal symptoms include nausea, vomiting, diarrhea, fatigue,
fever, and headache. There then follows a latent period, the
duration of which is related to the dose. Hematopoietic and
GI complications ensue. ARS can be subdivided into three
overlapping subsyndromes, which are related to the dose
exposure.
Hematopoietic Syndrome
This may occur after an exposure of 1–4 Gy. The bone
marrow is the most sensitive, and pancytopenia develops.
Opportunistic infections result from the granulocytopenia
and spontaneous bleeding from thrombocytopenia. Hemor­
rhage and infection can cause death.
Gastrointestinal Syndrome
This requires a larger dose exposure usually in the range of
10–12 Gy. Severe nausea and vomiting associated with
bowel cramps and watery diarrhea occur within hours of
irradiation. There is a shorter latent period of 5–7 days,
which reflects the turnover time of the gut epithelium (3–5
days). The epithelial damage results in loss of transport
capability, bacterial translocation with septicemia, bowel
ischemia, and bloody diarrhea. Large fluid imbalances can
result in hypovolemia, acute renal failure, and anemia from
both bleeding and the loss of erythropoiesis. Critical expo­
sure will lead to rapid deterioration with unrelenting bloody
diarrhea, fever, refractive hypovolemic shock, sepsis, and
death.21,22
Neurovascular Syndrome
An exposure to a dose of 15–30 Gy or greater can cause an
immediate total collapse of the vascular system superim­
posed on the aforementioned syndromes. This may be
caused by the massive release of mediator substances, nitric
oxide abnormalities, or destruction of endothelium.21 This
syndrome can progress rapidly with variable neurologic
symptoms, respiratory distress, cardiovascular collapse,
and death.
Table 41.4  Survival Rates With Major Resources
Available
Burn alone
<70% TBSA
50% survival
Burn alone
>70% TBSA
Probably fatal
Burn plus radiation
<30% TBSA
May survive
Burn plus radiation
>30% TBSA
Probably fatal
TBSA, Total body surface area.

41  •  Radiation Injuries and Vesicant Burns
418
Resuscitation should be the same as that for an uncompli­
cated thermal injury. Any resuscitation formula can be
used, but it must be closely monitored and adjusted as nec­
essary to maintain an adequate urine output. Fluid losses
from diarrhea and vomiting may be excessive and need to
be replaced.
Oral Resuscitation
Intravenous fluids may be limited, and the victims may be
advised to take oral fluids consisting of balanced salt solu­
tions and maintain a large urine output. Studies in humans
and animal models have shown that intestinal absorption
remains intact in burn patients. Kramer et al. reviewed the
use of oral resuscitation therapy in burn care and found 12
reports, most of which show equal outcomes to IV infu­
sions. This solution should be readily available, cheap, easy
to transport, and palatable (Table 41.5).28,29 A study
published by one of the authors shows a reduction in IV
fluid requirements by 58% on average when Parkland
formula-driven protocols are supplemented with oral resus­
citation (Fig. 41.1).30
CARE OF BURN WOUNDS
After the patient has been cleaned, decontaminated, and
debrided, the extent of any thermal burn and its depth can
be ascertained more accurately.
Mild erythema may require little treatment; however, it
is important to avoid further irritation of the skin by expo­
sure to abrasive decontamination, irritating solutions, and
sunlight. With a slightly higher radiation dose causing dry
desquamation, a bland lotion and loose clothing to alleviate
itching may be all that is required.
Deeper burns with moist desquamation are treated like
conventional thermal injuries. Burns are best treated closed
because of the high risk of sepsis in immunosuppressed
patients whose wounds are susceptible to dehydration and
colonization and invasion of organisms. Early tangential
excision and split-skin grafting promotes early wound
closure, decreases burn wound colonization and sepsis, and
them to unexposed areas. Thus, patients should not be
immersed in tubs. Irrigation should be continued until a
dosimeter such as a Geiger–Müller counter indicates a
steady state or minimum radiation count has been reached.
Intact skin may also be irrigated with a soft brush or
surgical sponge, preferably under a stream of warm tap
water. If this is inadequate, a second scrubbing with mild
soap or detergent (with a pH of 7) for 3–4 minutes is recom­
mended. This is followed by application of povidone-iodine
solution or hexachlorophene soap, which is then rinsed
again for 2–3 minutes and dried. If the patient is known to
have had exposure to less than 100 rem (1 Sv/Gy), he or
she can be followed as an outpatient. Exposures greater
than 100 rem (1 Sv/Gy) require full evaluation in the hos­
pital. Patients with exposures greater than 200 rem (2 Sv/
Gy) or who have symptoms of ARS should preferably be
sent to specialist centers with facilities to treat bone marrow
failure.25
ASSESSMENT
The assessment of thermal injury has been covered in pre­
ceding chapters. Exposure to radiation can be estimated
clinically by noting the onset of symptoms of ARS, sup­
ported by biological parameters. A complete blood count,
including platelets and differential count, should be per­
formed immediately and repeated at 12–24 hours if indi­
cated by a change in the absolute lymphocyte count. If the
patient sustains a fall in lymphocyte count of 50% or a
count less than 1 × 109/L in a time period of 48 hours
postexposure, a moderate dose of radiation has been
encountered.26 Levels of serum amylase and diamine
oxidase (produced by intestinal villi) may be useful biologi­
cal dosimeters of the future. Amylase levels are only reliable
when the salivary glands have been exposed, and diamine
oxidase has not yet been fully assessed in humans. Lympho­
cyte chromosomal analysis allows for accurate measure­
ment even at low levels of exposure. However, this test is
impractical with large numbers of casualties.27
GENERAL CARE OF IRRADIATED PATIENTS
A history should be obtained from the patient or others.
Factors such as age, concurrent medical problems, smoke
inhalation, and multiple trauma will affect the prognosis. A
full physical examination is carried out to exclude other
injuries. Those exposed to lethal doses of radiation will
exhibit early signs of radiation sickness and should be
triaged accordingly.
All patients should be administered adequate analgesia.
Opiates or opioids are the drugs of choice and must be
titrated to effect and administered by the intravenous (IV)
route. Early nausea and vomiting will be distressing and
must be treated with available antiemetic drugs. Ondanse­
tron may prove successful because it is used against similar
symptoms encountered in radiotherapy and chemotherapy
and can also be used in children.
Patients with thermal burns in excess of 40% TBSA or
with associated inhalation or major trauma should be
treated expectantly in the mass casualty situation. They
should be made comfortable and given adequate analgesia,
sedatives, or both if available and thought appropriate.
Table 41.5  Oral Resuscitation Formulas
Formula
Na
Cl
K+
Buffer
Use
WHO ORS (1975)
90
80
20
30
Diarrhea
WHO ORS (2002)
75
65
20
10
Diarrhea
Fox’s sodium lactate
161
0
0
161
Burns
Moyer’s citrated NaCl
85
63
0
29
Burns
Monafo’s HLS
300
200
0
100
Burns
Liquidsorb
60
44
4
28
Burns
Jiang’s burn drink
48
28
0
20
Burns
Ricelyte
50
45
25
34
Burns
Ceralyte 90
90
80
20
30
Diarrhea and burns
HLS, Hypertonic lactated saline; ORS, oral resuscitation solution; WHO, World
Health Organization.
Adapted from Kramer GC, Michell MW, Oliveira H, et al. Oral and enteral
resuscitation of burn shock the historical record and implications for mass
casualty care. Eplasty 2010;10:e56, with permission from ePlasty.

41  •  Radiation Injuries and Vesicant Burns
419
pathogens. Exogenous infection can be limited by adequate
aseptic technique and nursing the patient in a sterile envi­
ronment. Monitoring the patient adequately will allow the
early diagnosis of sepsis and its treatment. The antibiotic
chosen should reflect the current pattern of susceptibility
and nosocomial infections in the particular unit at the time.
Combination therapy will be required with profound neu­
tropenia. Broad-spectrum antibiotics such as imipenem,
ceftazidime, and ciprofloxacin can be considered. If Gram-
positive infection is suspected, vancomycin or teicoplanin
should be administered. In case of an inadequate response,
an antifungal agent must be added.
SUMMARY
Treatment of radiation injury, whether or not it is combined
with other injuries, requires specialized knowledge and
resources. The combination of radiation injury with associ­
ated injuries appears to have a synergistic effect on outcome.
Significant increases in mortality rates occur because of
immunosuppression secondary to radiation exposure in
patients already vulnerable to infections. For localized radi­
ation injury, it is often difficult to assess the level of severity
quickly and with accuracy because of the delay between
exposure and appearances of lesions and because of hidden
lesions in underlying tissues. Medical treatment deals with
inflammation, moist desquamation, and chronic pain; the
most favorable time for surgical intervention is difficult to
specify. Full intensive care support is needed for whole-body
irradiation causing ARS and is available only if small
numbers are involved. Oral replacement therapy may be a
feasible alternative to IV resuscitation of burns and could
potentially save many lives in mass casualty situations.
Those who survive and show signs of regeneration of
tissues will warrant late surgical intervention. Aplastic
anemia, immunosuppression, hemorrhage, and sepsis will
be major problems for survivors. The improving therapy of
bone marrow transplantation is the treatment of choice.
Large numbers of casualties will necessitate expectant
treatment only. In the event of a radiation mass casualty,
resources will be limited, and treatment may depend on oral
routes of resuscitation to maintain intravascular volume.
Evacuation of survivors will take days, and a natural selec­
tion will take place.
Vesicant Burns
INTRODUCTION
Vesicant agents are characterized by their ability to produce
cutaneous blisters resembling “burns.” In the 1980s, the
conflict between Iraq and Iran displayed the most open and
widespread use of chemical weapons on a battlefield in
recent decades. Although sulfur mustard is the most impor­
tant vesicant militarily, the vesicant category includes other
agents, such as lewisite and phosgene oxime. These com­
pounds affect not only the skin but also all epithelial tissue
with which they come into contact, particularly the eyes
and respiratory tract. Although most physicians are unlikely
to encounter casualties of chemical weapons, the prolifera­
tion of these agents has increased the risk to both military
leads to shortened hospital stays.31,32 Information regarding
the grafting of radiation burns is not yet available but is
probably best delayed. Dubos et al. performed early excision
and grafting of burns in irradiated monkeys, showing that
healing occurred fully by the end of the second week,
although histologically, there was a slight delay in the
healing process.33 Blood loss in excess of 300 mL/% TBSA
excised presents an increased anesthetic hazard and should
be monitored closely. In irradiated tissue that is severely
injured, definitive management often involves radical local
resection and reconstruction with well-vascularized nonir­
radiated tissue, usually from a distant site. Research sug­
gests injections of human mesenchymal stem cells may
have a role in the treatment of local radiation-induced
tissue injury.34
TREATMENT OF COMPLICATIONS
Hematologic
Blood and platelets are administered to maintain an ade­
quate hemoglobin concentration and a platelet level of 20
× 109/L. If surgery is contemplated, this level should be
raised to 75 × 109/L. All blood products should be irradiated
to avoid graft-versus-host disease.
Bone marrow transplantation is the treatment of choice
after total-body irradiation. It should be performed between
3 and 5 days postexposure as the immunosuppression is at
its peak.
The proliferation and differentiation of residual hemato­
poietic stem and progenitor cells can be stimulated. Admin­
istration of antiapoptotic cytokine combinations such as
stem cell factor, Flt-3 ligand, thrombopoietin, and
interleukin-3 may assist recovery, if administered early.35
Moreover, hematopoietic growth factors such as granulo­
cyte colony-stimulating factor (G-CSF) and granulocyte–
macrophage colony-stimulating factor (GM-CSF) have been
recommended based on improved survival rates in irradi­
ated primates and reduced neutropenia in humans after
accidental irradiation.36,37
Infection
The immunosuppression associated with irradiation makes
the victim susceptible to exogenous and endogenous
7000
2000
3000
4000
5000
6000
1000
0
8
16
24
IVF
Ceralyte
Parkland estimate
Urine
Volume (mL)
Time postburn (h)
Fig. 41.1  The addition of oral resuscitation reduces overall intravenous
fluid (IVF) requirements.

41  •  Radiation Injuries and Vesicant Burns
420
fluid and leaving painful shallow ulcers. Greater exposure
produces coagulative necrosis of skin, with either no blister­
ing or “doughnut blisters” surrounding a central necrotic
zone.39 This will be accompanied by severe conjunctivitis,
corneal erosion, and necrotizing bronchitis. A secondary
respiratory infection may develop over the next few days,
coupled with associated bone marrow suppression, which
may be fatal. Higher doses can lead to severe stem cell sup­
pression, pancytopenia, and involvement of the GI tract
with effects ranging from nausea and vomiting to severe
hemorrhagic diarrhea. Excitation of the central nervous
system, resulting in convulsions, has been reported.41
Lewisite (2-chlorovinyl-dichlorarsine) is the best known
arsine. It is more powerful than the mustards, and symp­
toms occur sooner. Eye irritation is produced immedi­
ately, and sneezing, salivation, and lacrimation occur
sooner. Nonlethal chronic exposure may lead to arsenical
poisoning.
Exposure to phosgene oxime, the most common haloge­
nated oxime, has the immediate effect of stinging, compa­
rable to contact with a stinging nettle.42 Within 1 minute,
the affected area becomes swollen, and solid lesions resem­
bling urticaria are seen. An eschar will form after 1 week,
but healing is often delayed beyond 2 months. Contamina­
tion of the eyes is extremely painful and may result in per­
manent blindness. Inhalation causes irritation and
coughing, hypersecretion, and pulmonary edema.42
Ghanei et al. reviewed 355 survivors and 108 deaths
from exposure to sulfur mustard during an attack on Sar­
dasht, Iran, in July of 1987. Their data revealed that mor­
tality from exposure to this agent occurs in two waves.
Initial deaths happened in the first 2–3 days after contact
and were due mostly to respiratory involvement. The second
wave of deaths occurred 1–3 weeks after contact and were
attributed to respiratory distress syndrome or infection
(pneumonia, septic shock, or wound infections). The
authors suggest that patients should be kept in the intensive
care unit (ICU) setting for the initial 4 weeks after contact
and that antibiotic therapy be continued for at least the first
2 weeks of treatment.43 Fig. 41.2 demonstrates numerous
vesicles and a crusting rash after exposure to a sulfur
mustard agent.
ACUTE TREATMENT FOR EXPOSURE TO A
VESICANT AGENT
Butyl rubber gloves, boots, and a respirator are effective
forms of prophylaxis. The first priority in treatment is to
eliminate contact with the agent and initiate decontamina­
tion. During this procedure, attendants should also be suit­
ably protected and contaminated clothing sealed in special
containers to minimize self-endangerment. After clothing is
removed, the skin is gently washed with soap and water.44
At the initial encounter, eyes should be irrigated with
copious quantities of water and the patient referred for oph­
thalmologic expertise.
Symptomatic relief is pivotal. Systemic analgesics can be
started immediately and itching treated with sedatives (ben­
zodiazepines or phenothiazines) and antipruritic agents.
Dimercaprol (British antilewisite), a chelating agent, is a
specific antidote for lewisite poisoning. It is of note that it is
incompatible with silver sulfadiazine. It is available as an
and civilian populations. They are likely to require expertise
found in burn centers; for this reason, an account of the
management of these injuries is included in this text.38
Chemical warfare was first introduced on a large scale
during World War I, 100 years ago, when sulfur mustard
(bis[2-chloroethyl]sulfide) and other agents were used
extensively with devastating consequences in trench
combat. The International Chemical Weapons Convention,
an arms control treaty to ban and destroy chemical weap­
onry, was signed and ratified by 192 countries, entering
into force in 1997, although the worldwide stockpile has
not been deactivated and dismantled. The low technology
required to manufacture the agents, easy stockpiling, and
difficulty in detection cause vesicant agents to pose a con­
tinued major threat to civilians and military personnel.
MECHANISMS OF ACTION
The mechanism of action of mustard has eluded identifica­
tion; however, most of the toxic effects are believed to be
related to alkylation of DNA and critical target molecules.
The DNA cross-links, which prevent replication and repair
of DNA, ultimately lead to cell death. The dermal–epidermal
separation, which causes the skin lesions, is believed to be
due to release of proteases and other enzymes. Breakage of
anchoring filaments connecting the basal cell layer to the
basement membrane results in a blister with the basement
membrane on its dermal side.39
CLINICAL FEATURES
Early symptoms ascribed to mustard gas include ocular
photophobia and a feeling of suffocation associated with
hoarseness and rhinorrhea with a burning throat.40 After
4 hours, erythema is seen; in 12 to 48 hours, blistering
appears accompanied by severe pruritus, which has a pre­
dilection for moist areas such as the axilla and perineum.
The blisters tend to rupture, discharging an amber serous
Fig. 41.2  Photograph of a child injured in the attack on Sardasht in
1987. (From Ghanei M, Aslani J, Khateri S, Hamedanizadeh K. Public health
status of the civil population of Sardasht 15 years following large-scale
wartime exposure to sulfur mustard. J Burns Surg Wound Care 2003;2(1):7-
18, with permission from ePlasty, formerly Journal of Burns and Wounds.)

41  •  Radiation Injuries and Vesicant Burns
421
otherwise, hyperpigmentation tends to predominate. Acute
and severe exposure can also lead to chronic skin ulcer­
ation, scar formation, and the development of skin cancer.39
Recurrent or persistent corneal ulceration can occur
after latent periods of 10–25 years. Chronic conjunctivitis
and corneal clouding may accompany this delayed
keratopathy.50
Clinical follow-ups on 200 Iranian soldiers who sustained
injuries from mustard during the Iran–Iraq War indicate
that about one third had experienced varied respiratory ail­
ments, such as chronic bronchitis, asthma, recurrent pneu­
monia, bronchiectasis, and even tracheobronchial stenosis,
more than 2 years after exposure. Some 12% of all British
soldiers exposed to mustard in World War I were awarded
disability compensation for respiratory disorders believed to
have been caused by mustard exposures during combat.51
SUMMARY
The vesicant agents are perhaps poorly named because they
have the ability to affect all epithelial surfaces, particularly
the eyes and respiratory surfaces, and not just the skin. The
most important vesicant is sulfur mustard, which acts as an
alkylating agent, causing a series of clinical reactions
ranging from vesicles to severe skin necrosis. Systemic
effects are seen with high doses, and the combination of
depressed bone marrow activity and respiratory involve­
ment often proves fatal. There is no effective antidote, and
treatment depends on prevention of contact and local
therapy to achieve wound healing, which tends to be slow.
There is no risk to the caregiver from the blister fluid, which
contains no active agent. Treatment may require respira­
tory care in an ICU setting for upwards of 4 weeks, as well
as several weeks of IV antibiotic therapy.
Complete references available online

Further Reading
Graham JS, Chilcott RP, Rice P, et al. Wound healing of cutaneous sulfur
mustard injuries: strategies for the development of improved therapies.
J Burns Wounds. 2005;4:e1.
Kramer GC, Michell MW, Oliveira H, et al. Oral and enteral resuscitation
of burn shock: the historical record and implications for mass casualty
care. Eplasty. 2010;10:pii, e56.
Kucan JO. Hiroshima and Nagasaki: Review of the consequences: implica­
tions in the post 9/11 world. J Burns Surg Wound Care [serial online].
2004;3(1):8.
Nenot JC. Medical and surgical management for localized radiation inju­
ries. Int J Radiat Biol. 1990;57:784.
ointment for skin lesions, as drops for eye applications
(5–10% in oil), and in an intramuscular preparation for
systemic toxicity. Other readily available chelating agents
are:
■ DMSA—mesodimercaptosuccinic acid
■ DMPS—2,3-dimercapto-1 propanesulfonic acid sodium
■ DMPA—N-(2,3-dimercaptopropyl) phthalamidic acid.
These have a high therapeutic index, are water soluble,
and are effective orally. There is no specific antidote to
mustard poisoning, and no pretreatments or treatments
exist that provide practical or effective protection against
mustard toxicity.39,45
Patients experiencing cutaneous injuries, erythema cov­
ering more than 5% TBSA in noncritical areas (face, hands,
perineum) require hospitalization. The systemic fluid
derangement is less severe than that seen with thermal
burns; however, patients should be carefully monitored.
Fluid requirements in Iranian casualties during the Iran–
Iraq war appeared to have been relatively independent of
affected TBSA.
Blisters should be deroofed and dressed with topical anti­
microbials. The mustard blister fluid is harmless.46 Favor­
able outcomes have now been demonstrated in a pig model
by use of various debriding techniques and resurfacing
with split-thickness skin grafts. Such methods have included
laser, dermabrasion, sharp surgical excision, and enzymatic
debridement.38,47,48
Respiratory injury requires symptomatic treatment
according to its severity. Inhalation of high-dose steroids is
controversial at present. Severe exposure will lead to agran­
ulocytosis or aplastic anemia.49 The pancytopenia seen
after 7 days with the Iranian casualties did not appear to be
helped by transfusion of relevant blood products. Bone
marrow transplantation may prove useful, although of
little practical value with large numbers of casualties. The
effect of bone marrow stimulants such as oxymetholone
and lithium carbonate is unknown but may be considered.
Fluid replacement may be carried out dynamically with
adequate cardiovascular monitoring. The maximum fluid
loss occurs during blister formation and not necessarily in
the first 24 hours.
LONG-TERM EFFECTS OF ACUTE EXPOSURE
Individuals who sustain mustard injury may experience dif­
ficulties after the initial effects of the injury have subsided.
Destruction of melanocytes leave hypopigmented areas;

421.e1
41  •  Radiation Injuries and Vesicant Burns
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43. Ghanei M, Aslani J, Khateri S, Hamedanizadeh K. Public health status
of the civil population of Sardasht 15 years following large-scale
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44. Eldad A, Weinberg A, Breiterman S, et al. Early nonsurgical removal
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46. Sulzberger MB, Katz JH. The absence of skin irritants in the contents
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47. Rice P The use of dermabrasion to accelerate the naturally slow rate
of epidermal healing mustard injuries in pigs. In: Proceedings of the
1995 NATO Research Study Group 3 Meeting on Prophylaxis and
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48. Graham JS, Schomacker KT, Glatter RD, et al. Bioengineering methods
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2016.

422
Exfoliative Diseases of the
Integument and Soft Tissue
Necrotizing Infections
SHAWN P. FAGAN, JOSHUA CARSON, CARLOS JIMENEZ, JIAKE CHAI, MARCUS SPIES,
MAUREEN HOLLYOAK, MICHAEL J. MULLER, CLEON W. GOODWIN, and
DAVID N. HERNDON
42 
only slightly higher at 1–7 cases per million persons per
year.5–10 This incidence is similar to 1.89 cases of TEN per
million persons per year reported for Europe in 1996, but
higher than reported for Asia.11,12 The overall rarity of this
disease process has been, and continues to be, a barrier to
research. However, over the past several decades, the con­
centration of physician experience with TEN into a limited
set of regional burn centers has facilitated an increasing
quantity and quality of active research.
These exfoliative disorders occur in all age groups;
however the incidence is increased in the elderly and
females.3,13–17 In addition, TEN has been linked to certain
infectious disease processes. The annual incidence of TEN
in the human immunovirus (HIV)-infected population is
1000-fold higher than in the general public.18 Whether this
increase is due to their immunocompromised state or to the
increased prescription of high-risk drugs, particularly sul­
fonamides, is debated.19,20 However cases with no drug
history or preceding illness have been reported. An addi­
tional infectious disease process associated with SJS/TEN is
Mycoplasma pneumonia. Finally idiopathic cases not related
to drugs account for 3–4% of TEN.6,7
Prognosis, Morbidity, Mortality
On the surface, these exfoliative disorders may mimic the
symptoms of a partial-thickness thermal injury, specifically
in relation to the involvement of the skin. However these
diseases also affect all epithelial surfaces, thus increasing
the risk and incidences of infections, other complications,
and death. Patients suffering from particularly complicated
cases of SJS may benefit from the expertise of a burn center,
although these patients are generally referred on an as-
needed basis. In contrast, those diagnosed with TEN carry
a specific set of severe and complicated medical needs that
are clearly best addressed in the context of a specialized
burn center.
Mortality of TEN ranges from 25% to 80%, with morbid­
ity being reported as high as 65%.21 However reports are
variable and usually based only on small patient popula­
tions.17,22,23 Death may occur early in the course of the
disease, with sepsis being the most frequent cause. Pseudo­
monas aeruginosa and Staphylococcus aureus are the predom­
inant organisms involved.17 Pulmonary embolism and
gastrointestinal hemorrhage are other causes of death.
Mortality is increased significantly in those patients at
the extremes of age and in relation to the percentage of
Introduction
Acute, severe, exfoliative and necrotizing diseases of skin
and underlying structures may cause significant morbidity
and mortality in the afflicted patient. The problems associ­
ated with these diseases, such as wound infection, sepsis,
inadequate nutrition, and pain, are similar to those seen in
patients with major burns. Thus burn centers, with their
multidisciplinary teams, have been advocated to provide the
treatment and management for this unique, critically ill
patient population. This chapter describes the pathophysi­
ological processes of severe exfoliative skin disorders, their
diagnosis, and the specialized treatment offered by burn
centers.
Severe Exfoliative Disorders
This classification of exfoliative diseases of the skin and
mucous membranes historically consisted of three specific
maladies, distinguished by the amount of skin involvement:
erythema multiforme major (EM), Stevens–Johnson syn­
drome (SJS), and toxic epidermal necrolysis (TEN). For the
terms of this chapter, we are maintaining that approach.
However, some recent classifications list EM as its own dis­
tinct disease entity separate from SJS and TEN and most
commonly associated with the herpes simplex.1 This new
designation does not affect the classifications of SJS and
TEN: Each are still determined by the extent of total body
surface (TBSA) affected by the disease process. SJS is con­
sidered to affect <10% total body surface area (TBSA),
whereas TEN covers >30% TSBA, leaving a zone of overlap
between 10% and 30% TBSA, which is referred to as SJS/
TEN.1,2 The most common characteristics of these disease
entities are defined in Table 42.1.3,4
Toxic Epidermal Necrolysis
EPIDEMIOLOGY
TEN represents the severe extreme of the spectrum of
necrolytic disorders. A rare disease, the incidence of TEN in
this country is estimated at 0.4–1.9 cases per million
persons per year and that of SJS has been reported to be

42  •  Exfoliative Diseases of the Integument and Soft Tissue Necrotizing Infections
423
SJS is associated with a mortality rate of 0–38%.14,28 EM
rarely causes death.29
ETIOLOGY
Keratinocyte apoptosis and secondary epidermal necrosis
represent the pathopneumonic cellular process of TEN. The
origins of the cellular process remain an active area of
research, with an intricate meshwork of overlapping risk
factors and processes starting to emerge as the picture
sharpens. What has become clear is that the TEN disease
process results from a complicated interaction of multiple
processes and risk factors: genetic predisposition, environ­
mental triggers, immunologic reaction, inflammatory
mediators, and cellular apoptotic machinery.
Triggers and Risk Factors
TEN appears to be driven by immunological reactions to
foreign antigens, often referred to as “triggers.” Medications
are by far the most commonly identified trigger, implicated
in 77–94% cases of TEN. Antimicrobials, anticonvulsants
analgesics, and nonsteroidal antiinflammatory agents of
the oxicam type have been implicated.6,16 Naturally the par­
ticular profile of TEN instigators will vary from population
to population depending on the epidemiology of medication
exposures in any given population.
Attempts to identify drugs suspected of having caused
exfoliative necrolysis by skin test and laboratory tests seldom
have been successful.17 While some assays are trialed in
research settings, there are currently no fully vetted, reli­
able methods available for identifying the inciting trigger in
a patient with TEN. Historically the medication-specific
trigger for any given case of TEN was ultimately a matter of
speculation. However Sassolas et al. in 2010 developed an
algorithm of drug causality for epidermal necrolysis termed
ALDEN. The algorithm assigns a score of 1 to 10 for each
drug based on six parameters.32 The score is then catego­
rized as very probable (>6), probable (4–5), possible (2–3),
denuded skin and serum urea nitrogen levels.17,22,24 Bastuji-
Garin et al. in 2000 created the Score of Toxic Epidermal
Necrolysis (SCORTEN), a scoring system to predict mortal­
ity in the adult population presenting with TEN. The scoring
system uses seven independent risk factors to predict mor­
tality by allotting 1 point for each variable:25
a. Age older than 40
b. Heart rate greater than 120 beats per minute
c. Comorbid malignancy
d. Epidermal detachment of greater than 10% of body
surface area (BSA) on day 1
e. Blood urea nitrogen of greater than 28 mg/dL
f. Glucose of greater than 252 mg/dL
g. Bicarbonate less than 20 mEq/L.
The scoring system should be performed on day 1 and day
3 postadmission to maximize its predictive value. Mortality
from TEN increases from 3.2% for a score of 0–1 to 90% for
a score greater than 5 (Table 42.2).
While originally developed for adults, the scoring system
has been validated in the pediatric population, but overall
has been challenged for its lack of incorporating no more
than one morbidity (malignancy) in its calculation.26,27
While other investigators have developed formulas based on
logistic regression analysis, the SCORTEN system is the
most widely utilized.
Table 42.1  Characteristics of Erythema Multiforme, Stevens–Johnson Syndrome, and Toxic Epidermal Necrolysis
Erythema Multiforme
Stevens–Johnson Syndrome
Toxic Epidermal Necrolysis
Prodrome
Absent
High fever, malaise
High fever, malaise
Acute phase
4–8 days
4–8 days
Sensation of skin burning or
tenderness
Sudden onset, 1–2 days
Sensation of skin burning or
tenderness
Skin lesions
Symmetrical, primarily located on the
extremities, some target lesions
without blisters
Variable distribution, individual
vesicles on an erythematous
base <10% TBSA
Nikolsky’s positive
Diffuse generalized epidermal
detachment, absence of
target lesions, large confluent
plaques >30% TBSA
Nikolsky’s positive
Mucosal involvement
Limited to one surface, usually oral
Severe, two or more surfaces
involved
Severe, two or more surfaces
involved
Histopathology
Dermoepidermal separation,
mononuclear perivascular cell infiltrate,
small areas of epidermal detachment
associated with target lesions
Dermoepidermal separation,
more intense dermal infiltrate,
areas of epidermal detachment
Epidermal necrosis,
dermoepidermal separation,
minimal dermal inflammatory
infiltrate, large areas of
epidermal detachment
Recovery
1–4 weeks
1–6 weeks
1–6 weeks
Mortality
0%
0–38%
25–80%
Table 42.2  SCORTEN Scores and Mortality
SCORTEN (Sum of Scores)
Predicted Mortality
0–1
3.2%
2
12.1%
3
35.8%
4
58.3%
>5
90%

42  •  Exfoliative Diseases of the Integument and Soft Tissue Necrotizing Infections
424
cause of EM and SJS, but not TEN.14,37,38 Quantifying the
association between TEN and antecedent viral syndromes
is complicated by the rarity of TEN and the similarities
between prodromal symptoms and other more common
disorders. This leads to patients presenting with relatively
prominent prodromal symptoms who are typically misdiag­
nosed as having a simple viral syndrome. Because of the
delay between early prodromal symptoms and the more
specific TEN rash, it is often impossible to determine in
retrospect whether the pertinent symptoms were actu­
ally prodromal or if the patient had an antecedent viral
infection. Furthermore, these prodromal symptoms are
often treated with medications before the TEN diagnosis
is considered. As such, medications used to treat pro­
dromal symptoms are frequently misinterpreted as TEN
triggers.
unlikely (0–1), and very unlikely (<0) (Table 42.3).32 The
results of this algorithm were compared to a case-controlled
analysis of the European Study of Severe Cutaneous
Adverse Reactions (EuroSCAR) and found to have good
accordance.32,33 The use of ALDEN in the clinical setting
may greatly improve the ability for clinicians and research­
ers to link medication-specific triggers and TEN.32
While advances have been made in correlating medi­
cations as the causative agent of TEN, the role of
nonmedication triggers in the etiology of TEN remains
murky. Upper respiratory tract infections, pharyngitis,
otitis media, or viral illness are frequently reported as
preceding or coinciding with the development of TEN in
some patients.13–15,34–36 Mycoplasma pneumoniae and herpes
viruses (cytomegalovirus, Epstein–Barr virus, herpes
simplex, and varicella zoster) have been implicated in the
Table 42.3  Algorithm of Drug Causality for Epidermal Necrolysis (ALDEN)
Criterion
Values
Rules to Apply
Delay from initial drug
component intake
to onset of reaction
(index day)
Suggestive +3
From 5 to 28 days
−3 to 3
Compatible +2
From 29 to 56 days
Likely +1
From 1 to 4 days
Unlikely −1
>56 Days
Excluded −3
Drug started on or after the index day
In case of previous reaction to the same drug, only changes for:
Suggestive: +3: from 1 to 4 days
Likely: +1: from 5 to 56 days
Drug present in the
body on index day
Define 0
Drug continued up to index day or stopped at a time point less
than five times the elimination half-lifea before the index day
−3 to 0
Doubtful −1
Drug stopped at a time point prior to the index day by more than
five times the elimination half-lifea but liver or kidney function
alterations or suspected drug interactionsb are present
Excluded −3
Drug stopped at a time point prior to the index day by more than
five times the elimination half-lifea, without liver or kidney
function alterations or suspected drug interactionsb
Prechallenge/
rechallenge
Positive specific for disease and drug: 4
SJS/TEN after use of same drug
−2 to 4
Positive specific for disease and drug: 2
SJS/TEN after use of similarc drug or other reaction with same
drug
Positive unspecific: 1
Other reaction after use of similarc drug
Not done/unknown: 0
No known previous exposure to this drug
Negative −2
Exposure to this drug without any reaction (before or after
reaction)
Dechallenge
Neutral 0
Drug stopped (or unknown)
−2 or 0
Negative −2
Drug continued without harm
Type of drug
(notoriety)
Strongly associated 3
Drug of the “high-risk” list according to previous case–control
studies30–32
−1 to 3
Associated 2
Drug with definite but lower risk according to previous case–
control studiesd
Suspected 1
Several previous reports, ambiguous epidemiology results (drug
“under surveillance”)
Unknown 0
All other drugs including newly released ones
Not suspected −1
No evidence of association from previous epidemiology stud with
sufficient number of exposed controlsc
Intermediate score = total of all previous criteria
−11 to 10
Other cause
Possible −1
Rank all drugs from highest to lowest intermediate score
−1
If at least one has an intermediate score >3, subtract 1 point from
the score of each of the other drugs taken by the patient
(another cause is more likely)
Final score
−12 to 10
<0, Very unlikely; 0–1, unlikely; 2–3, possible; 4–5, probable; ≥6, very probable.
ATC, anatomical therapeutic chemical; SJS, Stevens–Johnson syndrome; TEN, toxic epidermal necrolysis.
aDrug (or active metabolite) elimination half-life from serum and/or tissues (according to pharmacology textbooks, tentative list available in complementary
table), taking into account kidney function for drugs predominantly cleared by kidney and liver function for those with high hepatic clearance.
bSuspected interaction was considered when more than five drugs were present in a patient’s body at the same time.
cSimilar drug = same ATC code up to the fourth level (chemical subgroups), see Methods.

42  •  Exfoliative Diseases of the Integument and Soft Tissue Necrotizing Infections
425
Immunopathology
Multiple lines of evidence point to T cells as critical effectors
of the TEN process. T cells are the predominant cell type
found in the blister fluid and exudate of patients with acute
TEN.55
Suppression or cytotoxic T-cell infiltrates are observed in
the epidermis in TEN.56,57 The observation of blebbing of the
keratinocyte plasma membrane in TEN is considered a reli­
able morphological finding of cytotoxic T-lymphocyte cytol­
ysis.57 Serum and exudate levels of markers of T-cell
activation have been shown to correlate with disease activ­
ity and resolution.58–61
TEN is perhaps best understood as an immunologically
mediated burn. For the most part, TEN resembles a classic
type IV (delayed) hypersensitivity disorder. The delay
between exposure and reaction, the critical role of T cells,
and the accelerated reaction reported in cases of re-exposure
to an initial trigger all favor this characterization.39,62 While
some have pointed to immunofluorescence microscopy
findings of IgM and C3 deposited along the dermoepidermal
junction and dermal vessels in cases of postherpetic SJS and
EM as evidence of an associated type II hypersensitivity
reaction, others attribute this to simple nonspecific exuda­
tion.36,63–65 The exact antigen that activates the T-cell recep­
tor varies depending on the specific trigger agent: the
recognized moiety could be a molecule within the medica­
tion, a byproduct of agent metabolism, or a complex formed
between an endogenous peptide and either of the preced­
ing. Keratinocyte apoptosis is central to the pathogenesis of
TEN. This event is thought to be mediated by ligand/receptor
interaction of the tumor necrosis factor (TNF) superfamily
(as TNF-α/TNF receptor or FasL/Fas interaction).66,67
Through a series of experiments, Viard et al. observed, in
vitro, that TEN patients expressed lytically active Fas ligand
and that the action of this ligand could be blocked by both
a monoclonal antibody and human immunoglobins.68 In
SJS, keratinocyte DNA fragmentation has been found in
about 90% of cases associated with dermal perforin-positive
lymphocytes.39,69
CLINICAL PRESENTATION
A prodromal phase of TEN is frequently identifiable in ret­
rospect and usually characterized by some combination of
low-grade fever, malaise, cough, conjunctivitis, and dysuria.
These symptoms typically precede any cutaneous manifes­
tation by 1–21 days, but usually last for 2–3 days.1,14 This
prodrome precedes the development of a frank rash,
although patches of tender erythema and inflamed mucosal
membranes are sometimes present. Skin involvement
usually begins with subtle patches of tender erythema and
localized morbilliform eruptions or discrete erythematous
or purpuric macules. Later vesicles and large bullae emerge
from areas of erythema, either en masse or via coalescence
of initial morbilliform eruptions. On light digital pressure,
the epidermis desquamates in sheets: Nikolsky’s sign is posi­
tive (Fig. 42.1). The TEN rash is extremely painful, even
when bullae are still intact. Generally, a lag period of 1–3
weeks is observed from initiation of drug until skin erup­
tion, but this may be shorter, particularly in cases of re-
exposure in a previously sensitized individual.1,2,17
Genetics
Genetics clearly plays an important role in the pathophysi­
ology of TEN, with multiple alleles identified as potent risk
factors. Interestingly, the genetic risk factors identified thus
far all appear to be trigger-specific. That is, a particular
allele may place a person at risk for developing TEN in
response to one drug, but not increase that same person’s
risk for developing TEN in response to a different medica­
tion.39 The majority of those alleles identified thus far
appear to increase risk through two separate mechanisms:
drug–antigen metabolism and antigen presentation. As
early as 1986, Shear et al. identified a pattern of “slow”
sulfonamide metabolism in patients with a history of severe
cutaneous sulfonamide reactions. Insights and technolo­
gies developed through the maturation of the field have
allowed pharmacogeneticists to trace such associations
with polymorphisms in genes encoding for components of
the cytochrome P450 machinery. Investigators studying
TEN patients’ genotypes have assembled a sizable catalog
of cytochrome P450C variants that convey an increased
risk for developing TEN, with each polymorphism associ­
ated with a specific trigger agent.40–46 The largest family of
genes with a documented association with TEN include
polymorphisms at a number of HLA loci that have been
associated with drug-specific risks for TEN. These polymor­
phisms presumably alter the morphology of the HLA mol­
ecules on antigen-presenting cells, making them more or
less inclined to “recognize” a particular antigen. The
“antigen” may be the medication molecule, a drug metabo­
lite, a byproduct of drug metabolism, or a hapten created
by the binding of the drug, metabolite, or byproduct to
another peptide.47
The clinical application of these genetic markers is com­
plicated by the fact that their predictive value varies widely
when applied to populations of different ethnic makeups.
An example of this strong association between HLA, drug
sensitivity, and ethnic background was discovered by Chung
et al.48 They demonstrated a strong association between
HLA-B*1502, SJS, and carbamazepine in Han Chinese. This
unique relationship was later observed in a Thai popula­
tion, but was absent in the Japanese and European
populations.49–52 In fact, RegiSCAR, a large European study,
suggested that HLA-B*1502 is not a marker for carbamaze­
pine, sulfamethoxazole, lamotrigine, or NSAID oxicam-
type-induced SJS or TEN.52,53
Although the HLA-B*1502 and carbamazepine associa­
tion demonstrated significant ethnic variance, this is not the
observation for all HLA–medication interactions. A second
strong relationship among HLA, drug sensitivity, and SJS/
TEN was observed for allopurinol and HLA-B*5801.54 While
the strength of the relationship continued to vary between
ethnicities, the correlation persisted in Han Chinese, Japa­
nese, Thai, and Europeans, unlike for HLA-B*1502 and
carbamazepine.
In summary, for many of these markers, prevalence pat­
terns make the marker too rare to function as a screening
tool outside the context of specific ethnicities. Beyond issues
of prevalence, some markers are associated with a TEN
reaction in one population, but not in another: a phenom­
enon that likely traces to interactions between the “maker”
allele and other genetic variables.

42  •  Exfoliative Diseases of the Integument and Soft Tissue Necrotizing Infections
426
of the lesion (Fig. 42.2). Advancing edges of the target
lesions show scattered necrotic keratinocytes in the epi­
dermis and only mild dermal inflammation. In older
lesions and central zones of target lesions, the dusky
appearance corresponds to areas of extensive keratino­
cyte necrosis, often with the formation of subepidermal
C
B
A
Fig. 42.1  (A–C) Nikolsky’s sign. Epidermal separation induced by gentle pressure on the skin surface.
Fig. 42.2  Toxic epidermal necrolysis (TEN) is characterized by massive
sloughing of the epidermal tissue.
Mucosal involvement is extremely common in TEN, with
two or more areas typically involved. These mucosal lesions
are often most problematic in that they can cause signifi­
cant immediate and long-term complications and typically
persist
(symptomatically)
longer
than
cutaneous
lesions.6,16,17 Site involvement usually follows this order of
frequency: oropharynx (93%), ocular (78%), genitalia
(63%), and occasionally the anal mucosa.70
Mucosal involvement precedes skin lesions by 1–3 days
in one-third of cases.16,71 As such, any case presenting with
skin involvement with no mucosal involvement should raise
the suspicion for an alternative diagnosis. However it should
be noted that detection of mucosal involvement often
requires a significant index of suspicion: the fulminant skin
findings can frequently distract from more subtle mucosal
findings, such as enteral mucosal involvement and bron­
chial involvement, which are often more easily inferred
from symptoms rather than direct visualization.
DIAGNOSIS AND PROGNOSTIC EVALUATION
Histopathology
An early skin biopsy is essential for diagnosis. Skin mani­
festations vary from patient to patient and with the age

42  •  Exfoliative Diseases of the Integument and Soft Tissue Necrotizing Infections
427
and blindness (Fig. 42.3).4,76 Conjunctival scarring may
also result in lacrimal duct destruction, leading to reduced
tear production and keratoconjunctivitis sicca, a Sjögren-
like syndrome. Finally, scar changes can lead to distortion
of eyelid anatomy, which can result in ectropion, entropion,
trichiasis, and symblepharon.14,77
Other systems that may be impacted include:
■ Oropharyngeal: This is common and often results in
pain on chewing, severe dysphagia, and odynophagia
(Fig. 42.4). The mucositis is associated with an increase
in secretions and sloughing mucosa, which can present
an airway concern. Naturally, oropharyngeal involve­
ment can interfere with oral intake, requiring direct
enteral access for an alternate route of feeding. Buccal–
gingiva epithelial fusing can occur, thus demonstrat­
ing the importance of good oral hygiene.
■ Respiratory: Respiratory tract involvement occurs and
is associated with increased mortality.78,79 These com­
plications include diffuse erythema to extensive conflu­
ent tracheal and bronchial erosion covered by fibrinous
exudate. Epiglottal swelling necessitating intubation
has also been reported. However bronchopneumonia
has been found to be the most frequent complication,
occurring in 50% of patients.29,34,79
■ Gastrointestinal: The onset of intestinal symptoms gen­
erally occurs concurrently with the cutaneous
lesions.80 Epidermal and epithelial sloughing may
extend into the gastrointestinal mucosa and may
induce esophagitis with frequent subsequent stricture
formation.81 Gastrointestinal erosions macroscopically
resemble ulcerative or pseudomembranous colitis, and
massive hemorrhage requiring resection has been
reported.
■ Urologic: Male urethral involvement is fairly common,
with visible involvement at the meatus. Long-term
sequelae include urethral stricture and phimosis.
■ Gynecologic: Vulvar involvement appears to be quite
common in female patients, with reported incidences
increasing over the past few decades as increasing
bullae and dermoepidermal separation. The surrounding
erythematous zone shows papillary dermal edema, vascu­
lar dilation with endothelial cell swelling, and perivascular
mononuclear cell infiltrate. Extravasated erythrocytes may
be seen in the surrounding papillary dermis. The reticular
dermis is normal.17,22
Epidermal and dermoepidermal suppressor or cytotoxic T
lymphocytes, in addition to dermal infiltrates of helper T
lymphocytes, have been demonstrated.56,63,72 Hertl has con­
firmed that these epidermal cells are cytotoxic T cells.73
Langerhans cells appear to be reduced in the epidermis,
although numerous dermal macrophages are observed. A
more intense dermal cell infiltrate is present in SJS, espe­
cially in postherpetic cases.38 Dendritic lymphoid cells are
observed, opposed to damaged dermal macrophages and
necrotic keratinocytes. Furthermore, at the point where the
cytoplasmic processes contact the keratinocyte, the plasma
membrane of the keratinocyte is absent. Aberrant expres­
sion of HLA-DR on keratinocytes has been observed, a phe­
nomenon that has been present in many other inflammatory
skin disorders.63,74
COMPLICATIONS
TEN is frequently associated with serious complications. In
many cases, the skin re-epithelializes from the dermal ele­
ments without significant scarring and with long-term
affects typically limited to discoloration.75 Scarring may be
more prominent—and accompanied by contractures—if
the disease progresses due to secondary infection or periph­
eral vasoconstriction from shock or vasopressor use. Nail
plates are frequently lost and nail regrowth may be abnor­
mal or absent.
Complications may also affect mucosal membranes
throughout the body. One of the most severe long-term
complications is ocular sequelae, which occurs in half of
the survivors. Pseudomembranous or membranous con­
junctivitis resulting from coalesced fibrin and necrotic
debris can lead to ocular opacification, secondary infection,
Fig. 42.3  Ocular involvement in toxic epidermal necrolysis (TEN) is
common and can lead to blindness. Early and aggressive ocular care
must be initiated to prevent pseudomembranes. (Arrows demonstrate
membranous conjunctivitis.)
Fig. 42.4  Toxic epidermal necrolysis patient demonstrating significant
oropharyngeal involvement.

42  •  Exfoliative Diseases of the Integument and Soft Tissue Necrotizing Infections
428
reduce metabolic energy expenditure. Heat shields and
infrared lamps are beneficial in patients’ rooms, bathrooms,
and operating rooms.
Stress ulceration prophylaxis is advisable.
Immunomodulation Therapy
Because the pathophysiology of TEN appears to be initially
immunologic, it is logical to consider immunosuppressive
therapy as an early treatment modality. The following sec­
tions will briefly review the literature with regards to use of
corticosteroids, cyclosporine A, intravenous immunoglo­
bins, and thalidomide.
Corticosteroid Therapy.  Corticosteroid treatment of
TEN has produced much controversy. In relation to the
delayed hypersensitivity reaction or antibody-dependent
cytotoxicity theories of pathogenesis, corticosteroids would
seem to be an appropriate form of medical therapy. However
the practice of administering continuous high-dose cortico­
steroid in an attempt to stop the progression of the disease
is widely rejected.14,16,17,78,92,93 Rational assessment of the
benefit of corticosteroids is not possible due to the lack of
randomized, controlled, prospective trials. Many authors
feel that steroids enhance the risk of sepsis, increase protein
catabolism, delay wound healing, cause severe gastro­
intestinal bleeding, prolong hospitalization, and increase
mortality.29,34,90,94 One study found no decrease in the pro­
gression of SJS with steroids, but instead found significant
morbidity.94 In a prospective – although not randomized –
study, increased survival (66%) was seen in matched
patients who did not receive steroids compared to only 33%
survival in those who did receive steroids.34 Pediatric SJS
patients treated with steroids had a longer hospital stay and
a complication rate of 74% compared to 28% in those
without steroids.93 Another study demonstrated 80% mor­
tality associated with steroid therapy, which was reduced to
20% when steroids were withheld. In several studies,
patients with antecedent glucocorticoid therapy before the
onset of TEN showed no significant survival benefit, and
corticosteroid use itself has been linked to an increased risk
for developing TEN.11,31,95,96 Advocates of corticosteroid
therapy suggest that improved results are possible when
steroids are applied in a limited “pulse” dose early in the
course to interrupt the active necrolytic process and limit
complications. Kardaun et al. studied 12 patients over a
10-year period and suggested that short-term dexametha­
sone pulse therapy was safe and may contribute to a reduced
mortality rate.97 This was followed by the largest study of
this approach, the EuroSCAR, which did identify a trend but
not a statistically significant improvement with the early
pulse of systemic corticosteroids.98 Thus corticosteroid
therapy remains controversial in this disease due to the
absence of strong evidence of efficacy.
Cyclosporine A.  Cyclosporine A is an agent that has the
properties of both being a powerful immunosuppressant
and an antiapoptotic. The mechanism of action is inhibi­
tion of the synthesis of interleukin-2 by selective inhibition
of calcineurin, thus arresting the proliferation of T helper
cells.99 In the only case series, Arevalo et al. observed a
significantly shorter time to disease arrest (24–36 h) and
time to re-epithelialization when compared to historical
awareness has resulted in improved detection and
more frequent practice of routine screening exams.
Mucosal erosions are clearly quite painful, and involve­
ment of associated glandular structures can result in
obstruction and dysfunction. Long-term sequelae can
be particularly troublesome. Vaginal wall synechiae
and clitoral hood adhesions can result in significant
dyspareunia and sexual dysfunction.82,83 Vaginal
webbing and synechiae can result in dysfunctional
menstruation with resultant infertility.84–86 Consulta­
tion with a gynecologist is recommended for the major­
ity of these cases.
Systemic and Other Nonmucocutaneous
Complications
Although mucocutaneous erosions are the most common
features of TEN/SJS, the disease may present with multi­
system involvement. Renal manifestations like glomerulo­
nephritis and acute tubular necrosis, as well as hepatitis and
hepatocellular necrosis, have been described.6,16,87 Hypoal­
buminemia, asymptomatic hyperamylasemia, increased
erythrocyte sedimentation rate, leukocytosis, thrombocyto­
penia, and normochromic and normocytic anemia are not
uncommon.29,78 Leukopenia is a frequent and poor prog­
nostic sign.6,17,34 This is due in part to depletion of the T
helper/inducer lymphocyte population (CD4+).88 The white
blood cell count generally returns to normal levels after
2–5 days. The cause of this immunosuppression is unclear.
MANAGEMENT
As previously stated, TEN is a life-threatening disease and
is best managed in a burn ICU where a multidisciplinary
approach, including goal-directed fluid resuscitation and
nutritional support, is utilized.23,34,35,89
General Management and Resuscitation
Drugs suspected of having initiated the disease should be
discontinued immediately. Administration of pain medica­
tion is of high priority, and antipyretic agents may be
required. The use of broad-spectrum antibiotics should be
carefully considered: Neutropenia is the only complication
in which “prophylactic” antibiotics are indicated. Other­
wise systemic antibiotics only should be used for docu­
mented infections or suspected sepsis.
Intravenous replacement of fluid losses through the
exposed body surface is required. However, because patients
do not develop the massive edema and fluid losses evident
in burn patients, fluid resuscitation formulas commonly
employed in the management of thermal injuries overesti­
mate the actual need.90,91 Ringer’s lactate solution is given
at a rate determined by close monitoring of the patient’s
condition, resuscitation indexes, and urine output. Once
wound coverage is accomplished, fluid requirements usually
decrease.
Central line placement should be avoided if possible to
reduce the risk of infection and sepsis. To further minimize
this risk, lines should be placed in areas of uninvolved skin.
Invasive devices are removed as soon as possible, and oral
and nasogastric routes are utilized at earliest convenience.
Environmental temperature should be raised to 30–32°C to

42  •  Exfoliative Diseases of the Integument and Soft Tissue Necrotizing Infections
429
exploring the use of TNF-α antagonists and inhibitors
(infliximab, etanercept, etc.), in the treatment of TEN.108,109
Unfortunately, these new therapies have only been reported
in case reports and thus cannot be supported for routine use
in this patient population.
Until these treatment modalities have proved their effi­
cacy in controlled trials, the gold standard of treatment for
TEN patients consists of a multidisciplinary approach as
used in severe burns, focusing on wound care, infection
control, and prevention of complications.
Surgical Approach.  Débridement of necrotic epidermis
and coverage of the large wound surface with biological or
synthetic dressings have been advocated by several
authors.89,110,111 Sloughed epidermis should be removed in
order to reduce bacterial growth and the risk for infection.
The exposed and tender dermis should be covered. Débride­
ment is best undertaken under general anesthesia as soon
as diagnosis by histology is established. Blood loss associ­
ated with débridement is minimal, so over-resuscitation
must be avoided.
Synthetic dressings, such as Biobrane, and biological
dressings, such as homograft (cadaver allograft) and porcine
xenograft skin, greatly reduce the pain, decrease fluid loss,
and promote healing. Biobrane and similar products should
be used with caution when covering wound areas greater
than 40% TBSA secondary to the increasing incidence of
local infections. Porcine xenograft adheres well to the skin
and is commercially available in large quantities.91,112
Homograft is more likely to become vascularized and there­
fore reduces the number of graft changes.113 However this
must be weighed against the potentially poor cosmetic
results of vascularized homograft (Fig. 42.5). Grafted areas
must be immobilized and protected from shear forces. In
both adults and children, continuous rotation or air fluid­
ized (Clinitron) beds frequently are used.
Topical Therapy.  As separation occurs at the dermal–
epidermal junction, varying depths of viable dermis remain.
If this dermis can be protected from toxic detergents,
controls. This study was followed by a few small studies
suggesting a potential benefit of cyclosporine A. In 2010, a
phase II trial by Valleyrie-Allanore et al. found a treatment
of 3 mg/kg per day of oral cyclosporine for 10 days followed
by a tapering schema over the next month was not clinically
significant.100 However, mortality appeared to be reduced
when compared to predictive mortality. Although intrigu­
ing, the currently published studies do not have similar
methodologies, varying with regards to the dosage admin­
istered, route of administration, and duration of therapy.
Furthermore, cyclosporine A therapy has been associated
with a septicemia rate of 55%.101 Therefore, a well-designed
prospective clinical trial is warranted prior to advocating
the use of cyclosporine A in the treatment of TEN.
Intravenous Immunoglobulin.  Intravenous immuno­
globulin (IVIG) has been suggested as a means of interrupt­
ing the autoimmune process fueling TEN. Furthermore,
some have proposed that pooled human immunoglobins
may contain a Fas blocking antibody, which would directly
disrupt the keratinocyte apoptosis trigger.102 Unfortunately,
clinical data has been conflicting, creating difficulty in
advocating IVIG treatment for TEN. To date, there have been
12 noncontrolled clinical studies examining the efficacy of
IVIG in the treatment of TEN.103–105 Interestingly, the data
suggests that IVIG dosages of greater than 2 mg/kg may be
superior to less than 2 mg/kg. Huang et al. performed a
meta-analysis on the efficacy of IVIG therapy in TEN
patients.106 In adults, the high-dose IVIG group had a
significantly lower mortality rate when compared to the
low-dose IVIG group. However, the multivariate logistic
regression model found the dosing of IVIG did not correlate
with mortality when controlling for age, total BSA involve­
ment, and delay in treatment.21 This finding was supported
by the largest clinical study to date, EuroSCAR, which failed
to demonstrate efficacy of IVIG in the treatment of TEN.98
Despite these findings, some continue to advocate for the
use of high-dose IVIG (3 mg/kg total dose give over 3–4
days) in the treatment of TEN based on the low complica­
tion risk and lack of alternative therapies. As in the case
with cyclosporine A, a well-designed controlled multicenter
clinical trial is warranted prior to advocating the use of
human immunoglobins routinely in the treatment of TEN.
TNF-α Inhibitors, Thalidomide.  The primary mecha­
nism in the pathogenesis of TEN is keratinocyte apoptosis.
Accordingly, TNF-α has been implicated in the pathogenesis
of TEN. Thalidomide, a potent inhibitor of TNF-α, would
appear to be a logical therapeutic agent in the treatment of
TEN. Unfortunately, Wolkenstein et al. had to prematurely
terminate a randomized clinical trial of thalidomide versus
placebo in the treatment of TEN due to excess mortality in
the treatment group.107 Ten of 12 patients expired in the
thalidomide group compared to three of 10 in the control
group. The authors theorized that thalidomide may have
paradoxically increased the production of TNF in the treat­
ment group, a previously reported phenomenon of thalido­
mide administration. Therefore, thalidomide as a treatment
for TEN should not be initiated owing to the detrimental
effects, but this does demonstrate the usefulness of random­
ized, double-blinded, placebo-controlled clinical trials.
Despite the failure of thalidomide, investigators are still
Fig. 42.5  Homograft vascularization occurring over a second-degree
thermal injury, resulting in a poor cosmetic result.

42  •  Exfoliative Diseases of the Integument and Soft Tissue Necrotizing Infections
430
application, and (3) insertion of a scleral shell spacer to
prevent symblepharon formation.115 Regardless of the spe­
cific treatment options taken, involvement of an ophthal­
mologist is clearly indicated.
Although it is not common in TEN, genitourinary
mucosal involvement should be treated acutely with sup­
portive care: pain control, hygiene, and topical treatments
for pain relief and lubrication. Urinary catheterization
needs to be weighed against the clinical stability and clini­
cal scenario of the patient. Does the need for precise urine
output outweigh the risk of increased infections that could
occur with the placement of a catheter? Long-term
sequelae include urethral stricture and phimosis, which
can usually be managed with serial dilation and circumci­
sion, respectively.
Vulvar involvement should also be managed proactively
to minimize symptoms and (theoretically) attenuate the risk
of long-term sequelae. The use of some topical medication
options has been suggested, but none of these is considered
the standard of care at this point. Mechanical treatments
should be considered to prevent prolonged apposition of
opposing inflamed mucosal surface to avoid fusion and syn­
echiae. Vaginal dilators can be used to avoid fusion, although
monitoring and regular changing are necessary to avoid
infection. Finally, menstrual suppression should be consid­
ered to minimize the risk of vaginal adenosis.114 Depending
on the extent and severity of the involvement of the vaginal
area, consider a consultation with a gynecologist.
Nutritional Support
Enteral nutrition should be initiated immediately once the
patient is resuscitated. Due to the frequent presence of oral
mucosal ulcerations, patients may be reluctant to take
nutrition orally and thus require a nasogastric tube place­
ment. Unlike burned patients who have significantly ele­
vated metabolic rates, these patients appear to have
metabolic rates only slightly above basal requirements.
Weight stabilization and a positive nitrogen balance have
been achieved in adults with 2500 kcal/day.90,110
Soft-Tissue Infections and Other
Acute Skin Disorders
Staphylococcal scalded skin syndrome, necrotizing fasciitis,
and purpura fulminans are examples of a group of condi­
tions characterized by extensive soft-tissue loss, rapid onset
of critical illness, and death. Early, accurate diagnosis is
essential to initiate appropriate action, such as extensive
surgical excision in the case of necrotizing fasciitis or crepi­
tant soft-tissue infections. Burn care centers, with their
acute and reconstructive capacities, have much to offer
these patients with extensive skin loss.
STAPHYLOCOCCAL SCALDED SKIN SYNDROME
Staphylococcal scalded skin syndrome is the severe condi­
tion caused by exfoliative staphylococcal toxins and is char­
acterized by systemic signs and symptoms and generalized
involvement of the skin (Fig. 42.6). It is important to make
a diagnosis early, particularly to differentiate it from TEN,
which has a different management and much greater
desiccation, mechanical trauma, and wound infection,
then rapid re-epithelialization by proliferation of basal
keratinocytes from the skin appendages will occur.90 Bacte­
rial proliferation on the unprotected wound surface with
invasive infection leads to full-thickness skin necrosis.
Hydrotherapy and topical antimicrobials provide débride­
ment and infection control that should be initiated early in
the course of the disease. Effective topical antimicrobial
agents include silver sulfadiazine cream, silver nitrate solu­
tion, chlorhexidine gluconate solution, and polymyxin-
bacitracin ointment.16,37,110 While silver sulfadiazine is
widely used, concerns that its sulfonamide component can
exacerbate the disease process remain a theoretic concern
even though these concerns have not been confirmed in the
literature. Additionally, an inhibitory effect on epithelializa­
tion and leukopenia requiring discontinuation has been
observed. Alternatively silver nitrate solution does not con­
tribute to the ongoing drug reaction, and epithelialization
is not inhibited. For patients with contaminated wounds
due to delayed initiation of treatment, silver nitrate soaks
can reduce contamination and prepare the wound for even­
tual biological dressing. Silver nitrate solutions are hypona­
tremic and thus associated with approximately 350 mmol
of sodium loss per day/m2 treated. Serum electrolytes and
osmolarity must be carefully monitored.
Chlorhexidine gluconate and polymyxin ointment are
effective against Gram-negative organisms, including P.
aeruginosa, with low incidence of sensitivity. Moreover,
chlorhexidine gluconate also shows bactericidal effects
against Gram-positive organisms.
Oropharyngeal mouth erosion resulting in severe dys­
phagia can be alleviated by the use of viscous lidocaine or
cocaine rinses and thus ease oral administration of nutri­
ents and fluids. Oral debris should be removed and the
mouth rinsed or sprayed with antiseptic several times a
day.22 Oral nystatin prevents intestinal overgrowth of
Candida and decreases the risk of Candida sepsis.113
Pulmonary involvement requires close supervision, with
careful toileting including bronchoscopy, incentive spirom­
etry, mobilization, and coughing to prevent infections and
complications. If mechanical ventilatory support is neces­
sary, the prevention of bronchopulmonary infection gains
even more importance. Daily monitoring by blood assess­
ment, including blood gas analysis, chest X-ray, and
bacteriological culture, are required to initiate timely anti­
biotic therapy or ventilatory support. Measures to prevent
thromboembolism, such as low-dose or low-molecular-
weight administration of heparin, should be instituted on
admission.
Ocular involvement should be assessed daily by an oph­
thalmologist. Conjunctival crusting can be minimized by
the application of saline eye drops every hour. Any adhe­
sions should be broken using a blunt instrument and bland
eye drops or ointment applied frequently. Documented
ocular infections are treated with organism-specific antibi­
otic therapy. Lacrimal duct obstruction may be detected
early by performing Schirmer’s test. There are a wide range
of ophthalmic treatment options, a review of which would
be beyond the context of this chapter. One reasonable, prac­
tical approach is the “Triple-TEN” protocol described by
Tomlins et al., which includes (1) subconjunctival steroids
to blunt local inflammation, (2) amniotic membrane

42  •  Exfoliative Diseases of the Integument and Soft Tissue Necrotizing Infections
431
Diagnosis
Diagnosis of staphylococcal scalded skin syndrome can be
made rapidly with a skin biopsy. The characteristic intraepi­
dermal level of splitting is seen, with the split occurring at
the granular layer level (stratum granulosum) with no epi­
dermal necrosis or inflammatory cells in the corium. Immu­
nofluorescent studies of the skin are negative. A Tzanck
preparation from a scraping of the base of a freshly denuded
area will reveal the affected cell population (i.e., acantho­
cytic keratinocytes).118 Bullae, denuded skin, and blood are
usually sterile, however, and staphylococci can usually be
cultured from nares, conjunctiva, or pharynx.121
Management
With diagnosis, antibiotics should be started, and semisyn­
thetic penicillinase-resistant penicillin analogs are indi­
cated (e.g., meticillin or oxacillin) since the majority of
group 2 staphylococci show resistance to penicillin. Admin­
istration of steroids to these patients is contraindicated.118
After screening for colonization, decontamination of colo­
nized areas, especially the nasopharyngeal region in
patients and nursing staff, may be advisable to prevent
further spread. Fluid resuscitation is usually required at a
lesser volume compared to a burn patient with a similar
involved BSA. Fluid substitution should be guided by urine
output, hemodynamic parameters, and electrolyte and
colloid status.
Until skin barrier function is restored, patients should
receive appropriate wound dressings to prevent secondary
wound infection. Topical agents are soothing and bacterio­
static. It needs to be pointed out that the wound initially is
not colonized or infected, so alternatively, large areas can
be more effectively managed with biological or synthetic
dressings. They have the advantage of eliminating the need
for frequent dressing changes, which can be particularly
traumatic for young children. Mortality usually is low but
may occur in very young and adult patients, usually from
sepsis or electrolyte imbalance on the basis of underlying
disease.118 Complete wound healing is usually observed
within 7 days, and scarring and altered pigmentation are
not common.
NECROTIZING FASCIITIS AND
BACTERIAL MYONECROSIS
Necrotizing fasciitis is a soft-tissue infection characterized
by widespread necrosis of fascia and subcutaneous tissue,
which may progress to muscle and skin necrosis. Overall
mortality may still be as high as 50%.111,122 Most cases of
necrotizing fasciitis are due to polymicrobial infection
including both anaerobic Gram-positive cocci and Gram-
negative bacilli. Streptococcus, Staphylococcus, Enterococcus,
and Bacteroides are commonly found. Infection with many
bacterial species may result in bacterial myonecrosis.
However, gas gangrene by Clostridia spp. results in severe
systemic toxicity and higher mortality than necrotizing fas­
ciitis. A deep contaminated wound frequently precedes the
severe soft-tissue infection. Streptococcal myositis has a
mortality rate of between 80% and 100%.122,123 Risk factors
for both necrotizing fasciitis and bacterial myonecrosis have
been identified as diabetes mellitus, intravenous drug use,
mortality. Staphylococcal scalded skin syndrome is predom­
inantly a disease of infancy (Ritter’s disease) and early
childhood, with most cases occurring before the age of 5
years.116 Newborn nurseries are often the sites of outbreaks.
Attendant staff may be infected or colonized with Staphylo­
coccus aureus strains producing epidermolytic toxin, thus
emphasizing the importance of standard hygienic mea­
sures. Adult staphylococcal scalded skin syndrome is rare
and usually associated with compromised renal function.
Mortality is generally only 4%, but can be much higher in
adults (40%) depending on underlying diseases.116,117
Pathology
Two distinct epidermolytic toxins (ETA and ETB), are
responsible for the blistering in staphylococcal scalded skin
syndrome.81 ETA is heat-stable, whereas ETB is heat-labile
and encoded by a bacterial plasmid. Most toxigenic strains
of S. aureus are identified as group 2 phage.118 The exfolia­
tive toxin is metabolized and excreted by the kidneys, leading
to a predisposition of patients with renal immaturity (chil­
dren) or renal compromise. The exfoliative toxins produce
blistering by disrupting the epidermal granular cell layers
through interdesmosomal splittings but without epidermal
necrosis and with very few inflammatory cells. The exact
mechanism of action of the toxins has not been determined,
although it is felt that the toxins directly affect desmosomes.
One might be proteolytic disruption of desmosomes with
the toxin or part of its sequence acting as a serine
protease.116,119,120
Presentation
Onset may be marked by fever, malaise, and irritability.
Scarlatiniform erythema is often accentuated in flexural
and periorificial areas. The skin is generally tender to touch,
and sheets of skin may peel away in response to minor
trauma (Nikolsky’s sign). Blisters appear within 24–48 hours
of rupture, leaving a characteristic moist erythematous epi­
dermal base. Severe mucosal involvement is not a typical
feature.
Fig. 42.6  Staphylococcal scalded skin syndrome is characterized by
diffuse, erythematous lesions with bullae formation (see left forearm).
Epidermis is shed in sheets with minimal abrasion. The wounds are
partial thickness and heal without surgical intervention.