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C h ron i c B u r n Wo u n d
Stephen Tyler Elkins-Williams, MDa, William A. Marston, MDb,
Charles Scott Hultman, MD, MBAa,*
KEYWORDS
Chronic wound Hyperbaric oxygen therapy Marjolin ulcer Topical growth factor
KEY POINTS
There exists little evidence to promote or refute the use of hyperbaric oxygen therapy (HBOT) in
acute burn wounds.
Diabetic foot burns could be separately considered, given the body of evidence in chronic diabetic
foot wounds. Further research is necessary to prove the efficacy of HBOT in this setting.
Marjolin ulcers are malignant degeneration of chronic wounds and occur most commonly in unex-
cised full-thickness burns.
Average time from the initial injury to development of a Marjolin ulcer is 30 years. Cancers from Mar-
jolin ulcers tend to be more aggressive than common skin cancers.
There are many cytokine growth factors available for use on burn wounds. Some promising studies
have been performed; additional research will help determine optimum patient selection and treat-
ment regimens.
a
Division of Plastic and Reconstructive Surgery, Department of Surgery, University of North Carolina Medical
Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; b Division of Vascular Surgery,
Department of Surgery, University of North Carolina Medical Center, University of North Carolina at Chapel
Hill, Chapel Hill, NC 27599, USA
* Corresponding author.
E-mail address: Scott_Hultman@med.unc.edu
This article reviews 3 issues pertinent to man- Clostridial myositis and myonecrosis (gas
gangrene)
agement of the chronic burn wound: (1) use of hy-
perbaric oxygen to facilitate wound closure, (2) Crush injury, compartment syndrome, and
application of topical growth factors, (3) and diag- other acute traumatic ischemias
nosis and treatment of Marjolin ulcers. Decompression sickness
Arterial insufficiencies
HYPERBARIC OXYGEN THERAPY
Severe anemia
Introduction
Intracranial abscess
The Undersea and Hyperbaric Medical Society de-
Necrotizing soft tissue infections
fines hyperbaric oxygen therapy (HBOT) as “an
intervention in which an individual breathes near Osteomyelitis (refractory)
100% oxygen intermittently while inside a hyper- Delayed radiation injury (soft tissue and bony
baric chamber that is pressurized to greater than necrosis)
sea level pressure.”1 In clinical practice, this pres- Compromised grafts and flaps
sure typically exceeds 1.4 atm.1
Acute thermal burn injury
The concept of using hyperbaric pressure to
treat patients dates back to 1662; a British cler- Idiopathic sudden sensorineural hearing loss
gyman named Henshaw thought that hyperbaric
pressures could speed healing in acute medical
conditions. He created a sealed chamber that he HBOT can increase the partial pressure of oxygen
named the Domicilium, using organ bellows to in end organ tissues. This elevation is achieved by
control changes in pressure. Henshaw could not increasing the PaO2 of the blood to 10 to 15 times
use isolated elemental oxygen in his treatments, normal, which creates a steep gradient down
however, as it would not be discovered until which oxygen may diffuse into hypoxic tissues.5
more than a hundred years later.2 Theoretically, increasing oxygen tension in burn
Over the course of the late nineteenth and early patients could decrease leukocyte activation,
twentieth centuries, progress was made with the reduce so-called secondary injury, and even
use of oxygen for treatment of decompression sick- reduce tissue edema through an oxygen osmotic
ness, first in normobaric settings and later with the effect.
additional of hyperbaric pressures. But it was not
Evidence in Burns
until 1955 that Churchill-Davidson and colleagues3
published “High-Pressure Oxygen and Radio- Despite this, very little quality research has been
therapy,” using HBOT to potentiate the effects of ra- done on the effectiveness of HBOT on patients
diation therapy in patients with cancer, in The Lancet. with burn injuries. In the 2004 Cochrane review,
Thus began the era of modern HBOT in medicine. Villanueva and colleagues6 found only 2 quality
randomized controlled trials (RCTs) evaluating
Current Uses the effectiveness of HBOT in patients with acute
The use of HBOT quickly expanded to a be used in thermal injuries.6
a wide variety of medical conditions, most of which 1. Hart and colleagues,7 1974: 16 patients, 10%
initially lacked evidence or standard protocols. to 50% total body surface area (TBSA) burns,
The Undersea and Hyperbaric Medical Society randomized to routine burn management and
was founded in 1967 and maintains a current list HBOT or routine burn management with sham
of accepted medical indications for HBOT use, HBOT
one of which is acute thermal burn injury (Box 1).4 a. Intervention: 100% oxygen at 2 atmosphere
absolute (ATA) for 90 minutes every 8 hours
Hyperbaric Oxygen and Burns
for 24 hours, then every 12 hours until healed
The theory behind use of HBOT in burn injuries is b. Mean healing times shorter in the interven-
sound. Animal models have demonstrated that tion group (19.7 days vs 43.8 days, P<.001).
Management of the Chronic Burn Wound 681
c. Method criticisms: did not describe alloca- additional treatments. Those patients who are to
tion concealment methods; no definition of be skin grafted are treated both preoperatively
healing given, and no description of the and postoperatively. Unfortunately, this protocol
wound size and depth at presentation given has only ever been compared against a group of
d. Questionable applicability: skin grafts in less historic controls from the 1970s and 1980s. There
than half of the patients enrolled, calls into are no data currently available that compares
question relevance in the early excision HBOT with standard treatment in patients with dia-
and grafting era betic foot burns.
2. Brannen and colleagues,8 1997: 125 patients
randomized to routine burn management or Challenges
routine burn management plus HBOT There are practical challenges of administration of
a. Intervention: 100% oxygen at 2 ATA for HBOT in burn patients that must be considered.
90 minutes twice a day for a minimum of The most severely injured acute burn patients,
10 treatments, maximum of one treatment those who would stand the most to gain from the
per percent TBSA potential benefits of HBOT, are typically intubated
b. Primary outcome: length of stay and critically ill. The risks of leaving the burn
c. Secondary end points: mortality, acute fluid intensive-care-unit setting and being transported
requirements, number of operations to an HBOT chamber 2 to 3 times daily are not triv-
required ial. Additionally, these types of patients would
d. No statistically significant difference in any require the use of multi-place HBOT chambers to
of these outcomes accommodate nursing and support staff. Multi-
There have been several nonrandomized place chambers are not likely to be as available
comparative studies performed over the years as the cheaper and smaller mono-place chambers
that have suggested improvements with HBOT in more commonly in use.
survival, hospital length of stay, and speed of ree- Summary/Recommendations
pithelization.5 However, multiple investigators
have concluded that there is currently insufficient The theory behind application of HBOT in burn
evidence to either support or refute the use of wounds seems sound, and some early trials have
HBOT in the setting of acute thermal burns.5,6 shown promise. However, to date there is inade-
Any future studies seeking to clinically investi- quate evidence to make judgment on its efficacy.
gate HBOT in acute burn patients will need to There are some practical challenges in administra-
seek to understand the degree, type, and size of tion of HBOT in acute burn patients. Future study,
burn that will see the most benefit. Additionally, likely across multiple centers, will be necessary to
the optimal frequency, duration per session, and determine the optimum patient selection and
overall length of therapy need to be explored. treatment protocol for HBOT use.
Fig. 1. Algorithm for use of HBOT in diabetic foot burns. DM, diabetes mellitus; HbA1c, hemoglobin A1c. (Data
from Jones LM, Rubadue C, Brown NV, et al. Evaluation of TCOM/HBOT practice guideline for the treatment
of foot burns occurring in diabetic patients. Burns 2015;41(3):536–41.)
or nonhealing wounds. The key to successfully us- and investigators a diverse toolbox, the diversity
ing cytokine growth factors in burn wounds is to can also make it difficult to compare and pool
choose the proper growth factors that can speed studies.
wound healing without causing adverse effects.
Types of Burn Wounds
Types of Growth Factor
Further complicating matters are the different
There have been a wide variety of types of cyto- types of wounds with which one might wish to
kine growth factors that have been investigated use a cytokine growth factor. They could be
for burn wounds. These growth factors include applied to partial-thickness burns, full-thickness
platelet-derived growth factor (PDGF), fibroblast burns, the interstices of meshed skin grafts, or
growth factors (FGFs), epidermal growth factors even skin graft donor sites. Ching and col-
(EGFs), transforming growth factor (TGF) alpha, leagues12 performed a very thorough review of
vascular endothelial growth factor, insulinlike available studies, in both animal and human
growth factor I, nerve growth factor, TGF beta, models, investigating the use of the full spectrum
granulocyte-macrophage colony-stimulating fac- of cytokine growth factors. Although their use in
tor (GM-CSF), and amnion-derived cellular cyto- partial-thickness burns comprised most of the
kine solution.12 Although the heterogeneity of the data, studies have been performed in full-
types of available growth factors gives clinicians thickness burns as well as over skin grafts and
Management of the Chronic Burn Wound 683
even to donor sites. There is encouraging evi- directly on the keratinocyte and endothelial cell.
dence for all types of cytokine growth factors in Because deeper structures, such as subcutane-
speeding wound healing. They do note, however, ous fat, muscle, and blood vessels, are spared,
further study to generate high-quality human growth factors targeting these additional tissue
data is warranted. types are likely unnecessary.16
Future Challenges
Current Evidence
There is certainly a theoretic concern for cytokine
There have been several recent high-quality RCTs
growth factors to stimulate oncogenesis. The
demonstrating the effectiveness of EGF and PDGF
mechanisms by which growth factors promote tis-
in simulated partial-thickness burns in animal
sue repair are also those implicated in malignant
models.13,14 In addition, as Zhang and col-
degeneration. Fortunately, tumor development
leagues15 demonstrated, at least 13 RCTs
has not yet been seen in clinical or experimental
have been performed in human subjects. All of
studies.16 Given our knowledge of the latency
these studies were performed in Asia (China and
time for Marjolin ulcers, however, the typical
Japan), and many of them were never published
follow-up time seen in human studies of GFs is
in English. Although the investigators expressed
inadequate to detect future chronic malignant
concern over various methodological flaws in the
changes as an adverse effect.
studies, they did note a consistent positive
improvement in speed and quality of wound heal-
Summary
ing seen with FGF, EGF, and GM-CSF in partial-
thickness burns. Overall, the use of cytokine growth factors, partic-
These particular cytokines are likely suited to ularly FGF, EGF, and GM-CSF, has shown prom-
partial-thickness burns. By definition, the depth ise in speeding the healing of partial-thickness
of a partial-thickness burn is limited to the papillary burns. Additional large trials attempting to deter-
dermis (grade IIa) or reticular dermis (grade IIb). mine the optimum dosage regimen and delivery
FGF and EGF are mitogens for endothelial cells method of GFs will be useful in the future to maxi-
and dermal fibroblasts, whereas GM-CSF works mize patient benefit.
684 Elkins-Williams et al
Box 3
Box 2 Establishing relation of cancer to burn scar
Other conditions potentially leading to
Marjolin ulcer 1. Incontrovertible evidence of the burn (by
wound or scar)
Vaccinations
2. Cancer origin within the boundaries of the
Snake bites burn scar
Osteomyelitis 3. Absence of precursory or similar neoplasm
Pressure sores on the site before the burn
Spinal Cord Injury 4. Histologic type of cancer compatible with
the type of tissue that was burned (ie, SCC,
Pilonidal abscess BCC, and so forth, in burned skin)
Dermatitis artefacta 5. Appropriate interval of time between burn
Venous stasis ulcers injury and development of cancer
Management of the Chronic Burn Wound 685
ulcer. The clinical appearance is most commonly a In developed nations, early excision and grafting
flat, ulcerative lesion with elevated margins and is standard. The patients most at risk for develop-
surrounding induration. They can also appear as ment of Marjolin ulcers are those with poor access
an exophytic lesion resembling granulation tis- to health care. In a recent large series from
sue.11,17,19 There should be a low threshold to Bangladesh, Das and colleagues21 included 140
obtain a biopsy in the appropriate clinical scenario. patients with burn scar ulcers over a 10-year
period, of which 46 (33%) were found to have ma-
Workup and Treatment lignant changes. Of the patients with malignancy,
Once a biopsy confirms the diagnosis, patients 77% had a primary-level education or less. Appro-
should be worked up with staging in accordance priate treatment of deep burns with excision and
with usual oncologic principles. grafting at the time of injury minimizes the future
risk of malignant transformation of resultant scars
There is no TMN staging specific to Marjolin to Marjolin ulcers.
ulcers.
The staging system for the histologic type of Case Report
tumor should be used.
Marjolin ulcers tend to be more aggressive The authors present a 75-year-old woman who
than common skin cancers. had sustained a more than 50% TBSA burn
Metastasis rate of 27.5%14 from a house fire when she was 4 years old.
A thorough lymph node examination should Over the course of 11 months, she developed a
be performed. nonhealing ulcer in the right upper quadrant of
Consider imaging to look for distant her abdominal wall, managed initially by a wound
metastases. care center, with topical growth factors and bio-
Chest radiography logical dressings. Punch biopsy was eventually
Brain computed tomography obtained, revealing a diagnosis of SCC, arising
Abdominal ultrasound or cross-sectional from her burn scar. Physical examination by the
imaging senior author was positive for an ulcerative,
5 8-cm skin lesion (Fig. 3), which was fixed to
Surgery remains the primary treatment of Marjo- the underlying fascia but negative for axillary or
lin ulcers. A wide excision of the primary lesion
should be performed. Most investigators advocate
for at least 2-cm margins,11,17,19 with a split-
thickness skin graft or flap coverage of the wound.
Occasionally, amputation is needed. Most agree
that a prophylactic lymph node dissection is not
indicated. Clinically positive nodes warrant biopsy
and/or lymph node dissection. Some investigators
advocate for a sentinel node biopsy to be per-
formed if nodes are clinically negative. There is
no standard agreed on protocol for the addition
of adjuvant therapies after adequate surgical exci-
sion. Those described include radiotherapy;
chemotherapy with agents, such as topical 5-fluo-
rouracil, methotrexate, and L-phenylalanine
mustard; and intra-arterial limb isolation perfusion
therapy.17 Poor prognosis when compared with
other types of skin cancer is to be expected.
Prevention
Prevention is perhaps the best strategy in treat-
ment of Marjolin ulcers. Allowing burn wounds to
go unexcised and heal by secondary intention pla-
ces patients at much high risk for development of
Marjolin ulcers in the future. Patients with resultant
fragile burn scars should have these re-excised, or
at the minimum closely monitored, to ensure that Fig. 3. A 75-year-old woman with a Marjolin ulcer in
they do not undergo malignant transformation. right upper abdominal wall.
686 Elkins-Williams et al
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