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A. De Cosmo et al.
Patients with circumferential neck, trunk, and
extremity burns are at particularly high risk of
developing a perfusion injury or compartment
syndrome and often require fasciotomies.
Due to the large amount of edema present, disruption of vascular supply, and the potential for
other extremity injuries, the extremities and the
abdomen must be monitored for adequate perfusion, so escharotomy or potentially fasciotomy
may need to be performed. These procedures
incise burned tissue (escharotomy) or fascial
compartments (fasciotomy) to relieve pressure on
the surrounding structures and improve
perfusion.
Surgical debridement/excision is currently
considered the standard of care for eschar
removal for patients affected by intermediatedeep and deep burns.
Skin grafting is then applied once burn wounds
are cleaned, and debrided autologous grafting or
split-thickness skin grafting (STSG) involves
using the patient’s own skin to close an integumentary defect created after removing burned,
nonviable tissue. The donor skin is usually
meshed to increase its surface area and thus
allows a smaller amount of donor skin to cover a
larger recipient area. For areas such as the face
and hand sheet (or unmeshed), grafts are used for
improved cosmetic appearance. Various biologic
dressings can also be used as temporary wound
coverage to provide a protective barrier, giving
time for donor sites to heal for future splitthickness skin grafts. Allografts (human cadaver
skin) and xenografts (skin from a different species) can be used as temporary dressings.
Cultured epidermal autografts (CEA) are used
primarily for patients who have sustained large
TBSA burns (> 50%) and therefore may not have
enough donor skin available to provide complete
wound coverage following primary excision. A
section of the patient’s own skin is sampled and
grown in a laboratory. It can take several weeks
to become ready for use. This technique is expensive, and once the new skin is ready for use, it
must be applied immediately, regardless of the
status of the recipient wound beds. CEA also
requires up to 2weeks of immobility following
application, including interruption of all OT/PT
range of motion activities, exercises, and functional mobility. Even mobilization and positioning with nursing staff are minimalized [3].
Patients with burn injuries involving supercial, partial-, or full-thickness skin with potential
extension into fascia, muscle, or bone are at
higher risk for scar contracture and often require
reintervention. These burns can result in impairments such as loss of joint ROM, peri-articular or
intra-articular joint changes, sensory loss, edema,
pain, impaired ventilation/aerobic capacity,
impaired activity tolerance, impaired balance,
coordination, and strength. They can cause functional decits such as impaired mobility, difculty performing activities of daily living
(ADLs), and instrumental activities of daily living (IADLs).
28.3 The Minimal Invasive
Modality Treatment (MIMo)
forBurn Care
Surgical debridement/excision is associated with
several drawbacks such as signicant blood and
heat loss and it is hindered by poor selectivity,
which means both viable and necrotic tissue may
be excised. In order to overcome these limitations, several alternative techniques for eschar
removal have been developed over the years,
including hydrosurgery and enzymatic debridement. None has currently become the standard of
care. NexoBrid, a bromelain-based type of enzymatic debridement, has gained popularity in
recent years. The term MIMo refers to a minimal
invasive approach for burn care based on the use
of a selective enzymatic escharolysis, which can
preserve uninjured dermis and reduce the need
for grafting. In addition to this, the potential
wound healing capacity of stem cells can be used
to favor spontaneous re-epithelization.
28.3.1 Enzymatic Selective
Escharolysis
The use of plant-based products for burn treatment dates back to 1600BC.The Egyptian Smith
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301
Papyrus describes the use of resin and honey for
treating burn wounds. By 1500BC, other herbal
remedies such as Cyperus esculentus had been
added to the list of substances for treating burns.
However, it was not until 1940 that enzymes of
plant origin were used for eschar removal. At
rst, papain was extracted from the juice made
using the fruits and leaves of Carica papaya.
Papain was activated by adding either
triethanolamine or cysteine hydrochloride with
sodium salicylate. All of these solutions had a
strong debriding effect. Guzman et al. used
papain solution on wet surgical gauze as dressing
for burn wounds without any additional activator
and achieved satisfactory debridement results. In
addition, an enzyme made from g tree latex
(debricin) showed a rapid debridement effect on
second-degree burns; however, no further investigation was performed due to lack of standardization. Currently, bromelain-based products are
commonly used in most parts of the world.
Another group of enzymes with debriding
properties has bacterial origin. In 1951, Altemeier
etal. described enzymes derived from Clostridium
histolyticum, Escherichia coli, Pseudomonas
aeruginosa, and Bacillus proteus. In vitro and
invivo collagenase made from Clostridium histolyticum showed the most potent effects. The only
such product with Food and Drug Administration
approval in the USA is clostridial collagenase
ointment (CCO) (Santyl). There is evidence for
CCOs’ positive effect on burn wounds. The ndings suggest that CCO can be used to debride
burn wounds with less pain and nursing labor
than traditional therapy with other silverimpregnated products. However, large randomized controlled trials are needed in the future to
draw denitive conclusions. In contrast, streptokinase and streptodornase (Varidase) showed disappointing results, especially in the case of
debridement of full-thickness burns. This is why
they have not gained acceptance in burn therapy
[4].
Garret was the rst to publish a study on neutral proteases made from Bacillus subtilis (sutilains) in 1969. Over 100 patients were treated
efciently using sutilains. Under the tradename
Travase, sutilains gained increasing attention in
the 1970s and 1980s. However, treatment with
Travase led to an increasing number of wound
infections soon after the application of the
enzyme. A possible postulated reason for this
side effect was the need for a moist environment,
which stimulates bacterial growth. To compensate for this adverse effect, simultaneous treatment with antiseptic substances such as silver
sulfadiazine or mafenide is recommended.
Moreover, depending on the debriding effect in
that case, the patient needs to be treated in a moist
environment for 3–10days, which is a long treatment time. The debridement effect can be accelerated by applying Travase twice a day instead of
once and by starting application on day 1 postburn. Using this process, full debridement can be
obtained within 24 h. Wound closure can be
achieved faster by autologous skin grafting than
with standard conservative treatment. This made
Travase the most commonly used enzyme in
American burn units until it came off market in
the 1990s.
Another non-surgical method for the debridement of eschar involved the use of acids, mainly
pyruvic acid and phosphoric acid, until the 1960s.
An obvious disadvantage of this therapy was
uncomfortable, painful, and long-lasting debridement. Therefore, this approach was abandoned
and replaced by early surgical eschar removal in
the 1970s.
During 1965–1979, several scientific
groups examined additional enzymes such as
trypsins, chymotrypsins, and fibrinolysindesoxyribonuclease. These enzymes prevented
wound infection but did not reach relevant
clinical use. Vibriolysin extracted from Vibrio
histolytica and blowfly larvae extracts met the
same fate.
Searching for an agent that could supersede
surgical debridement, Klasen et al. reported in
2000 that chemical or enzymatic debridement
had not yet achieved the status of general application. The main reasons were poor quality, high
variability of composition, and lack of standardization of enzymatic treatment. With the help of
novel technologies in enzyme extraction and
processing, these obstacles have now been
overcome.
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A. De Cosmo et al.
In the eld of burn research, bromelain has
gained the most attention during the last decade.
Thus, it is the only enzyme that has achieved general application in Europe.
NexoBrid (NXB), formerly known as debriding gel dressing (DGD, Debridase, or Debrase),
is an enzymatic debriding orphan drug derived
from the pineapple bromelain group of enzymes.
The lyophilized dry powder enzyme is mixed
with a vehicle gel to be applied onto the burn
wound and covered with an occlusive dressing
for 4 h. The active enzymes cannot penetrate
intact keratin, its activity is limited to a few hours,
and together with its eschar specicity, it has
been proven to be a safe and effective debriding
agent that usually completes the debridement
phase in a single 4-h application. NXB specicity
and selectivity to burn eschar offer the physician
the option to apply it on burned surfaces and to
completely debride the eschar without the need
for an initial diagnosis of burn depth and without
committing to a diagnosis-based surgical treatment plan involving excisional debridement and
skin grafting.
It is applied to the area of burnt skin after the
wound has been appropriately prepared. It should
only be used in specialized burn centers and should
not be applied on more than 15% of the patient’s
total body surface area. For a burn wound area of
100cm2, 2g/20g gel is used. For a burn wound
area of 250cm2, 5g/50g gel is used. It should be
used within 15min after mixing and should be left
in contact with the skin for 4h.
Several published studies have assessed its
efcacy and safety on burn wounds. Its advantages, compared to the standard of care, include
decreased surgical morbidity and blood loss,
length of hospital stay, rates of infection, need
for skin grafting, and costs. In addition, this
product allows eschar removal without sacricing viable or healthy tissue, returning entirely
vital dermal or subcutaneous tissue. Such selective debridement allows maximal exploitation
of the dermal and epidermal salvaged component’s regenerative potential and subsequent
wound healing by dermal epithelialization,
offering an option for a minimal invasive modality (MIMo) for burn care [5].
28.3.2 Stem Cell Use inBurns
Recent years have seen advancements in regenerative medicine for burn wound healing encompassing stem cells and stem cell-derived products such
as exosomes and conditioned media with promising results compared to current treatment
approaches. Different sources of stem cells have
been utilized in regenerative medicine within the
scope of burn wound healing, such as embryonic
stem cells (ESCs), umbilical cord stem cells
(USCs), mesenchymal stem cells (MSCs) (such as
bone marrow-derived mesenchymal stem cells
(BM-MSCs), and adipose tissue-derived mesenchymal stem cells (AD-MSCs), burn-derived mesenchymal stem cells (BD-MSCs)) epidermal stem
cells (EpSCs), and hair follicle stem cells (HFSCs).
Stem cells utilize various pathways for wound
healing, such as PI3/AKT pathway, WNT-β
catenin pathway, TGF-β pathway, and Notch and
Hedgehog signaling pathway. The therapeutic
potential of stem cells for burn wound healing
arises from their ability to modulate the release of
the chemokines, cytokines, and growth factors
necessary for wound healing. Furthermore, it is
increasingly being accepted that rather than postengraftment differentiation and proliferation, the
therapeutic effects of stem cells lie in the secretion of paracrine or signaling molecules.
Not only have stem cells shown effectiveness
in acute care, but they have also shown therapeutic potential in scarring. Scarring is one of the
long-term outcomes after burn and has remained
a consistent challenge to overcome [6]. Burn
scars tend to be thick, painful, and itchy, causing
contractures and limited functionality of the
injured area. Stem cells help in reducing scars
inhibiting the activity of keloid broblasts
through paracrine signaling.
The treatment is provided either as direct
injections or embedded in a natural/articial
scaffold.
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28.3.3 MIMo Operative Technique
MIMo approach consists of a first step that is
performed within 48h from the burn event; the
patient undergoes an enzymatic debridement
using NEXOBRID ®. It is spread in sedation
at bedside or in an operating room, on a maximum of 35% of TBSA of the patient each
time; following application of NXB, the
wounds are covered with an occlusive film
dressing for 4h, which is then removed using
aseptic techniques. The treated area is scraped
with a sterile tongue depressor in order to
remove dissolved eschar and NXB remnants.
This is followed by a short wet-to-dry soaking
to remove all remaining remnants and then a
medication with collagenase ointment is
performed.
After 7days, a pseudo-eschar is formed on
the treated area, and it is removed in surgery
room with hydrosurgical treatment.
Subsequently, medication with a hyaluronic
acid scaffold soaked with stem cells obtained
through lipoaspirate is performed. Ten days
later, the scaffold is removed and from that time
serial dressings are performed. These steps are
repeated on each burn area with the target to
obtain the best wound bed to be able of spontaneous healing [7].
The main purpose of using scaffold is to
mimic the skin ECM and its properties. They
facilitate cell growth, organization, and differentiation into functional tissues. Scaffolds containing MSCs can provide a microenvironment
suitable for cell adhesion, proliferation, and differentiation. Scaffolds are versatile and can be
modied using computational modeling to withstand changes in uid composition, cell density,
and mechanical stress, as well as to help in the
timely release of molecules from the matrix.
Scaffolds can be made from natural materials
like collagen, hyaluronic acid, brin, and polysaccharides such as chitosan. These materials
have high biocompatibility and show enhanced
epithelialization and granulation of wounds in
preclinical studies [8] (Figs. 28.1, 28.2, 28.3,
28.4 and 28.5).
Fig. 28.1 31-year-old patient affected by intermediatedeep and deep burns caused by ame and covering over
50% of total body surface area
Fig. 28.2 NexoBrid application within 12h of the hospital admission
28.3.4 Anesthetic Protocols
Patients must be treated in different settings
depending on age, comorbidities, extension, and
location of the injury. According to the setting
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andSettings ofTreatment
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Fig. 28.3 Results of the escharolysis 4h later the application of NexoBrid. Note the absence of necrotic tissue
and the preservation of vital dermis
A. De Cosmo et al.
Fig. 28.4 Postoperative picture 4days after the application of the debriding agent. Small island of reepithelization can be observed
Fig. 28.5 Postoperative picture at 30days of follow-up.
Complete wound healing has been reached through both
split-thickness skin grafts and spontaneous healing
where the patient is treated, different anesthetic
protocols can be used: a soft sedation with midazolam or another benzodiazepine, with 5 mg
intramuscular injection of morphine for pain
control, can be applied in the outpatient setting
on the burns only 30min before the application
and removal of the product. Patients with a more
extensive TBSA% require a controlled anesthetic procedure in the recovery room. For
patients with extensive burns (where not only
the upper limb is involved or depending on age
and comorbidities), general anesthesia or deep
sedation is performed.
28.3.5 Advantages ofMIMo
Compared totheSOC
This technique is more effective than SOC at
reducing the proportion of the deep partialthickness burn wounds that need surgery to
remove skin tissue or require a skin graft. It
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results in faster eschar removal with reduced
blood loss than the SOC.Furthermore, a reduction in the need for autografting is achieved
because of more selective debridement, which
spares the vital dermis. This again led to a reduction in donor site morbidities while achieving
comparable long-term results of wound healing
in esthetics, function, and quality of life.
Bromelain-based substance has also been seen to
be an effective debridement treatment for burn
wounds of all thicknesses, including fullthickness wounds, and it is faster than standard
treatments [9].
Moreover, the management of burn patients is
notoriously expensive in terms of patient hospitalization time, surgical procedures, transfusion,
dressings, and other accessory therapeutic measures, and dedicated intensive care unit (ICU)
personnel and related costs. The clinical efcacy,
safety, and favorable cost-effectiveness of NXB
have been demonstrated by a recent randomized
controlled trial. Enzymatic debridement is associated with less surgery for both excising burns
and coverage resulting in a reduction in hospitalization times and sanitary costs. These characteristics also result in improved patient quality of
life [10, 11].
28.4 Conclusions
In our experience, MIMo is a valuable tool for
the treatment of burn wounds. The simplicity of
its application, its selectivity, and effectiveness
in digesting only nonviable tissue and the possibility of an early treatment and diagnosis of
burn depth make an optimal management of the
burn wounds possible. Saving the vital dermis
and using the potential healing capacity of stem
cells allow for higher rates of spontaneous reepithelialization, reducing the need for
autografting.
Moreover, prompt enzymatic escharolysis
can prevent, solve, and vicariate the treatment
of compartment syndrome, lowering intracompartment pressure. This does not mean
that in case of severe and deep circumferential
burns, escharotomy must not be performed. It
does suggest, however, that in the case of
moderate burns we can prevent unnecessary
incisions.
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A, Singer AJ, Rosenberg L, Shoham Y. Bromelainbased enzymatic debridement and minimal invasive
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Thermal Burns
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AlbinStritar andMarkoMikša
29
29.1 Introduction
Burnt skin is an ideal medium for bacteria, so the
idea of removing dead tissue is not new. Surgical
ablation or surgical necrectomy reduces the
amount of avital tissue and thus improves the
patient’s chances of survival.
Excision of the carcass was suggested in the
second half of the nineteenth century (Lusgarten
1871) at the rst microbiological ndings that it
was a favorable medium for bacteria. It was rst
performed by Wilms in 1901. The importance of
graft coverage, after necrectomy of a burn wound,
is described in Sneve 1905 [1].
The ndings on the use of skin grafts were
certainly benecial (Reverdin 1871, Ollier 1872,
Wolfe 1880, Krause 1893, Thiersch 1890).
However, major excisions were then abandoned,
due to high mortality, numerous operative complications, and poor results.
A new opinion about the importance of excision was then formed only after 1960 (Jackson,
MacMillan, Switzer). New patient preparations,
A. Stritar (*)
Clinical Department of Plastic Surgery and Burns,
University Medical Centre Ljubljana,
Ljubljana, Slovenia
e-mail: albin.stritar@amis.net
M. Mikša
Clinical Department of Surgical Infections,
University Medical Centre Ljubljana,
Ljubljana, Slovenia
new ndings in transfusion medicine and anesthesiology and better techniques, and work in
burn centers all developed a method that technically allows for early excision between days 1
and 5 of all deep dermal and completely deep
burns. This ensures healing and the best possible
functional and esthetic results [2].
The method, developed by Zora Janžekovič
(Fig.29.1), was recognized all over the world and
named early tangential excision. This is how burn
surgery came about. Multiannual results then
demonstrated that the best time for primary excision was between days 3 and 5. Any delay in
excision after day 5 results in deepening necrosis,
colonization of bacteria, activation of infection,
and changes in blood vessels and blood components, resulting in profuse and prolonged bleeding during surgery. Even later reduced burn
edema complicates the operative approach [3].
The Ljubljana School of Surgery then supplemented the method, such as the use of the
Esmarch garter, the elevation of the extremities
during surgery, and the use of adrenaline to
reduce bleeding (Brčič and Zdravič 1979). The
axiomatic rule, however, is that the necrectomy
must be accurate and “healthy,” with excellent
hemostasis, without drying out the wound [4].
The method later in the 1980s had numerous modifications from other authors (Baxter,
Herndon, Jankiewicz), such as extension of
primary necrectomy to day 7, multiple staged
excision on a daily basis, narrower selection of
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
M. Maruccia et al. (eds.), Pearls and Pitfalls in Skin Ulcer Management,
https://doi.org/10.1007/978-3-031-45453-0_29
307
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Fig. 29.1 Dr. Zora Janžekovič, the pioneer of modern
burn care (1918–2015). (Reproduced from Trop M,
Schiestl C.Zora Janžekovič. Z britvijo na sam vrh opeklinske kirurgije. Celovec: Mohorjeva; 2010)
A. Stritar and M. Mikša
Clinically, the changes are manifested in three
zones: necrosis, stasis, and hyperemia. In the rst
three days, the most important changes are in the
vascular system. In the zone of stasis, the following changes occur: stasis, thrombosis, wall disruption, hemorrhage, and changes in the intact
arterioles. The survival of the zone of stasis
depends on the restitution of the capillary endothelium and the restoration of venous outow.
Around post-burn day 3, the primarily reversible
compromised tissue is denitely destroyed.
The body reacts to such changes with inammation, which accelerates tissue deterioration.
The progressively deepening necrosis often turns
a deep dermal burn into a subdermal burn.
After post-burn day 3, under the inuence of
autolytic processes in the damaged tissue and the
activation of the saprophytic ora in the ducts of
the sweat glands and sebaceous glands, a process
of demarcation begins, accompanied by destruction of the biologically, compromised tissue. The
resulting complications are predominantly infection and later symptoms of a long-exposed
surface.
Hypermetabolism, changes in defense mechanisms, catabolic reaction, and weight loss put the
patient at risk in proportion to the extent of the
injury and his/her general condition.
patients according to burn size, and respiratory burn. Tangential excision has been combined by some authors with excision “en bloc”
to the fascia (Soerensen 1976). The method is
certainly still in use and an integral part of the
doctrinal principle of the treatment of burns.
With timely and correct excision, we achieve
the healing of deep burns with a suitable cover,
as well as the best functional and cosmetic
result [5].
29.2 Local, Histomorphological
Changes inaBurn Wound
The induced thermal state causes changes in the
affected tissue that decreases in intensity with
depth, but gradually increases in intensity due to
slow cooling until the temperature stabilizes.
29.2.1 General Changes
The thermal state is transferred from the burnt
tissue to the extravascular space via the vascular
space and the endothelium of the entire capillary
system. Changes occur in all components of the
blood and in the capillary endothelium, resulting
in disturbances in the perfusion of all organ
systems.
This is a dynamic process whose ow can be
interrupted at any time from the moment of the
rst change until the end of the granulation phase
or the end of the scar development phase.
The success of the treatment therefore depends
on appropriate rst aid, primary care, and appropriate anti-shock therapy for extensive burns,
timely and appropriate surgical management, and
good postoperative care.
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29.3 Admission ofaBurn Patient
In addition to the burn wound, the general status
and condition of the respiratory burn are important for the surgeon as part of the work and tasks
in the admission of a burn patient in the anesthesia or resuscitation room. It is important to get
acquainted with previous illnesses. Before carefully evaluating soft tissue status, it is very
important to rst identify other injuries, and
fractures and rule out craniocerebral trauma
with impaired consciousness. We need to pay
attention to internal and external bleeding. We
try to calm the burn. We protect it from heat and
liquid loss. While obtaining patient history, in
addition to the patient’s general information, the
following information is important: type of
burn, place of the accident, whether the accident
is indoors or outdoors, method of referral, allergies to medications, which medications the
patient is taking, and previous illnesses.
Inhalation injury information is important. The
attached documentation and therapy are also
required if the patient has previously been cared
for in a specialized institution. In the anesthesia
room, we also take care of the peripheral and
central venous canal for uid therapy and later
parenteral nutrition, swab collection, and blood
collection for laboratory tests.
In the dressing room, under anesthesia or analgesia, we perform a bath and a mechanical toilet.
This is followed by an evaluation of the burn.
After the nal assessment and graphic presentation of the burn, the burnt surfaces are wrapped
with compresses, and a nasogastric tube and a urinary catheter are introduced. In severe burns, the
patient remains intubated. Tracheotomy follows
laryngeal edema, extensive facial burns, and
expected prolonged intubation.
Before placing the brick in the intensive care
unit, we must think about preventing bedsores, so
on special beds the exposed parts are lined with
pillows, the extremities are immobilized and
slightly elevated, and placed in anti-contractile
positions.
29.4 Burn Assessment
The surface extent of a burn, measured as a percentage of the burned body surface area, is the
rst major practical criterion for triage. In addition, the decision on the question of where and
how we will treat the burn is based on its depth
and localization. This is an extremely important
piece of information for the anesthesiologist at
admission and later the intensive care specialist
in the ward.
Upon admission, a scheme of the burn is
drawn, which is also an ofcial document, in
terms of dimension and depth. Uniform criteria
must be used to avoid misunderstandings. When
assessing the area, erythema is excluded and
only burnt skin is assessed. It is by no means a
problem if the surgeon re-marks the scheme the
day after admission or later. A simple rule
employed is “number 9”, a tool to assess the
total body surface area (TBSA) involved in
burn patients. The Rule of Nines estimation of
body surface area burned is based on assigning
percentages to different body areas (Wallace
1951) [6]. The percentage difference is in children, where the whole head is rated higher than
in adults, while the lower extremities are
smaller compared to adults. The Lund- Browder
scheme (1944), which is a modication according to Berkow (1924), draws the depth of the
burn in addition to the percentages [7].
With novel software technologies, many new
schemes are being developed to achieve the fastest results [8].
According to the nal assessment of the area
in burns, we distinguish:
– Minor burns (up to 10% of total body surface
area).
– Moderate burns (up to 20% of total body sur-
face area).
– Severe burns (20–60% of total body surface
area).
– Critical burns (over 60% of total body surface
area).
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