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L. Téot and S. Fluieraru
during terminal limb ischaemia or during angiodermatitis. Microvascular impairment, autoimmune vasculitis, macroangiopathy and venous
blockade are the most frequent causes, together
with infection and microarterial emboli.
Other toxins and venoms may be secreted by a
series of different animals (snails, mosquitoes)
and may create an intense local inammatory
process leading to localised skin necrosis combined with an extensive subepidermal tissue degradation [2].
2.3 Wet Necrosis
Epidermal-dermal necrosis may rapidly appear at
the skin surface. However, in some areas, such as
the foot or when the depth of keratinised epidermis is thick, the necrotic tissue may resemble a
subepidermal collection. This is partly because of
the Tyndall effect—a light scattering observed
when particles are present in colloid suspension,
with blue light being much more strongly affected
than red light.
When mature, this subdermal necrosis is easily confused with a deep haematoma. This situation is often observed on the heel. When the
wound macerates, a wet necrosis may be
observed, without any crust covering the necrosis. This situation is easily infected, with the
mechanical protection of the crust being absent.
Dermal necrosis may be present during a severe
infection such as necrotising fasciitis, where the
presence of germs secreting highly active toxins
quickly involves all surrounding tissues and creates a regional progressive necrosis, a spreading
infection rapidly leading to a septicaemic lifethreatening shock. The proliferation of germs is
facilitated inside the fatty tissue, such as in
Fournier gangrene involving the perineal area
and progressing very quickly in the perineum and
under the abdominal skin.
In some situations, the necrotic tissue presents as wet, usually when necrosis is covered
with damp dressings, allowing anaerobes to
develop. This wet necrosis is often seen on the
heel or other parts of the foot, the perineum,
and places where maceration usually occurs.
Wet skin necrosis is considered to be at high
risk of local infection and should be quickly
removed.
2.4 Debridement
1. Evidence-Based Medicine
When analysing the literature from an
evidence- based point of view, the Cochrane
review considers that debridement has not yet
demonstrated its efcacy. Nevertheless, most
of the practitioners and paramedics involved
in wound healing recognise the benecial
effect of debridement.
Skin necrosis is not infected for the rst few
days but becomes heavily colonised when the
edges are dissociated from the healthy skin.
The time effect depends on a number of factors, grouped under the name of comorbidity
markers. These markers may dene the capacity of the patient to heal. Some of them, such
as ankle brachial pressure index, albuminaemia, glycated haemoglobin and blood pressure measurement, are easily collected.
Others, such as inammatory markers or evolution with time of the wound healing process
(surrogate end point), should be accurately
determined.
2. Indications and Contraindications of
Debridement
Debridement in leg ulcer or heel pressure
ulcer is only indicated when the limb is vascularised enough to prevent renecrosis on the
edges of the wound. Lower limbs presenting
an ankle brachial pressure index (ABPI) lower
than 0.5 should not be debrided. When the
ABPI is over 0.5, the debridement should follow an algorithm depending on multiple factors such as accessibility to surgery,
availability of expertise in the use of advanced
dressings such as hydrogels, hydrobalance or
new debriders. Wet to dry techniques are not
recommended any more.
2 Dry Necrosis, Wet Necrosis: When toDebride, When Not toDebride
9
2.4.1 Algorithm ofDebridement
(Fig.2.1)
The strategic decision of debridement is multifactorial and should take into account local and
systemic factors.
Depending on the rst assessment, the
debridement is possible or not. If the local vascularisation has not been checked, debridement is
not recommended. If the patient is in a palliative
situation, debridement is not recommended.
When debridement is possible, determine if a
surgical debridement is needed and transfer the
patient to an expert surgical team. If local availability of sharp debriding agents like scalpel or
curette is poor or if expertise of the caregiver is
poor, do not debride. In most of the situations, a
large choice of solutions exists and can be used,
depending on the local skills and the technical
availabilities.
During a post-operative period after ap surgery, when the skin ap becomes necrotic, a sur-
gical revision removing the necrotic areas is
required.
2.4.2 Dissecting Haematomas
In the presence of spreading extended necrotic
areas, an adapted debridement should be quickly
proposed. In necrotising fasciitis, extravasation
injuries, haematomas or Fournier gangrene, a
large and extensive surgical debridement, including the edges of undermined cavities (decap procedure), is needed and must be considered as an
emergency. The immediate post-debridement
period should consider the need for repetitive
debridement procedures when infection is still
present. New debriders such as Versajet or
NPWT Instill with VCC foam are useful in
destroying local germs and preventing biolm
formation.
In the case of necrotising angiodermatitis,
pain and skin necrosis may need surgical
Fig. 2.1 This algorythm of surgical debridement describes the different possible strategies including or not a surgical
debridement and when to redebride
10
debridement and rapid skin grafting using pinch
grafts to stop pain.
Pressure ulcers are common causes of necrosis, particularly in the perineal area and over the
heel. On the perineal area, undermining is frequently observed, as a consequence of the shearing forces exerted on the skin. The skin is more
mechanically resistant than the underlying structure, with a relatively small opening covering a
large undermined area being frequently observed.
In this situation, all hidden cavities need to be
opened to expose living edges. The granulation
tissue and retraction are more rapidly obtained.
Excision of the cover (decap surgery) by nonsurgeon means is an option, but deep excisions
along the undermined area are realised by surgeons (Figs.2.2, 2.3, and 2.4). Concerning heel
PU, a vascular assessment is mandatory (pedal
pulse absence is the rst sign and should indicate
ABPI and Doppler ultrasound, and in case of
arteriopathy, a vascular surgery consultation is
needed to prevent renecrosis of the edges before
any mechanical debridement). An ABPI below
0.5 is a contraindication to debride. Poor vascularisation, end-of-life and palliative situations are
contraindications to surgical debridement.
Toe necrosis in diabetic foot ulcers realises a
complete dry necrosis, and mummication can be
recommended (spontaneous evolution towards
spontaneous amputation). Below the second meta-
L. Téot and S. Fluieraru
Fig. 2.2 Heel pressure ulcer: a spreading infection is
observed some days after the necrotic tissue appeared
Fig. 2.3 A tigh haematoma presenting an “iceberg-like”
situation. The necrotic skin hides a large undermined zone
of dissecting blood, source of potential infection
ab
Fig. 2.4 (a, b) Progressive necrosis of the distal phalanx in a renal insufcient patient submitted to an arterial thief after
arteriovenous stula for haemodialysis
Curetage
Section
Enzyme
Syringe
2 Dry Necrosis, Wet Necrosis: When toDebride, When Not toDebride
11
tarsal joint, plantar ulcers present as a skin necrosis reduced to a small black spot with a large cavity
behind, with the foot becoming oedematous and
inammatory. Pus may leak from different zones
on the foot, the dorsal aspect, the interdigital webs
or from any necrotic area. Early surgical debridement may prevent amputation if carried out rapidly, in close collaboration with the vascular
surgery team in order to prevent amputation.
2.5 How toManage Skin
Necrosis
1. Wet to dry is a technique used in the past to
eliminate debris on the wound.
Classically, the technique involves applying a
wet gauze soaked in sterile water and waiting
for its desiccation. When dry, it will be
removed together with crusts, pus and debris.
This painful technique will harm the granulation tissue, inducing local haemorrhage, and
should not be used any more.
2. Which techniques can be proposed? (Fig.
2.5)
Multiple technologies are now available for
debridement. At home, grating, scalpel and
syringe water projection under pressure can
be easily utilised, as well as adsorbing and
moisturising dressings. In advanced wound
care centres, hydrojets or NPWT Instill plus
VCC foam can be proposed.
Progressive Autolytic Debridement
Conservative solutions such as dressings providing moisture (autolytic debridement) will
induce a progressive release and detachment
of undesired tissues over the wound.
Hydrogels are the most used dressing at home,
Adsorbing
s
Hydrojet-aspiration
Fig. 2.5 Multiple techniques are available for debridement, depending on the availability and the skill to use
them. Negative-pressure wound therapy instillation plus a
Dressings
Moisturizers
NPWTI+VCC
NPWT I+VCC
Maggots
specic VCC foam has recently demonstrated its capacity
to debride large cavities
12
ab
cd
L. Téot and S. Fluieraru
Fig. 2.6 (a–d) Midtarsal amputation after a failing ap in
a young diabetes type 1 patient 42years old; high level of
comorbidities. Amputation could be prevented using local
with the nurse moisturising the wound 1day
and gently removing the sloughy tissue the
next. This less painful technique allows a better psychological management; curettage of a
leg ulcer every 2days induces pain impacting
the quality of life. Mechanical debridement
remains extremely painful and should be reevaluated in the light of the new dressing performances, the capacity to remove
metalloproteases from the wound surface and
using local irrigating uid. Negative-pressure
wound therapy was proposed as a possible
treatment for soft necrotic tissue [3].
3. Preventing Elimination Folds Around Skin
Necrosis: Playing the Dry Card
Flammacerium, an antibacterial cream composed
of silver sulfadiazine and 0.2% cerium nitrate,
offers a solution involving stopping all possi-
application of silver sulfadiazine plus cerium nitrate for
11 consecutive months
bilities for germs to penetrate the edges of
necrosis and stabilising the crust in order to
transform it into a protective calcied armour
against infection. The dry necrotic process is
stuck in its evolution and no longer becomes
infected (Fig. 2.6). Flammacerium was initially proposed as a barrier to germ penetration in third-degree burns [4] and then
proposed for arteriopathic necrotic wounds
when revascularisation is not possible to limit
or prevent amputations [5]. When applied
onto extensive areas such as an 80% thirddegree burn surface, methemoglobinaemia
may cause life-threatening damage [6]. Blood
dosage of methemoglobinaemia is required in
these specic situations, but this has not yet
been described for wounds presenting small
surfaces [7].
2 Dry Necrosis, Wet Necrosis: When toDebride, When Not toDebride
13
2.6 Conclusion
Necrosis may present under a dry aspect, evolving spontaneously towards wet necrosis, depending on the local bacterial status. Each situation
should be evaluated clinically in the context of
the patient, taking care of the comorbidities, the
vascularisation of the segment of limb and the
availability of resources.
References
1. Doornaert M, Monstrey S, Roche N. Extravasation
injuries: current medical and surgical treatment. Acta
Chir Belg. 2013;113(1):1–7.
2. Kaafarani HM, King DR. Necrotizing skin and
soft tissue infections. Surg Clin North Am.
2014;94(1):155–63. https://doi.org/10.1016/j.
suc.2013.10.011. Epub 2013 Nov 5.
3. Teot L, Ohura N.Challenges and management in wound
care. Plast Reconstr Surg. 2021;147(1S-1):9S–15S.
https://doi.org/10.1097/PRS.0000000000007628.
4. Signe-Picard C, Cerdan MI, Téot L.Flammacérium
in the formation and stabilisation of eschar in chronic
wounds. J Wound Care. 2010;19(9):369–70, 372, 374
passim.
5. Boeckx W, Focquet M, Cornelissen M, Nuttin
B.Bacteriological effect of cerium-amazine cream in
major burns. Burns Incl Therm Inj. 1985;11(5):337–42.
6. Poredos P, Gradisek P, Testen C, Derganc M.Severe
methemoglobinaemia due to benzocaine- containing
‘burn cream’: two case reports in an adult and
in a child. Burns. 2011;37(7):e63–6. https://doi.
org/10.1016/j.burns.2011.05.015.
7. Barker E, Shepherd J, Asencio IO.The use of cerium
compounds as antimicrobials for biomedical applications. Molecules. 2022;27(9):2678. https://doi.
org/10.3390/molecules27092678.
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Ischemia/Reperfusion: APotential
Cause ofTissue Necrosis
PoonApichartpiyakul, RajMani,
SupapongArworn, andKittipanRerkasem
3
3.1 Introduction
Ischemia/reperfusion injury (IRI) is a sequelae
following the restoration of circulatory ow to an
ischemic organ. IRI can occur following different
forms of acute vascular occlusion, for example
acute myocardial infarction, stroke, limb ischemia, free-tissue transfer, and organ transplantation [1]. Injuries can manifest from both local
and systemic effects, ranging from tissue edema,
dysfunction, and necrosis to multi-organ failure.
The pathophysiology of IRI includes the triggering of cellular oxidative stress and inammatory
response. Cellular oxidative stress and inammatory response are caused by reactive oxygen species (ROS) overproduction in mitochondria.
There are several preventative interventions in
IRI that have shown benecial outcomes in
P. Apichartpiyakul · S. Arworn
Department of Surgery, Faculty of Medicine, Chiang
Mai University, Chiang Mai, Thailand
R. Mani
Research Institute for Health Sciences, Chiang Mai
University, Chiang Mai, Thailand
K. Rerkasem (*)
Department of Surgery, Faculty of Medicine, Chiang
Mai University, Chiang Mai, Thailand
Research Institute for Health Sciences, Chiang Mai
University, Chiang Mai, Thailand
in vitro, in vivo, and clinical studies [2]. This
chapter focuses on tissue necrosis, which is a
potential local manifestation of IRI.
3.2 Pathophysiology
Tissue ischemia/reperfusion injury (IRI) manifests in either local or systemic effect. Local
effect such as tissue necrosis from IRI can be
found from skin to bone and muscle. Etiologies
of IRI-involved muscle and skin necrosis are
found in acute tissue ischemia of musculoskeletal
system such as tissue free-ap transfer and acute
limb ischemia, which receives immediate restoration of blood supply. Systemic effects can range
from remote organ injury to multi-organ failure.
IRI is a consequence of two phases of injuries.
The initial ischemic phase, microcirculation to
the affected tissue, has been occluded by masses
of platelets in postcapillary venules [3]. Local
effects, such as skeletal muscle necrosis during
tissue ischemia in low collateral blood ow, were
also detected in skeletal muscle model of IRI [4].
Muscle edema and systemic effects, which are
observed in later phases, are not evident at this
phase [5]. The reperfusion phase then follows,
leading to further tissue damage. In this phase,
despite successful revascularization of ischemic
tissue, tissue perfusion is decreased compared to
during its pre-ischemic state. This has been seen
in acute myocardial infarction tissue, where up to
© The Author(s) 2024
L. Téot et al. (eds.), Skin Necrosis, https://doi.org/10.1007/978-3-031-60954-1_3
15
16
P. Apichartpiyakul et al.
50% of myocardial microvasculature remained
non- perfused, an event known as a “no-reow
phenomenon” [6, 7]. These ndings could be
caused by intravascular hemoconcentration and
thrombosis, which leads to further tissue malperfusion. In the reperfusion phase, tissue necrosis,
edema, and muscular contractile dysfunction are
increased dramatically during reperfusion, in
comparison to ischemic period [4, 8, 9]. Lactic
acidosis, rhabdomyolysis, and increased proinammatory cytokines were also observed in
previous studies, which are affect to systemic
organ during skeletal muscle IRI
[5, 10, 11].
Pathology in cellular level from IRI originated
from triggering oxidative stress and inammatory response. There are studies that mimic
human skeletal muscle in order to investigate
subcellular and cellular pathophysiology. In vitro
and invivo studies have demonstrated that several intracellular molecules are involved in the
inammatory cascades of IRI.At a cellular level,
mitochondrial dysfunction plays a crucial role in
the pathogenesis of IRI [12]. Mitochondrial functions dene as adenosine triphosphate (ATP) production, reactive oxygen species (ROS)
generation, detoxication, metabolite synthesis,
catabolism, and regulation of apoptosis. During
tissue hypoxic period, ATP, a major source of
energy and produced by oxidative phosphorylation, is depleted [12]. Moreover, IRI has been
shown to shift mitochondrial dynamics toward
mitochondrial ssion, resulting in cellular apoptosis [13]. Under conditions of ischemia, xanthine dehydrogenase (D-form) is changed to
xanthine oxidase (O-form), resulting in increased
ROS generation [14]. These excessive ROS levels result in cellular oxidative stress, which leads
to protein carboxylation, lipid peroxidation, and
DNA damage. Furthermore, ATP depletion
induces the translocation of Bax, Bad, and Bcl2
proteins to the mitochondrial membrane, which
results in mitochondrial swelling and mitochondrial ssion [15]. Additionally, an increase in
intracellular calcium ions (Ca2+) level during
ischemia may alter mitochondrial permeability
transitional pores (mPTPs) from a transient to a
persistent opening state. The opening of the
mPTPs allows the efux of ROS and cytochrome
c into the cellular matrix, and the inux of the
Ca2+, leading to mitochondrial swelling and
membrane rupture, thus causing cellular apoptosis in the cells [16].
In clinical studies, there are different presentations during ischemia and reperfusion phases. In
the ischemic phase, local effects in skeletal muscle tissue such as decreased intramuscular blood
ow and increased cellular acidosis were
observed [17]. In the case of systemic effects,
oxidative stress and inammatory markers from
the peripheral blood samples were increased
[18–24]. Leukocyte activation, leukocyteadhesion molecules, and oxidative stress parameters such as glutathione and free sulfhydryl
groups increased to a greater extent during the
reperfusion phase than in the ischemic phase
[18]. Local effects during the reperfusion phase
were observed as cellular endothelial dysfunction
as indicated by decreased brachial artery owmediated dilatation, which is observed in an
healthy arm IRI model [19]. Intramuscular acidosis was decreased compared to the ischemic
phase, measured by an increase in inorganic
phosphate/phosphocreatine ratios, observed from
31
P nuclear magnetic resonance [17]. Skeletal
muscle injuries including muscle edema, mortor
dysfunction, and tissue necrosis were also
observed after 3h of ischemia [25]. Multi-organ
failures, such as rhabdomyolysis and increased
kidney, intestine, and liver injury biomarkers,
were observed [21, 26]. In addition, preoperative
rhabdomyolysis, positive uid balance, poor
intraoperative back bleeding, and an increase in
end-organ injury markers were proposed as predictors of the occurrence of post-reperfusion
compartment syndrome [20]. A summary of the
proposed mechanisms in musculoskeletal tissue
IRI is illustrated in Fig.3.1.
3 Ischemia/Reperfusion: APotential Cause ofTissue Necrosis
17
Fig. 3.1 Pathophysiology in tissue ischemia/reperfusion
injury. Abbreviations: ARDS acute respiratory distress
syndrome; Ca2+ calcium ion; Cytc cytochrome-C; mt
3.3 Clinical Manifestations
Tissue necrosis after IRI is the end stage of injury.
Tissue necrosis, including of the skin, subcutaneous fat, and skeletal muscle, as a result of IRI has
been observed in acute limb ischemia and after
tissue free-ap transfer surgery. Injuries begin
during the ischemic phase, and more severe damage subsequently occurs in the reperfusion phase.
Clinical manifestation can be well observed in
the reperfusion phase. Local changes in the skin
and muscle resulting from IRI are listed below.
1. Tissue edema
Following reperfusion of ischemic tissue,
mild tissue edema can be observed as a result
of successful restoration of blood ow to the
affected area. This is a result of uid shifts
from intravascular to interstitial spaces by
endothelial dysfunction. However, if severe
edema is observed early, venous outow
obstruction of the organ/tissue ap should be
mitochondria; mPTP mitochondrial permeability transition pore; O2 oxygen; ROS reactive oxygen species; XO
xanthine oxidase
considered. Initial management of tissue
edema includes elevation and adequate blood
pressure raising to ensure capillary perfusion
pressure of the affected tissues. IV uid and
blood transfusion should be done to keep systolic blood pressure at normal range.
2. Acute compartment syndrome
Sequelae of ischemia/reperfusion injury is
tissue edema in close space, such as intramuscular compartment, where the compartment
pressure raises enough to compress capillary
bed and compromise blood supply to tissue, are
called “acute compartment syndrome.” This
syndrome is caused by compression of edematous tissue to venous outow and increased
venous pressure, which then results in increased
uid shifts into interstitial spaces, resulting in
further tissue edema. The intramuscular pressure gradient overcomes vascular supply to
skeletal muscle cell. This vicious cycle leads to
acute compartment syndrome, which is dened
as tissue malperfusion occurring as a result of
the intra- compartment pressure overcoming
18
P. Apichartpiyakul et al.
the vascular bed. Lower extremity compartment syndrome manifests as massive leg
edema and severe pain of the leg. Intracompartment pressure measurement should be
evaluated if clinical results are inconclusive,
such as if the patient was unconscious. White
side method [27] is used to evaluate absolute
static intra- compartment pressure, which,
when greater than 30 mmHg, indicates compartment syndrome. However, prospective
studies found that dynamic pressure measurement called “delta pressure,” which is diastolic
blood pressure minus the intra-compartment
pressure, has more value in the diagnosis of
compartment syndrome than static pressure. If
delta pressure is less than 30 mmHg, acute
compartment syndrome could be diagnosed
and therapeutic fasciotomy should be performed to release compartment pressure [28,
29] as delays in diagnosis and treatment can
result in muscle dysfunction and tissue necrosis. Figure 3.2 shows the patient’s necrosed
skin after acute compartment syndrome. After
therapeutic fasciotomy, edematous muscle was
protruded out of skin.
3. Tissue Necrosis
End processes of local effects of IRI are
tissue ischemia and necrosis. These can be the
result of either process of IRI or delay in treatment of acute compartment syndrome.
Preoperative factors, such as prolonged isch-
Fig. 3.2 Skin necrosis caused by acute compartment syndrome (above picture). Patient’s muscle was protruded
after fasciotomy (below picture)
Table 3.1 Maximal tissue ischemia, which leads to
necrosis, applied from S.Gillani etal. [30]
Type of tissues Ischemic time (normal temperature)
Muscle 4h
Nerve 8h
Fat 13h
Skin 24h
Bone 4days
emia, can lead to tissue necrosis after
IRI.Tissue ischemic time, which can tolerate
ischemia, is different depending on the type of
tissue. Summary of ischemic time is given in
Table 3.1. If necrotic tissue is observed, the
tissue is irreversible. Treatment should be
adequate debridement of the necrotic tissue in
case it will proceed to local infection and systemic bacteremia.
3.4 Treatment andPrevention
Debridement of necrotic tissue is the main treatment of tissue necrosis. Adjudication of tissue
viability remains primarily dependent on the
clinical judgment of the healthcare team. Fixed
mottling skin and noncontractile muscle are signs
of irreversible tissue damage indicating tissue
necrosis. Adequate tissue debridement, including
amputation, until viable tissue is present is
required if tissue necrosis has occurred.
Unremoved necrotic tissue can lead to sepsis and
drain toxic metabolites to systemic circulation.
There were many investigations in therapeutic
modalities to prevent tissue IRI. These have
shown promised outcome in the prevention of tissue necrosis. Clinical studies in tissue and skin
necrosis IRI were investigated in free-ap tissue
and acute limb ischemia patients. Both pharmacological and non-pharmacological therapeutic
interventions are used in studies on secondary
prevention of tissue necrosis from IRI.Examples
of preventive strategies, that are currently investigated in tissue necrosis after IRI, are listed in
Table 3.2. Several preventive interventions have
shown signicant warranty but have not yet been
investigated in humans [2]. Further clinical studies are needed.