position document

Transcription

position document

POSITION DOCUMENT
ITALIAN WOUND CARE ASSOCIATION
(ASSOCIAZIONE ITALIANA ULCERE CUTANEE - AIUC)
ISCHEMIC ULCER AND
CRITICAL ISCHEMIA
P. E. MOLLO, M. M. DI SALVO, G. FAILLA, A. MARCOCCIA, G. MOSTI, G. GUARNERA
ACTA VULNOLOGICA 2012
VOLUME 10, N. 4

ACTA VULNOL 2012;10:173-205
POSITION DOCUMENT
Associazione Italiana Ulcere Cutanee – AIUC
Ischemic ulcer and critical ischemia
P. E. MOLLO 1, M. M. DI SALVO 2, G. FAILLA 2, A. MARCOCCIA 3, G. MOSTI 4, G. GUARNERA
5*
1Medical
Angiology, Unit of Cardiology, Anagni Health Local Unit, ASL Frosinone, Frosinone, Italy
2Unit of Angiology, Policlinico Vittorio Emanuele, Catania, Italy
3Centro Riferimento Interdipartimentale Interdisciplinare Specialistico per la Diagnosi precoce della
sclerodermia, la cura delle ulcere sclerodermiche e la videocapillaroscopia
Unit of Angiology, S. Pertini Hospital, Rome, Italy
4Department of Angiology, Clinica MD Barbantini, Lucca, Italy
5Vascular Surgery Unit for Wound Care, IDI-IRCCS, Rome, Italy
PRESENTATION
This is a choral chant on an issue which has been well identified as the third evolutional stage of
chronic obstructive arteriopathy, which has still to be planned as a stand alone signal and symptom.
The debate is still open on whether a consequence of several and different vascular and non vascular
diseases, could have, in therapeutic response, a common denominator or if the various causes represent the right way to arrive at a proper approach of the consequences. This is not a simple problem to
be underestimated given that the whole History of Medicine throughout centuries, since the Priestly
Medicine of the Egyptians, has always revolved around this dilemma : whether it is a holistic concept
in a therapeutic sense or a “reductive” one of cause and effect. Not really like “the egg or the hen”
because in this specific case all the eggs are equal but the hen changes although it apparently keeps
laying the same eggs. So congratulations to the Authors and particularly to my friend Giorgio Guarnera for his umpteenth attempt to combine, with courage, a sign and so the Scientific Association to
which he belongs, with the several causes constituting it.
They are definitely not a re-copy of the useful but boring Guidelines, but rather a personal flair
founded on Medicine Based on Experience; it was about time to solidify into a personal object something which, while respecting the norms of Evidence, would produce something on which to reflect
and work.
This is not insignificant, because this position document should be read with constructive criticism
while thinking that the apparent contrast with official science, is not the product of a lack of awareness but a careful reflection which our French colleagues have never abandoned: “il faut reflechir”
is a dictum appearing nearly very slavishly in the science programs of our Colleagues from the other
side of the Alps.
And so here it is, an innovative and brave document, which has been both difficult and bold to
compile.
Prof Claudio Allegra
Head of Vascular Disease Master
Azienda Ospedaliera S. Giovanni-Addolorata, Roma
*with the contribution of: E. Melillo, Unit of Angiology, Department of Cardio-Thoracic and Vascular Surgery, University
Hospital of Pisa, Pisa, Italy; F. Pomella, Angiology, Poliambulatorio Specialistico ASL Frosinone, Frosinone, Italy; C. Salvucci,
Centro Riferimento Interdipartimentale Interdisciplinare Specialistico per la diagnosi precoce della sclerodermia, la cura delle
ulcere sclerodermiche e la videocapillaroscopia, Unit of Angiology, S. Pertini Hospital, Rome, Italy; G. Ardita, Unit of Angiology, Policlinico Vittorio Emanuele, Catania, Italy; F. Mugno, Unit of Angiology, Policlinico Vittorio Emanuele, Catania, Italy.
Vol. 10 - No. 4
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Ischemic ulcer and critic ischemia
DEFINITION OF CRITICAL ISCHEMIA
T
he definition of critical lower limb
ischemia (CLLI) indicates the clinical
picture characterized by rest pain and/or
trophic lesions of different degrees and extents (see the Lériche-Fontaine and Rutherford classifications reported in Table I) such
as ulcers and/or gangrene, having arisen
over 15 days prior, secondary to arteriopathy with an obliterative evolution, and in
hemodynamic terms, from systolic pressure
measurements <50 mmHg at the ankle and
<30 mmHg at the big toe. Under the microcirculatory profile, it is characterized by the
regional reduction of the transcutaneous
oxygen tension (<30 mmHg) at the affected
forefoot.
The diagnosis of critical ischemia must be
suspected in the presence of the following
signs or symptoms:
—— rest pain in the lower limbs, mainly
at night or when supine (Lériche-Fontaine
stage III or Rutherford degree II, cat. 4) that
lasts more than 15 days and requires analgesic treatment;
—— acral focal skin lesions (Lériche-Fontaine stage IV or Rutherford degree III, cat.
5);
—— extensive skin lesions or gangrene
(Lériche-Fontaine stage IV or Rutherford
degree III, cat. 6)
Many experts believe that the finding of
severe claudication, intending, with this adjective, a range of free movement of a few
steps, should also be added to this “official”
classification.
This definition joins different clinical
stages that correlate to a high risk of amputation and death, criticalities that also characterize the finding of severe claudication.
The incidence of critical limb ischemia in
Europe is approximately 450 cases/million
inhabitants with a relative risk of amputation of 50% in non-revascularized patients
and 26% in patients subjected to direct or
indirect revascularization treatments, while
the relative risk of death is 50% and 18%,
respectively. As known, radical limb surgeries are burdened by a very poor prognosis; about 30% of the patients die within the
subsequent 12 months, while another 30%
achieve partial self-sufficiency and only the
remaining 30% reach a condition of total
autonomy and self-sufficiency. However, a
notable difficulty remains in the study of
populations with CLLI in consideration of
the notable number of patients lost during
the various follow-ups or deceased during longitudinal studies, resulting, unfor-
Table I.—Clinical staging of chronic obliterative arteriopathy of the lower limbs according to Lériche-Fontaine and according to Rutherford.
- Lériche-Fontaine classification
Stage
Symptomatology
I
Asymptomatic
II
Intermittent claudication
Clinical examination
Manifestation of skin and skin adnexa dystrophy
III
IV
Rest pain
Trophic lesions
Pallor - cyanosis
Focal ulcers - gangrene
- Rutherford
Degree
0
I
I
I
II
III
III
classification
Category
0
1
2
3
4
5
6
Clinical
Asymptomatic
Mild claudication
Moderate claudication
Severe claudication
Rest pain
Minor tissue lesions
Major tissue lesions
The two classifications substantially correspond. To better identify the claudication and monitor any improvement, Rutherford’s
classification applies three categories; for similar reasons, in the course of time, Lériche’s original stage II has been classified into
IIA and IIB in relation to the seriousness of the symptom.
174
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MOLLO
tunately, in an incompleteness of the data
collected.
The diagnosis of CLLI should be based
on the ABI, the systolic pressure measurement at the big toe, or on the measurement of the transcutaneous oxygen tension.
Ischemic pain is normally manifested below
a pressure at the ankle of about 50 mmHg
or a systolic pressure value at the big toe
<30 mmHg.
The percentage of patients with obstructive-type peripheral arteriopathy varies from
3% to 10% of the population in the range
between 50 and 70 years old inclusive, but
reaches 20% after 70 years of age. The natural history of chronic peripheral obliterative
arterial disease, if not promptly diagnosed
and properly treated, progresses to critical
ischemia (over 5% in the five years after
diagnosis of chronic peripheral obliterative arterial disease). CLLI primarily due to
peripheral chronic obliterative arteriopathy
leads to an expectation of the risk of cerebrovascular events with an adverse course
in at-risk individuals including people with
diabetes, dyslipidemia, and heart disease,
smokers, and people with congenital or acquired coagulation disorders, with respect
to the control population. The unexpected
preponderance of asymptomatic individuals (55%), essentially the absence of the
“claudication” symptom as the main clinical
manifestation of hypoperfusion with a consequent relative discrepancy, accounts for
the notable proportion of underestimated
cases, which are therefore added to the first
observation under emergency conditions.
This situation involves not only a significant reduction of the possibilities for saving
the limb, in a manner that is directly proportional to the duration of the ischemia,
but consistently conditions the patient’s
very survival. A precise evaluation of the
incidence of chronic peripheral obliterative
arteriopathy in the population seems impossible due to its asymptomaticity or paucisymptomaticity in the initial clinical action
stages (I-IIA). Often the symptoms are nonspecific, and the patient does not consult
the specialist but treats himself with selfdressings that are sometimes inappropriate.
Vol. 10 - No. 4
A sufficiently homogeneous datum is the
increase in the incidence of this nosological
finding after sixty years of age.
Epidemiology of ischemic ulcer
The ischemic ulcer is set in the nosological context of a critical limb ischemia.
On the score of evaluations based on
the percentages of major amputations for
aterosclerotic lesions, it could be affirmed
that the annual incidence of critical limb
ischemia is between 500 and 1000 new cases every year per million population.1
It is perhaps still more difficult to obtain
definite data on the prevalence of ischemic
ulcers. There exist significant differences
between several studies, linked to a series
of factors: 1) studies of global or actual
prevalence (should all ulcers so be considered or only active ones?); 2) the specialist branch to which the concerned clinician
belongs; 3) inclusion and exclusion criteria
(some studies only consider leg ulcers but
not foot ulcers); 4) age of the population
sample (there is a clear association between
age and some types of chronic ulcers); 5)
methodology of the study (a questionnaire
offered directly to the population can lead
to a high percentage of false positives).2
To all these factors, presenting a potential
major limit to the epidemiological investigations on all types of skin ulcers, it is essential in ischemic ulcers to consider the
gangrenous ulcer as separate.
Generally, it has been presumed that a
combination of questionnaires addressed
to specialists and to a random population
sample could be the best method of estabTable II.—Prevalence of ischemic ulcer.
Author
Cornwall, 1986
Callam, 1987
Baker, 1991
Salaman, 1995
Nelzen, 1996
O’Brien, 2000
Country
Prevalence
UK
Scotland
Australia
UK
Sweden
Ireland
9%
22%
22%
9%
9%
10.5%
From G. Guarnera.3
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lishing the real prevalence of skin ulcers.
Presently available data show a prevalence
of ischemic ulcers varying from 9% to 22%
(Table II).3
References
1. Norgren L, Hiatt WR, Dormady JA et al. Inter-society
consensus for the management of peripheral arterial
disease (TASC II). J Vasc Surg 2007;45(1 Suppl):S5S67.
2. Briggs M, Closs SJ. The prevalence of leg ulceration: a
review of the literature. EWMA Journal 2003;3:14-20.
3. Guarnera G. Le ulcere vascolari degli arti inferiori
(Vascular ulcers of the lower limbs). Salerno: Momento Medico; 2011.
CLINICAL EXAMINATION
If well conducted, the clinical examination is generally sufficient to make a diagnosis of ischemic ulcer and critical limb
ischemia. A proper clinical examination is
not possible without an accurate and complete medical history which, naturally, must
not be limited to the study and evaluation
of the vascular situation, but must be oriented to the search for possible risk factors
including arterial hypertension, diabetes
mellitus, hyperdyslipidemias, tobacco use,
thrombophilic conditions and coagulation
disorders, intake of estrogen/progestins etc.
and the presence of any related pathologies
such as cardiopathies (ischemic, dilated,
sclerotic-hypertensive), cerebrovascular pathology, respiratory diseases, polycythemia,
renal failure, etc.
A careful medical history must be followed by an equally accurate physical examination that must include a systematic
passage through the classical portions of
physical symptomatology, with particular
regard to inspection, auscultation and palpation.
It is fundamental, before the regional
clinical examination, to carry out a general
physical examination and a physical examination of the individual organs and systems,
aimed at excluding clinical pictures attributable to cardiac, internal medicine, metabolic, renal or neurological pathology (arte-
176
rial hypertension, heart failure, arrhythmias,
diabetes mellitus, chronic renal failure, cerebral vasculopathies, neural radiculopathies, etc.) that condition and/or aggravate
the peripheral vascular disease.
The observation of the skin of an ischemic limb, of its coloring (pallor, cyanosis,
erythrosis), of possible variations in relation
to posture (acral pallor in decubitus), of trophism and of alterations of the skin adnexa
(dystrophy of the skin, absence of hair and
onychodysplasie), the presence of trophic
lesions in acral locations or, according to
the location, of an angiosomic type, scars
from previous ulcerative lesions and the
outcomes of minor and major amputations,
the absence of arterial pulses upon palpation at the brachial-antebrachial landmarks,
at the inguinal site, in the popliteal area and
at the common subpopliteal landmarks, the
palpation of pulsating masses in the abdomen, the detection through auscultation of
“indigenous” murmurs in correspondence
with the anatomical auscultation sites such
as the lateral-cervical regions, the supraclavicular fossae, the inguinal regions, Scarpa’s
triangle, the popliteal compartment, etc.
confirm the suspected diagnosis of arteriopathy.
Instrumental and laboratory
diagnostics
Ultrasound examinations
The execution of a basic instrumental
parameter that is extremely important for
discriminating between healthy patients
and patients with pathology must follow
the classical physical symptomatology: the
ankle-brachial index (ABI according to the
known Anglo-Saxon acronym or the Winsor Index), which precisely expresses the
relationship between the systolic pressure
value measured at the ankle and the systolic pressure value measured at the humerus
on a patient at rest, in the supine position.
The reading must be performed on both
limbs during the first visit and checked in
case of a change in the clinical picture. It is
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appropriate to measure the two pressures
at the same time, in consideration of the
variability that can be encountered in the
first minutes of detection with relation to
the patient’s movements. If not performed
by experienced personnel and with the required accuracy, the ABI reading can have
rather high “intraobserver” variability.
Paradoxical ABI results (values greater
than 1.3) can emerge in patients with incompressibility of the arterial walls, as in
the case of diabetics or in those with medial calcinosis (Monckeberg’s disease). The
continuous wave Doppler examination still
retains its validity for diagnostic purposes
for the measurement of the segmental pressures of the transversal pressure gradients
between the healthy limb and the limb with
stenotic-obstructive lesions and for dynamic
tests during the study of irroration prevalences of the palmar and plantar arches.
A portable device is sufficient for the ABI
reading (Figure 1).
The color-Doppler ultrasound, a method
with the advantages of being non-invasive,
low-cost, reproducible, and having high
specificity and sensitivity, and with the
only limit of being an operator-dependent
method, is used to locate the site and assess
the severity of the arterial lesion responsible for the clinical manifestation and to
exclude a possible ectasia pathology borne
Figure 2.—Color-Doppler ultrasound machine.
by the arterial region in question. It is an
instrumental investigation that should not
be used routinely in the vascular diagnosis
of the lower limbs while, on the contrary,
it is indicated in the morphological study
of the femoral bifurcation and the superficial femoral and deep femoral segments
and as an evaluation prior to angiography
in cases in which a revascularization surgery is hypothesized. After angiography it
provides useful details for the surgical treatment, since it can give useful information
such as the caliber, characteristics of the arterial wall, morphology of the saphenous
vein to be used for the by-pass, and the
mapping of the collateral and perforating
circulations in the case of the in situ surgical option. The use of color-Doppler ultrasound as a replacement for the angiographic investigation does not seem rational, as
the ultrasound method lacks homogeneous
execution criteria and still has operator-dependent reporting (Figure 2).
Radiological examinations
Figure 1.—Continuous wave (bidirectional) Doppler device.
Vol. 10 - No. 4
As known, angiography is an invasive contrast investigation that is moreover burdened
by a significant rate of morbidity (serious reactions to contrast media in 0.1%) and mortality (0.15%), even if the use of non-ionic
contrast materials, the quality of the devices
for the introduction of the media, and digital
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image subtraction techniques have contributed to significantly reducing complications.
However, for these reasons, angiography is
only indicated in those patients with critical limb in which there is an indication for
surgery, and maintains the role of the intraprocedural method of choice during invasive
therapy, of both the traditional and above all
endovascular types, in a completely prejudiced and codified way.
CT angiography and MR angiography are
invaluable investigations in the study of patients in which a dilatative and/or desiccating pathology is associated with the stenotic-obstructive pathology responsible for
the hypoperfusive finding. In recent years,
in vascular surgery, the spiral CT scan with
three-dimensional image reconstruction has
acquired an important role, as it is a method that allows a very accurate definition of
complex pictures.
Complementary investigations
In the clinical-instrumental course of evaluation of patients with critical limb, there are
other complementary investigations that are
extremely useful due to their predictive significance on the possibility of healing trophic
lesions and for evaluating the optimal level
of amputation. These examinations are the
detection of the segmental systolic pressure,
transcutaneous oximetry, laser Doppler, and
capillaroscopy. The measurement of the seg-
Figure 3.—Digital video capillaroscopy.
178
mental systolic pressures provides quantitative information on the hemodynamic significance of the arterial lesions.
The detection of the transcutaneous oxygen (TcPO2) and carbon dioxide (TcPCO2)
tensions offers useful data for a metabolic
evaluation of the ischemic tissue. These
parameters represent an important instrument for the prediction of the healing of
an ischemic ulcerative lesion; partial oxygen tensive values less than 20 mmHg are a
limit of therapeutic failure while 40 mmHg
are predictive of possible healing.
Laser Doppler is less used for diagnostic
purposes; it finds its rightful place primarily
in pathophysiology clinical research and
studies. Capillaroscopy, which is specifically mentioned elsewhere in this document,
finds a unique indication in the diagnostic
confirmation of ischemic trophic lesions
during scleroderma (Figure 3).
Oscillography and plethysmographic investigations are to be entirely proscribed, as
they are now obsolete diagnostics.
Clinical-diagnostic approach to
the ischemic ulcerative lesion
The clinical process remains the most
important one also with regard to the diagnostic approach to ulcerative lesions in
the context of the nosographic finding of
chronic critical ischemia (Lériche-Fontaine
stage IV – Rutherford degree III, cat. 5-6). In
fact, a careful clinical-morphological examination of the lesion allows the confirmation
of the diagnostic direction through the evaluation of the classic parameters represented
by the size, depth, shape, number, site, and
border and background characteristics and
by the examination of the perilesional skin.
The ischemic ulcer usually has a pale background with little granulation tissue, irregular margins and edges that are often necrotic, inserted in a context of perilesional skin
with marked dystrophic manifestations (loss
of the normal pilifer assets and ungual alterations). The regional and perilesional skin
looks pale, and is often characterized by ecchymotic marbling and/or diffuse cyanosis.
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Edema from the forced antalgic declivous
position frequently coexists, and is particularly feared in the arteriopathic patient with
regional insufficiency because it triggers a
vicious cycle of tissue suffering that progressively aggravates the perfusion deficit
and the metabolic exchanges on the microcirculation. The site of the ischemic ulcerative lesions can be acral (toes), localize to
the heel, have a mechanical genesis “from
pressure” on an arteriopathic base (and thus
be localized to areas subjected to prolonged
tissue crushing), or have a typically “vascular” disposition in the sense that it can localize to the distribution area of an artery that
feeds that area (anterolateral region of the
leg, heads of the first and fifth metatarsal,
plantar surfaces). The concept of angiosome
is thus introduced to indicate the anatomical
units characterized by a specific and readily
identifiable vascularization. The leg’s three
distribution vessels (anterior tibial artery,
posterior tibial artery and peroneal artery)
“feed” six distinct angiosomes at the ankle
and the foot. A correlation is demonstrated
between vasal obliteration and localization
of the ulcers, and this allows the surgical
treatment to be directed in an elective manner toward the vessel that is at the origin of
the regional perfusion deficit.
The clinical examination therefore does
not deviate from the usual path that must be
followed in every wound care patient with
regard to the ulcer’s evaluation. The site must
be evaluated for the pathophysiological reasons described previously, the shape and the
number, the background (coloring, presence
of signs of bacterial contamination or colonization, granulation centers, necrotic eschars),
the skin and more generally the skin adnexa
and the perilesional tissues, the presence of
pain, its characteristics and the modalities of
occurrence, and the possible presence of olfactory peculiarities related to tissue necrosis.
The clinical-diagnostic approach to patients with ischemic ulcer is essentially
based on four elements: 1) medical history;
2) clinical-morphological examination of
the ulcer and perilesional skin; 3) vascular
symptomatological examination; 4) laboratory-instrumental study (Figure 4).
Vol. 10 - No. 4
Figure 4.—Ischemic ulcer.
Role of the clinical
pathology laboratory
In the clinical-diagnostic path of the patient with a critical limb and ischemic ulcerative lesion, the laboratory represents a
precious support for the clinical monitoring of the patient and for the application of
correct and targeted therapeutic options of
both a systemic and topical class.
The reference is to the control of the routine laboratory parameters to show any infections (leukocytosis, sedimentation rate),
alterations in glucose metabolism, protein
levels, renal function and myocytolysis parameters.
A frequent and relevant problem from
the clinical point of view is bacterial and
fungal colonization of ulcerative lesions;
the appearance of signs and symptoms
that can be correlated with the presence
of an infection including fever, pain, lymphangitic involvement, extension of the lesion or delay in scarring, coloring of the
background, and worsening olfactory modifications must be orienting towards this
complication, particularly in lesions with a
primitively ischemic genesis. In these cases
it is extremely important from the pathophysiological point of view to identify the
responsible microbial agent through targeted microbiological surveys such as the
culture test, which is now standardized
and reproducible. This examination allows
the isolation of any pathogenic agents and
the evaluation in vitro of the antimicrobial
agents most appropriate for the treatment
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MOLLO
PHYSIOPATHOLOGY
Figure 5.—Infection and in vivo evaluation.
of the infection on the basis of an antibiogram, thereby reducing possible empiricism margins (Figure 5).
The role of histopathology in ulcerative lesions in the course of critical limb
ischemia is marginal due to intuitive reasons tied to the patient’s clinical history and
to the evolution, even if in some cases of
overlap of different nosographic elements it
may be necessary to turn to histology for a
reliable differential diagnosis.1-11
References
1. Bettmann MA, Heesen T et al. For the SCVIR Contrast
Agent Registry Investigators. Radiology 1997;203:61120.
2. Dormandy J, Stock G. Critical legs ischaemia: its
pathophysiology and management. Berlin: SpringerVerlag; 1990.
3. Guarnera G, Papi M. Skin ulcer of the lower limbs.
[Italian: L’ulcera cutanea degli arti inferiori]. Saronno,
Varese: Ed. Monti; 2000.
4. Guarnera G. Vascular ulcers of the lower limbs. [Italian: Le ulcere vascolari degli arti inferiori]. Testo Atlante. Salerno: Ed. Momento Medico; 2011.
5. Koelemay MJ, Denhang D et al. Diagnosis of arterial
disease of the lower extremities with duplex ultrasonography. British Journal of Surgery 1996;83:404-9.
6. Petruzzellis V et al. Vascular ulcers of the lower limbs.
[Italian: Le ulcere vascolari degli arti inferiori.] Roma:
Pragma. Ed. 1992
7. Ruangsetakit C et al. Transcutaneous oxygen tension:
a useful predictor of ulcer healing in critical limb ischaemia. J Wound Care 2010;19:202-6.
8. Rutherford RB, Baker JD et al. Recommended standards for reports dealing with lower extremity ischaemia: revised version. J Vasc Surg 1997;42:128-33.
9. Stoffer HE, Kester AD et al. The diagnostic value of
signs and symptoms associated with peripheral arterial occlusive disease in general practice. A multivariate approach. Med Decis Making 1997;17:61-70.
10. Taylor GI, Pan WR. Angiosomes of the leg. Anatomic
study and clinical implications. Plast Reconstruct Surg
1998;102:599-616.
11. Waugh JR, Sacharías N. Arteriographic complications
in the DSA era. Radiology 1992;182:243-6.
180
The peripheral arterial insufficiency,
causing the tissue damage in the peripheral
arteriopathy is provoked by a reduction in
the blood flow, determined, in 80-90% of
cases, by the presence of atherosclerotic
plaques (Figure 6).
The atheroma is the location of platelet
aggregation and of coagulation cascade
activation causing alterations in the blood
flow. The vessel’s haemodynamics becomes
altered: the blood flow velocity at stenosis
level increases proportionally to the severity
of the lesion, diminishing significantly the
further down the lesion is located together with arterial pressure. The endothelium
performs a basic role in the microcirculatory homeostasis in that with the production
of several molecules it actively participates
in the haemoreological and coagulative
processes. The macrocirculatory alterations
determined by the atherosclerotic disease
effect the microcirculation.
In microcirculation there are at least two
systems giving rise to the local regulation
of the flow. The microvascular flow regulating system (MFRS) is always active, with
the production by the endothelium of some
molecules with both a vasodilatation and a
vasoconstrictive action, in the local regulation of micro-haemodynamics, including
the skin. Prostacyclin, nitric oxide, EDRF
and tissue plasminogen activator are only
some of the molecules produced by the
MRS system regulating the blood inflow
into the microvessels.
The microvascular defence system (MD)
is the other system involved in circulatory
microregulation. It concerns molecules and
soluble receptors and membranes produced by the endothelium, but above all by
the circulating cells (leukocytes and platelets), in a broad reply to a “threat” which
can disturb the microcirculatory homeostasis, which on the whole activate the platelet
aggregation and promote vasoconstriction
(DCF, thromboxane A2, serotonin, coagulation factors, PAI, endothelin). These two
regulatory systems are normally in homeostatic balance between activators and re-
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Figure 6.—Peripheral arteriopathy.
Figure 7.—Diabetic foot ulcer.
spective inhibitors. The reduction of macrocirculatory perfusion is “read” by the system
as a loss of function and a check is made on
the prevalence of the MDS activity on the
MFRS; it brings about an increase of proaggregatory and vasoconstrictor activity.1 This
mechanism contributes to activating the
“endothelial dysfunction”,2 being the main
cause of the altered control of the fibrinolytic-coagulative balance and of the haemodynamics with negative involvement of
the haemoreological and proinflammatory
mechanisms (activation of leukocytes) and
physiopathological implications influencing
the microcirculation tissue. In the advanced
stages of the arteriopathy (severe claudication, critical ischemia) the hypoperfusion
causes persistent hypoxia, prevalence of
the MDS on the MFRS, intense activity of
leukocytes, major endothelial pain, microvascular thrombosis, pain tissue reaching
necrosis and the formation of skin ulcer.
The onset of critical limb ischemia (CLI)
occurs when arterial stenoses or occlusions
reduce the blood flow to the extent that,
notwithstanding the compensation mechanisms (formation of collateral circulations,
activations of vasodilatory and antiaggregant factors), the nutritional needs of peripheral microcirculation could not be ensured, even at rest.
In its classical definition the CLI is a manifestation of the chronic peripheral obstructive arteriopathy inflicted on patients with
chronic ischemic pain at rest or patients
with ischemic skin lesions be they ulcers or
gangrene, with symptoms and indications
being present for at least two weeks, as attributed to a demonstrated arteriopathy.3
A subgroup of patients does not fall within this definition, in that it comes with a serious peripheral arteriopathy with reduced
pressure of perfusion at the ankle joint,
even if this is asymptomatic. These patients,
suffer from “chronic subclinical ischemia”,
owing to their sedentariness do not have
claudication, have a reduced perception of
pain due to diabetic neuropathy and are at
high risk of progression of the pathology,
since they have the same local and systemic
outcomes as patients with full-blown CLI.2
The trophic lesions (ulcerations and/or
distal gangrene) often follow microtraumatisms and could interest the distal extremity with digital or interdigital localisations.
The sensory neuropathy typical of diabetic
persons worsens the clinical picture since,
owing to reduced skin sensitivity and to
reduced sweating, it could determine fissures of the dry skin, an increase of arteriovenous shunt and the evolution towards
a ulcer-gangrene clinical picture, although
paucisymptomatic (Figure 7).
The presence of the diabetes mellitus
worsens the clinical picture of the critical
ischemia and of the peripheral arteriopathy. Some 15% of diabetic patients develop
a foot ulcer (more likely in the sole and
toes), while from 14% to 24% undergo an
amputation. The accompanying neuropathy
Vol. 10 - No. 4
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Figure 8.—Limb that requires revascularization.
contributes to the occurrence of the typical osteoarticular deformities of the diabetic
foot.4 Clinically the opening of several arteriovenous shunts could be the cause of
objective evidence of a warm foot, while
caring for the distal arteries and the microcirculatory area could lead to the discovery
of an “eusfigmia” of the tibial pulses (with
normal ABI or exceeding 1).
Pharmacological therapy
In consideration of the variety of onset
clinical pictures, of the multi-area localisation of the atherothrombosis, of associated
comorbidities, of possible therapeutic options (medical-surgical-endovascular) the
approach made to the patient should be as
early and multidisciplinary as possible.
Given that the reduction of the incidence
and severity of critical ischemia (ulcers and
amputations) could not overlook an early
diagnosis of chronic peripheral obliterative
arteriopathy and an aggressive management
of the risk factors of atherothrombosis, the
objectives of CLI treatment are: to resolve
ischemic pain, to heal ischemic ulcers, to
avoid limb loss, to improve functional ability, to improve the patient’s quality of life
and life expectancy.
The first step is to treat the pain, be it
localised in the skin or in deeper tissues
(joint, muscular, bone). Revascularization
improves the pain. The control turns out to
182
be more efficient if the analgesic is administered regularly according to the WHO scale
for pain control.5
In some selected and refractory cases
an implant of spinal cord stimulators (SCS)
could be required for pain therapy. Cord
stimulation (spinal cord stimulation) induces
an inhibition of nociceptive sensitivity and is
thus an analgesic. The mechanisms through
which electro-stimulation applies its antalgic
effect have not yet been made clear at all.6, 7
The anxiety-depressive component often
found in patients with CLI also requires the
use of anti-anxiety drugs and antidepressants (Figure 8).
Although revascularization constitutes
the best option, where indicated, it could
not overlook an intensive medical treatment preceding, accompanying and following the said revascularization to guarantee
better results in terms of healing ulcers, of
amputations and of survival.
The drugs which are recognised and validated for the treatment of critical ischemia
are the prostanoids, iloprost (a stable analogue of PGI2) and PGE1 (alprostadil). No
other drugs are available which could be
alternatively used (TASC II).
Iloprost performs its action by inhibiting
the production and release of TXA2, PDGF
and factor V of the coagulation; it besides
inhibits adherence and limits the tissue
damage caused by the aggregation of leukocytes and platelet, while its more evident
and more immediate action lies in vasodilatation. It besides interacts with the NO,
inhibiting the adherence and endothelial
permeability, interacts with the build-up of
leukocytes in the ischemic location, inhibits
the interactions between endothelium and
phagocytes, reduces the levels of T-lymphocytes and cytokines, reduces the levels of ICAM-1, reduces blood viscosity and
lastly takes part in the angiogenesis mechanisms through an increase in VEGF levels.8,
9 Iloprost administered during femoral-distal
reconstructions allows a marked reduction
in peripheral resistances, in a significantly
superior manner to alprostadil, though with
major collateral effects (Figure 9).10
Recently a few scientific Associations
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December 2012
MOLLO
(ESC, European Society of Cardiology,
EASD, European Association for the Study
of Diabetes, CHEST 2012) have recommended with an “A” level of evidence treating patients with critical limb ischemia who
are not susceptible to revascularization with
prostacyclin infusion.11
A retrospective Italian study of the Società Italiana di Angiologia e Patologia Vascolare – Italian Association of Angiology and
Vascular Pathology - (SIAPAV) has shown
that intensive treatment and the repetition
of therapeutic cycles improves the long
term outcome, with a significant increase of
the number of saved limbs. This concerns
patients requiring assistance under a regime
of hospitalisation and the so called “taking
on” by a dedicated structure, which can
provide all diagnostic and therapeutic procedure as may be necessary from time to
time, and above all to ensure an adequate
and careful follow-up.12
Some other drugs are considered indispensable in “intensive” CLI treatment: antiaggregant platelet (ASA and ticlopidine)
13, 14 and anticoagulants (heparins and dicoumarols) which are useful in reducing
the risk of major cardiovascular events, in
reducing the progression of atherosclerosis in the distal femoral-popliteal areas, in
favouring a clear airway for the peripheral
bypass 15. The vasodilators (pentoxifylline,
naftidrofuryl) have given little significant
results in this context. Other drugs which
are used are the analgesics and the painkillers by systemic route and/or epidurally (or
SCS). Support drugs are considered to be
antihypertensives and congestive heart failure drugs, statins and hypolipemiants and,
generally, all drugs for risk factor control
and the reduction of vascular events.
The intensive pharmacological treatment
associated to revascularization, when indicated, would allow stabilisation of the pathology in 61.8% of the cases, clinical improvement in 24.5%, with percentages of
13.6% of amputations, 3.8% of mortality and
3.4% of major cardiovascular events. It was
possible to heal ulcers in 77.5% of treated
lesions (datum from the of the Angiology
Multispecialty Department of the Vittorio
Vol. 10 - No. 4
Figure 9.—Limb that requires revascularization.
150
107
120
90
57
60
38
32
30
6
2
9
0
Pazienti stabilizzati
AOCP IV ulcere stabilizzate
TIA
AOCP da IIB a IIA
Amputazioni
Figure 10.—Results associated with drug intensive treatment and revascularization.
Emanuele Polyclinic of Catania) (Figure 10).
These results are better than those carried
in international literature.16-22
Rehabilitation methods
and programmes
The rehabilitation of patients suffering
from CLI envisages the activation of specific rehabilitation programmes, in which
controlled physical activity constitutes the
main methodology used. Rehabilitation programmes are adopted according to deambulation protocols only for those patients in
whom trophic lesion healing was obtained
as well as the passing from an advanced
stage of arteriopathy (stage III, IV) to a less
advanced stage (stage IIB, IIA).
Patients are advised to run a daily specific track, under controlled speed and in-
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clination, or, if they can attend at a vascular rehabilitation outpatients’department, to
perform deambulation exercises on a treadmill. Some protocols envisage 15 controlled physical exercise sessions each lasting
about 30 minutes. The distance to be run
equals about 70% of the patient’s deambulatory capacity (painless interval walking)
with a 10% inclination and a speed of 3.2
km/h. Each exercise is spaced out over a
recovery period equivalent to the recovery period, after maximum exercise, necessary for the disappearance of pain after
the exercise is stopped.23 The reason is
to increase walking autonomy by training
and the development of collateral circulation. For the same purpose exercises could
also be undertaken for the improvement of
walking techniques, deambulatory capacity
and posture.
Patients who instead present trophic lesions such as to prevent proper deambulation, should undertake the rehabilitation
even if enticed by the performance of specific programmes featuring the execution of
active and passive rehabilitation exercises
to improve limb effectiveness and muscle
tone. These activities, at least initially, must
be repeated on a daily basis, through the
support given by the physiatrist and/or
physiotherapist.
Rehabilitation also envisages the support
of psychologist specialists, who should allow the patient, during the various stages of
the disease, to overcome specific psychological blocks which could influence the
therapeutic effects of the given therapy.
The purpose is that of developing an integrated system of therapy/rehabilitation,
by minimising the effects of the cure’s fragmentation. Moreover, the identification of
some psychological factors could be useful to increase adherence to treatment by
drugs, through psycho-educational interventions and by psychologically sustaining
the patient.
Since some psychological variables are
strictly connected with amputation interventions, the treatment of the psychological
component assumes a fundamental position in favour of interventions which sustain
184
the patient in adapting oneself to the loss
of a limb.
BOX 1
Therapy aims in severe arteriopathy:
—— to resolve ischemic pain
—— to heal ulcers
—— to avoid limb loss
—— to improve the patient’s quality of
life
—— to prolong life expectancy.
BOX 2
—— Revascularization should be considered in therapeutic strategy, taking
into account the risks linked with the intervention, be they surgical or endovascular, the anatomical-functional nature
of the altered vessels, run off, comorbidity, the patient’s life expectancy and the
functional recovery capacity of the limb
suffering the ischemia.
BOX 3
—— The chronic critical ischemia of
the lower limbs can obtain benefit from
an integrated medical-surgical-rehabilitation treatment.
—— The association of several therapeutic options determines a synergic effect on the improvement of the clinical
picture and on the patient’s quality of
life.
—— The intensive treatment is based
on the use of active drugs on the microcirculation system (prostanoids, antiaggregants, anticoagulants, haemorheologics) associated with analgesic treatments
(pharmacological painkiller or by using
SCS) and with ongoing clinical and instrumental monitoring, to be performed
in a specialist environment.
ACTA VULNOLOGICA
December 2012
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—— Personalised intensive treatment
should be established as early as possible.
—— A correction of risk factors should
be performed (smoking, diabetes mellitus, arterial hypertension, dyslipidemia,
hyperhomocysteinemia, hypercoagulability syndromes etc.).
—— A primary and secondary prevention of cerebro- and cardiovascular
events should be performed (with antiaggregants, statines, ace-inhibitors).
—— Association of accompanying comorbid vascular therapy (carotidopathies, aortic abdominal aneurysms,
ischemic heart disease etc.) and otherwise (chronic respiratory and renal insufficiency etc.).
—— Intensive angiological treatment in
specialist structures dedicated to patients
suffering from chronic critical ischemia
constitutes an alternative to early amputation.
—— In a chosen sample of patients
who cannot be revascularized evaluate the neo-angiogenic therapy option, above all by using the progenitor
cells of the endothelial cells through in
situ differentiation of autologous stem
cells.
References
1. Andreozzi GM L’Ischemia critica (The Critical
ischemia), La Presse Medicale, ed. it. Suppl. no. 3
March 1993.
2. Smith FB, Lee AJ, Hau CM, Rumley A, Lowe GD,
Fowkes FG. Edinburgh Artery Study. Blood Coagul
Fibrinolysis 2000;11:43-50.
3. Second European Consensus Document on chronic
critical leg ischemia. Circulation 1991;84(Suppl):IV1IV26.
4. TASC II - Working group. Inter-Society Consensus for
the Management of PAD. Eur J Vasc Endovasc Surg
2007.
5. Aronow WS, Ahn C. Prevalence of coexistence of
coronary artery disease, peripheral arterial disease,
and atherothrombotic brain infarction in men and
woman <62 years of age. Am J Cardiol 1994;74:64-5.
6. Guarnera G, Mascellari L, Bianchini G, Furgiuele S,
Zucchi R, Camilli S. Il ruolo dell’elettrostimolazione
midollare nell’ischemia dell’arto (Il ruolo of the electro-stimulation midollare in the ischemia of the limb).
Minerva Cardioang 1996;44:663-7.
Vol. 10 - No. 4
7. Jivegard LE, Augustinsson LE, Holm J, Risberg B, Ortenwall P. Effects of spinal cord stimulation in patients with inoperable severe lower limb ischemia: a
prospective randomised controlled study. Eur J Vasc
Endovasc Surg 1995;9:421-5.
8. Mazzone et al. The effects of iloprost infusion on microcirculation is independent of nitric oxide metabolites and endothelin-1 in chronic peripheral ischemia.
University of Pavia, IRCCS S. Matteo Hospital, Pavia,
Italy 10.1046/j.1365-2362.1999.00411
9. Mazzone A et al. Effects of iloprost on adhesion molecules and F1 + 2 in peripheral ischemia. European
Journal of Clinical Investigation 2002;32:882-8.
10. Krueger U et al. Effect of intravenous iloprost and
alprostadil (PGE1) on peripheral resistance during
femoro-distal reconstructions. International Angiology 2000;19:358-65.
11. Guidelines on diabetes, pre-diabetes, and cardiovascular disease: full text. The task force on diabetes
and cardiovascular disease of the European Society
of Cardiology (ESC) and of the European Association
for the Study of Diabetes (EASD). European Hearth
Journal 2007;doi:10.1093/eurhearthj/ehI261.
12. Andreozzi GM, Martini R, Cordova R, D’Eri A, Todini AR, of Salvo MM. Il management intensivo
dell’arteriopatia periferica in fase avanzata (Intensive
management of advanced stage periferal arteriopathy). Min Cardioangiol 2001;496(s1):67-70.
13. Antithrombotic Trialist’s Collaboration Collaborative
meta-analysis of randomised trials of antiplatelet
therapy for prevention of death, myiocardial infarction and stroke in high risk patients. BMJ 2002.
14. Clagett P, Sobel M, Jackson MR, Lip GYH, Tangelder
M, Verhaeghe R. Thrombolytic Therapy Conference on Antithrombotic and Occlusive Disease: The
Seventh ACCP Antithrombotic Therapy in Peripheral Arterial. Chest 2004;126;609-626 DOI 10.1378/
chest.126.3_suppl. 609S.
15. Antithrombotic Trialist’s Collaboration Collaborative
metanalysis of randomised trials of antiplatelet therapy for prevention of death, myiocardial infarction
and stroke in high risk patients. BMJ 2002.
16. ICAI study Group: Prostanoids for Chronic Critical
Leg Ischemia. Ann Intern Med 1999.
17. Treatment of limb threatening ischemia with intravenous Iloprost: A randomised double-blind placebo
controlled study. UK Severe limb Ischemia Study
Group. Eur J Vasc Surg 1991;5:511-6.
18. Dormandy JA, Loh A. Critical limb ischemia. In:
Tooke JE, Lowe GDO, eds. A Textbook of Vascular
Medicine. London: Arnold; 1996. p. 221-36.
19. Dormandy J. Use of the prostacicline analogue iloprost in the treatment of patients with critical limb
ischemia. Therapie 1991;46:319-22.
20. Staben P, Albring M. Treatment of patients with peripheral occlusive disease Fontaine stage III and IV
with intravenous iloprost: an open study in 900 patients. Prostaglandines, Leuokotrienes and Essential
Fatty acids 1996;54:327-33.
21. Duthois S et al. Tolerance of Iloprost and results of
treatment of chronic severe lower limb ischemia in
diabetic patients. A retrospective study of 64 consecutive cases Diabetes & Metabolism 2003.
22. Loosemore TM, Chalmers TC, Dormandy JA. A metaanalysis of randomized placebo control trials in Fontaine stages III and IV peripheral occlusive arterial
disease. International Angiology 1994;13:133-42.
23. Hied WR, Hirsch AT, Regensteiner JG, Brass EP. Clinical trials for claudication: assessment of exercise performance, functional status, and clinical end points.
Circulation 1995;92:614-21.
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SURGICAL TREATMENT
The basic treatment of critical limb
ischemia consists in surgical or endovascular revascularization, with the main aim of
saving the limb.
In therapeutic strategy one need consider
the angiosome concerned and collateral areas.
The angiosome concept was introduced
towards the end of the eighties to identify
anatomical units with their own specific vascularization. With regard to the ankle joint
and the foot six distinct angiosomes have
been identified, as supplied by the three leg
arteries (posterior tibial artery no. 3; anterior tibial artery no. 1; peroneal [fibular] artery no. 2), with a possibility of anastomosis
and connections between adjacent areas.1
These anatomical studies have allowed correlating the localisation of ulcers with the
stenotic or obstructed vessel and address-
ing the surgical intervention of revascularization selectively towards the vessel which
supplies the angiosome where the lesion is
located (Figure 11).2
A high percentage of trophic lesion healing and limb saving (between 70% and
90%) can be obtained in case of surgical
or endovascular revascularization of vessels
directly supplying the damaged angiosome.
In case of adequate interconnections, even
the revascularization of the feeding artery
of the adjacent angiosome could cause the
healing of the lesion (in 60-70% of the cases ).3-6 Such data are confirmed by a recent work which has shown the positive
influence on the healing of ulcers of an
adequate collateral distal circulation after
a revascularization procedure. Seventy-six
ischemic ulcers, classified according to the
angiosome concept, have been followed after a revascularization intervention of a single vessel. After twelve months of follow-up
Figure 11.—According to the anatomical concept of angiosome, the localisation of an ulcer leads back to the vessel
where the lesion is located. (From: Guarnera G. Le ulcere vascolari degli arti inferiori - Vascular ulcers of the lower
limbs. Salerno: Momento Medico Ed.; 2011).
186
ACTA VULNOLOGICA
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the percentage of lesion healing in case of
direct revascularization (92%) was higher in
respect of cases of indirect revascularization
(73%), but similar to cases in which indirect
revascularization was supported by a rich
collateral circulation (85%).7
In a recent review of 249 patients, suffering from limb ischemic lesions and who underwent a distal bypass, a total percentage
of healing of ischemic ulcers was obtained
of 84.7%, with lower values in cases of indirect revascularization, only in patients with
chronic kidney failure.
In this study the localisation and the extension of the ulcers and the comorbidities
appear to be more important than the angiosome concept in terms of lesion healing.8
Adversely, another recent review of 369
patients who underwent an endovascular
procedure for a subpopliteal lesion has
documented the importance of revasculating the feeding artery of the pathological
angiosome in terms of limb saving and the
prevention of major amputations.9
From a technical point of view the revascularization could take place with an endovascular procedure or with a surgical
bypass intervention. The TransAtlantic
Inter-Society Consensus has identified the
profile and the extension of the vessel lesions as reference parameters in choosing
between the two methods, while the BASIL
trial shows the benefits of the traditional
surgery for patients with a life expectancy
exceeding two years, besides emphasising
the importance of an autologous vessel as
an ideal conduit for a bypass.10, 11
Generally speaking, the more widespread
therapeutic attitude consists in reserving
traditional surgical therapy to extended lesions of the aortoiliac area, of the common
femoral and superficial femoral arteries and
the endovascular treatment of isolated lesions of the iliac arteries, of the superficial
femoral artery and of the subpopliteal vessels.
For the purposes of lesion healing, one
should finally consider that it is often necessary to adopt a series of post-revascularization procedures (debridement surgery, minor amputations, VAC therapy, skin grafts).
Vol. 10 - No. 4
BOX
—— The main aim of the surgical treatment is limb saving
—— In the therapeutic strategy account
need to be taken of the involved angiosome and collateral areas
—— Endovascular procedure should be
the first-choice method, while traditional surgery could be reserved for lesions
which are technically not appropriate for
angioplasty
—— The endovascular procedure and
revascularization surgery are often complementary
References
1. Taylor GI, Pan WR. Angiomes of the leg. Anatomic
study and clinical implications. Plast Reconstruct Surg
1998;102:599-616
2. Setacci C, De Doned G, Setacci F, Chisci E. Ischemic
foot: definition, etiology and angiosome concept. J
Cardiovasc Surg 2010;51:223-31.
3. Neville RF, Attinger CE, Bulan EJ et al. Revascularization of a specific angiosome for limb salvage: does
the target artery matter? Ann Vasc Surg 2009;23:36773.
4. Soderstrom M, Aho P-S, Lepantalo M, Alback A. The
influence of the characteristics of ischemic tissue lesions on ulcer healing time after infrainguinal bypass
for critical leg ischemia. J Vasc Surg 2009;49:932-7.
5. Alexandrescu VA, Hubermont G, Philips Y et al. Selective primary angioplasty following an angiosome
model of reperfusion in the treatment of Wagner 1-4
diabetic foot lesions: practice in a multidisciplinary
diabetic limb service. J Endovasc Ther 2008;15:58093.
6. Iida O, Nanto S, Uematsu M et al. Importance of the
angiosome concept for endovascular therapy in patients with critical limb ischemia. Catheter Cardiovasc
Interv 2010;75:837.
7. Varela C, Aci NF, Bleda S et al. The role of foot collateral vessels on ulcer healing and limb salvage after
successful endovascular and surgical distal procedures according to an angiosome model. Vasc Endovascular Surg 2010 [In press].
8. Azuma N, Uchida H, Kokubo T, Koya A, Akasaka
N, Sasajima T. Factors influencing wound healing of
critical ischemic foot after bypass surgery: is the angiosome important in selecting bypass target artery?
Eur J Vasc Endovasc Surg 2012;43:322-8.
9. Iida O, Soga Y, Hirano K, Kawasaki D, Suzuki K, Miyashita Y et al. Long-term results of direct and indirect endovascular revascularization based on the
angiosome concept in patients with critical limb
ischemia presenting with isolated below-the-knee lesions. J Vasc Surg 2012;55:363-70.
10. Bradbury AW, Adam DJ, Bell J, Forbes JF, Fowkes FG,
Gillespie I et al. Bypass versus angioplasty in severe
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ischemia of leg (BASIL) trial: analysis of amputation
free and overall survival by treatment received. J Vasc
Surg 2010;51:18Se31S.
11. TASC II Working Group. Inter-society consensus for
the management of peripheral arterial disease. J Vasc
Surg 2007;45:S1e68.
LOCAL TREATMENT OF
ISCHEMIC LESIONS
Topical treatment has a non secondary
role in patients suffering from ischemic ulcers of the skin and it should be supplemented to systemic drug and surgical treatment. Actually, any improper action might
compromise the healing of an ischemic
ulcer rendering useless proper therapeutic
medical/surgical management.
A mistaken local treatment could however determine amputation as a result, even
if a technically perfect revascularization
intervention has been performed. Awareness of the principle regulating the local
management of chronic skin lesions would
allow a further improvement of the clinical results in patients with critical ischemia
and a consequent reduction in amputation
rates.
Local treatment follows some basic rules
which are still valid for the various clinical
forms of ischemia.
Ischemic lesions could present themselves as:
—— ulcers localised in various, often multiple, areas with variable impairment of surface and deep tissues;
—— dry gangrene or moist gangrene;
—— ulcers as sequelae of revascularization
surgical interventions, or of amputation;
—— acral ischemic lesions in the scleroderma areas, in patients with an arterial
disease embolic disease or with Raynaud’s
disease or suffering from perniosis etc.
Prior to revascularization, when this is
indicated and possible, the ischemic ulcers should be treated with a non-adherent
gauze associating a reduction of the pressure load 1 which could be made, in the
lower limbs, by altering the shoes, orthopedic shoes and plaster casting techniques
188
depending on the locality of the ulcer and
the seriousness of the ischemia.2, 3
Following revascularization it is even
more important to reduce the “load” and
avoid the repetitive traumas caused by footwear. Without such devices one would take
the risk of jeopardizing the beneficial effects of revascularization.
All authors associate the concept of
“good clinical practice” with the possibility
of using a “range”, the widest possible, of
technological products for the treatment of
the trophic lesions.4
If used well, according to pre-set protocols, the possibility of choice of technology
becomes a resource in itself for the containment of health expenses as long as there
would be, on the part of users, an in-depth
awareness of the clinic, techniques and materials.
The basic technologies sustaining proper
management of the skin lesion, further to
its etiology, could be thus, partially, summarised:
—— fast and selective debridement;
—— topical antimicrobials for the prevention of the recurrent septic episodes (ionic
Ag, nanocrystalline Ag, PHMB) in combined
action dressings;
—— negative topical pressure;
—— control of procedural pain;
—— FREM, PESF;
—— compression therapy;
—— growth factors;
—— use of dermal substitutes or of cadaver skin;
—— preservation of the perilesional skin.
The possibility that the clinician can
make use of available advanced technologies widens the clinician’s possibility of interventions and improves the patient’s healing expectancy.
Fast and selective debridement
While the debridement of neuropathic
ulcers in a diabetic person could be surgically performed without any hesitation, in
ischemic ulcers and critical ischemia ulcers,
particularly, it should be assessed whether
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to proceed with enzymatic or autolytic debridement, which is less painful and less
traumatic. Atraumaticness is a prerogative
which should always be taken into account
when healing an ischemic skin ulcer.
After every intervention of debridement,
the lesion is frequently dressed, if possible
daily, having first irrigated it or footbathed it
with tap water and small amounts of soapy
solutions (e.g., chlorhexidine 1%), or with a
sterile physiological solution.5
As soon as the local signs of inflammation
and infection fade, the dressings could be
applied every two or three days by applying, after irrigating with water, the most suitable combined action advanced dressings,
chosen on the score of local conditions.
There are no comparative studies on surgical cleansing, with respect to between enzymatic or autolytic, but experts are unanimous in retaining that cleansing is essential
in case of callus and necrosis and that surgical debridement represents the best choice
when one can practise it.
In the most recent guidelines emphasis
has been made on the precocity of debridement interventions with the removal of the
tissue defined as “non active”, highlighting
the time factor; debridement should be the
fastest possible and performed the soonest possible. It is considered, above all in
ischemic ulcers, as the most efficient action
in the abatement of the bacterial load of the
skin lesion.6
Topical antimicrobials for the prevention
of recurring septic episodes in combined
action dressings.
Treatment with advanced dressings
should be reserved, according to TASC
II, to ulcers in patients who have already
been revascularized according to the basic principles of the “Wound Bed preparation”.4 Much emphasis is laid on the role
of the bacterial population present in the
bed where the ischemic ulcer 5 is found and
above all the role of the staphylococcus aureus representing about 30% of the causes
of infection; polymicrobial infections turn
out to constitute about 40% of the total.7
The infections are considered as extremely
dangerous, above all in diabetic patients,
Vol. 10 - No. 4
because they precede amputation in a percentage of cases which, in the presence
of osteomyelitis, could reach 40%. For this
reason targeted systemic antibiotic therapy
is not considered to be sufficient, and it is
emphasized as very important to associate
very early procedures such as surgical toilet
and drain, followed by an antibiotic therapy
which is targeted and prolonged in time. All
this would be in preparation for any revascularization intervention. Wherever has already been revascularized, or in patients in
whom revascularization cannot take place,
a surgical or hydrosurgical debridement of
the ulcer is performed and subsequently
treatment with advanced dressings and/or
with technologies suitable for the clinical
status of the skin lesion.
Even if there is at least one clinical study
witnessing to the effectiveness of enriched
dressing with ionic silver in accelerating the
healing of chronic lesions and another study
on the effectiveness of cadexomer iodine,
there do not exist in literature any definitive
proofs of the effectiveness of dressings with
antiseptics, although these are abundantly
used in day to day practice and show, in
some studies, certain advantages and are
lower priced.8
The concept of the “recurrent septic” has,
however, been recently introduced and this
corresponds to the stages where a failure
occurs, in the clinical history of skin lesions,
in the healing process set in course by an
increase in the bacterial load of the bed
where the ulcer is found. It is exactly in
the prevention of recurrent septic episodes
that authors confirm the effectiveness of the
dressings with antiseptics.9 This could be
the definitive arrangement in this type of
advanced dressings for the management of
ulcerative skin lesions.
Negative topical pressure
In those lesions where exudation could
not be controlled with absorbent dressings,
use can be made of negative topical pressure, above all in the diabetic foot and in
lesions after partial amputation.10
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Unfortunately, a review of current literature does not presently furnish any proofs
which can affirm that such technology can
accelerate the healing processes of ulcers.
Moreover, negative topical pressure is much
more resorted to, to the greater satisfaction
of operators and patients alike.
Some scientific pharmacoeconomic workers have shown that the use of these dressing systems leads to a decrease in financial
and company costs in the administration of
patients suffering from lower limb ulcers;
unfortunately these studies are not considered to be useful to obtain any recommendation for use at a higher level.11
Pain
Pain control in patients with ischemic ulcer is extremely difficult and is exasperating when dressings are changed. The pain
caused by the procedure requires various
stratagems about which reference is made
to the EWMA position document of 2004.12
The release of FANS through advanced
dressings (polyurethane foams) could contribute towards reducing the pain in some
“responder” patients in vasculitic ulcers,
where there exists a strong inflammatory
component, and in ischemic ulcers, above
all those which are scleroderma with a sufficient exudate component.13
characteristics to be able, in the short term,
to be a treatment technique in aid of the recovery of the microcirculatory homeostasis
in patients with critical chronic ischemia,15
and the consequent speeding up of healing
processes of ischemic ulcers.16
Dermal substitutes
A net reduction in pain is generally obtained after the application of a grafting
of artificial skin (bovine or shark acellular
dermal matrix or silicon supported horse
collagen) or of cadaver skin. The artificial
skin could also be used on avascular surfaces (covers of tendons and bones) in that
it is colonised by new vessels deriving from
nearby tissues. These surgical techniques
are considered in ischemic ulcers only after revascularization or in cases of stabilised
critical ischemia which could not be revascularized after intensive drug treatment with
Iloprost. Bioengineered skin is very useful in
scleroderma patients and in some cases of a
diabetic foot, also after partial amputation.
When the vascularization is completed
the silicon is removed and, if necessary, an
autologous grafting is proceeded with. It appears that the repaired skin with this system
is more elastic and functional with respect
to the procedure with homologous skin.17, 18
Compression therapy
FREMS and PESF
Pain control could be, in some patients,
realised by using the FREMS therapy (Frequency Rhythmic Electrical Modulation System), a comfortable methodology which
is easy to apply and is well accepted by
patients. Pain reduction, in responder patients already occurs after 24-36 hours and
the healing rates are speeded up. Even this
technology lacks relevant clinical studies.14
The PESF, namely the use of the pulsating
electrostatic fields, acts by improving the
deformability of the red globules and the
ability to re-establish the best hematic pH,
by regulating arteriolar activity; it has the
190
In patients with skin ulcers caused by
critical ischemia associated with peripheral oedema, the use of sequential pressure
therapy at low pressure (20 mmHg) is associated with an improvement of the trophic lesions for the resolution of the edema.
Bandaging could be practised with these
patients, but only by expert personnel: it
should be anelastic and at low pressure.19
Growth factors
The re-epithelization stage, above all if
the revascularization procedure was suc-
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cessful, could occur spontaneously in small
sized ulcers. Larger ulcers could require the
use of some further applications such as
the growth factor of granulocitary derivation (granulocyte-colony stimulating factor,
G-CSF) and the growth factor of platelet
derivation (platelet-derived growth factor
(PDGF)-BB human recombinant).20, 21
Perilesional skin
Perilesional skin in patients with peripheral ischemia show up as dry and dehydrated. The use of softening creams is particularly useful in preserving it because it
avoids the formation of cracked skin which
is often at the base of the formation of new
ulcers. Skin dryness and xerosis decrease
cellular migration and the deposition of extracellular matrix, altering the repair process.22
References
1. TASC II (Documento di Consenso InterSocietario
TransAtlantico per il trattamento dell’arteriopatia
periferica – TransAtlantic InterCompany Agreed Document for the treatment of peripheral arteriopahy. G
Ital Cardiol 2007;8 (Suppl 2-12):3S-71S.
2. ADA. Peripheral arterial disease in people with diabetes. Diabetes Care 2003;26:3333-41.
3. Nabuurs-Franssen MH, Sleegers R, Huijberts MS, Wijnen W, Sanders AP, Walenkamp G et al. Total contact
casting ofthe diabetic foot in daily practice: a prospective follow-up study. Diabetes Care 2005;28:243-7.
4. Falanga V et al. European Wound Management Association (EWMA). Position Document: Wound Bed
Preparation in Practice. London: MEP Ltd, 2004.
5. Linee Guida della Società Italiana di Angiologia e
Patologia Vascolare (SIAPAV) Gruppo di studio arteriopatia diabetica - Guidelines of the Italian Association of Angiology and Vascular Pathology (SIAPAV)
- Study Group on diabetic arteriopathy. Review of the
Italian Association of General Medicine No. 2 • April
2010.
6. Carnali M, D’Elia MD, Failla G, Ligresti C, Petrella F,
Paggi B, TIMECare™. Un approccio dinamico e interattivo per affrontare le sfide del wound care – A
dynamic and interactive approach to face the challenges of wound care. Acta Vuln 2010;8(Suppl. 1 no.
4).
7. Lipsky B. International consensus group on diagnosing and treating the infected diabetic foot. A report
from the international consensus on diagnosing and
treating the infected diabetic foot. Diabetes Metab
Res Rev 2004;20(Suppl 1):S68-S77.
8. Frykberg R. An evidence based approach to diabetic
foot infections. Am J Surg 2003;186:S44-S54.
9. Vermeulen H, van Hattem JM, Storm-Versloot MN,
Vol. 10 - No. 4
Ubbink DT, Westerbos SJ. Topical silver for treating infected wounds. Cochrane Database of Systematic Reviews 2007;1. Art. No.: CD005486. DOI:
10.1002/14651858.CD005486.pub2
10. Armstrong DG, Lavery LA. Diabetic Foot Study Consortium. Negative pressure wound therapy after
partial diabetic foot amputation: a multicentre, randomized controlled trial. Lancet 2005;366:1704-10.
11. Ubbink DT, Westerbos SJ, Evans D, Land L, Vermeulen H. Topical negative pressure for treating chronic wounds. Cochrane Database Syst Rev
2008;3:CD001898.
12. Principles of best practice. Minimising pain at wound
dressing-related procedures. A consensus document.
London: MEP Ltd; 2004.
13. Failla G et al. Use of Ibuprophen realising foamin patients affected by progressive Systemic Sclerosis OR
130 Act of Third Congress Of WuWHS Toronto June
2008.
14. Jankovi AT, Bini I. Frequency rhythmic electrical
modulation system in the treatment of chronic painful leg ulcers. Arch Dermatol Res 2008;300:377-83.
15. Gargiulo G et al. Effetti sul trattamenti con campi
elettrostatici pulsati sui pattern flussimentrici micro
vascolari cutanei - Effects on treatment with pulsating
electrostatic fields on skin micro vascular fluximentric patterns. 5th Conference of the European Study
group on cardiovascular oscillations.
16. Pullar EC. The physiology of bioelectricity in development, tissue repair and cancer CRC Press 2011.
17. Mansbridge J. Skin substitutes to enhance wound
healing.Expert Opin Investig Drugs 1998;7:803-9.
18. Jeng JC, Fidler PE, Sokolich JC et al. Seven years’ experience with integra as reconstructive tool. J Burn
Care Res 2007;28:120-6.
19. Mosti G, Mattaliano V et al. Laterapia compressiva nel
trattamento delle ulcere cutanee - Compressive therapy in the treatment of skin ulcers. Acta Vul 2009;11335.
20. McIntosh A, Peters J, Young R et al. Prevention and
management of foot problems in type 2 diabetes:
clinical guidelines and evidence. Sheffield: University
of Sheffield; 2003.
21. Koblik T, Sieradzki J, Sendur R et al. The effect of
insulin and sulodexide (Vessel Due F) on diabetic
foot syndrome. Pilot study in elderly patients. J Diab
Compl 2001;15:69-74.
22. Forma O, Lui P. Il paziente ipomobile dalla cute sana
all’ulcera - The hypomobile patient, from healthy skin
to ulcer. ed. Mattioli 1885; Ottobre 2006.
OTHER TREATMENT OPTIONS
The patient with critical lower limb
ischemia is a natural candidate for revascularization surgery aimed at saving the limb.
Use of other types of treatment is justified
only in case of contraindications to the surgery that can be general (patients in critical condition or with multiple pathologies
that contraindicate surgery) or local (distal
stenotic-obstructive pathology that is not
susceptible to revascularization) or in case
of failure of the surgical and/or endovas-
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cular therapy. It is primarily based on the
pharmacological therapy discussed in the
previous chapters and on treatments that
are complementary to medical therapy.
Compression therapy, spinal cord electrical stimulation and hyperbaric oxygen therapy may number among these.
Compression therapy
The rationale of compression therapy
in chronic obstructive arteriopathy is well
known: the treatment of a possible coexistent venous pathology, skin ulcers, and
edema that aggravates the arteriopathy.
Compression therapy is possible in patients with chronic obstructive arteriopathy,
also with an ankle brachial pressure index
(ABI) reduced down to 0.5-0.6.
Numerous clinical studies and guidelines
do not exclude the possibility of using a
modified compression, “lighter” than what
is generally practiced, when the ABI is between 0.5 and 0.8.1-12 In this clinical situation, not only is the pressure at the big toe
not reduced 13, 14 but an increase in the periulcerous blood flow below the compressive system may be encountered.14-18 In one
of our works in patients with mixed-etiopathogenesis ulcers and an average ABI of
0.6, we were able to demonstrate that the
arterial flow under the bandage increases
when it is applied with a pressure of 20-30
and also of 30-40 mmHg; the arterial flow
begins to go down again when the pressure of the bandage rises further to 40-50
mmHg while always remaining above the
baseline values.14 Obviously the utmost
care is always given so that the pressure of
the bandage is significantly lower than the
systolic pressure of the ankle. The increase
in flow registered under the bandage may
be induced by the reduction of the transmural and venous pressures, which induce
an increase of the arteriovenous gradient,
but also from the release of vasodilating
substances together with a reduction of
pro-inflammatory mediators that occur at a
microcirculatory level.1, 18
The condition of critical ischemia and
192
skin ulcer is very different from critical
ischemia. In this condition the pressure
at the ankle is, by definition, less than 50
mmHg, the value that contraindicates any
continuously-applied compression therapy.
However, in these conditions, intermittent pneumatic compression therapy (IPC)
has been shown to play a relevant role, being able to increase the arterial flow not
only in normal patients but also in arteriopathic ones.
Even though IPC administration methods
and times vary depending on the studies, in
arteriopathic patients with critical ischemia,
there tends to be a very high pressure
(around 120 mmHg) that is rapidly reached
and maintained for a few seconds. Fifteen to
20 seconds pass between one cycle and another; the administration modality is, therefore, very different from that generally used
in IV-lymphatic pathology for edema reduction. The first studies on IPC in the claudicating patient go back 20 years ago and reported beneficial effects on the distance of
travel, symptoms, and the systolic pressure
at both the leg and the arm.19-22 Among the
mechanisms that may explain the increase
in arterial flow induced by IPC in arteriopathic patients, one is well-documented and
is represented by the reduction in the venous pressure that increases the arterial-venous gradient and therefore the arterial flow,
which can increase up to 70%. Two other
mechanisms are hypothesized but until now
have never been proven in a definitive way:
the suppression of the venoarteriolar reflex
which leads, again, to a reduction in venous
pressure, and the increased release of nitric
oxide from the vessel walls due to an increase in shear stress induced by IPC that
can, in turn, lead to an increase of arterial
flow. Also in critical ischemia, an increase
of arterial flow with intermittent pneumatic
compression was observed in retrospective
studies that have shown: healing in 50% of
cases of patients with ischemic ulcer and
TcPO2 <20 mmHg:23 an improvement in the
ischemic ulcers in all patients, with any level of TcPO2;24 the salvage of 9/14 ischemic
limbs in inoperable patients.25
At three months 58% of the limbs were
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saved, the rest pain improved in 40% of the
limbs saved, 26% of the ulcers were healed,
and the pressure at the big toe increased
significantly.26
In a more recent prospective study, 48
patients with an amputated foot due to critical ischemia and with open wounds were
randomized into two groups in which the
only difference in the therapeutic regime
was the use, in one group, of intermittent
pneumatic pressure. At 18 months from the
start of the IPC therapy, the patients who
received IPC were healed to an extent three
times higher (58%) compared to patients
that did not receive IPC (17%) and an equal
proportion of the lower limbs had been
saved (P<0.01).27 In another study with
more cases,28 171 patients were enrolled
for three months. After 13 months the pain
was significantly reduced and the pressure
at the big toe and the popliteal flow were
significantly improved. The salvage of the
limb at 3.5 years was 94%.
In critical ischemia the benefits on the
arterial flow were observed at both the
macrocirculatory level (increase of the flow
evaluated with duplex on the popliteal artery and on the leg arteries) and on a skin
microcirculatory level (laser Doppler on the
dorsum of the foot).29 The mechanisms that
induce an increase in blood flow are similar
to those of the arteriopathic patient without
critical ischemia and are substantially attributable to the increase of the arterial-venous
gradient and production of vasodilating
substances by the endothelial cells consequent to the increase in shear stress.
Spinal cord stimulation
The electrical stimulation of the spinal
cord, defined by the Anglo-Saxons as spinal cord stimulation (SCS), was proposed
for the first time in 1967 by Shealy, who
used laminectomy in an attempt to treat
uncontrollable pain syndromes.30 Dooley
then proposed the percutaneous introduction of the stimulator electrode in the
vertebral medullary epidural space in the
treatment of various pain syndromes.31
Vol. 10 - No. 4
Subsequently the technique, first introduced into clinical practice in the management of pain syndromes refractory to
conservative treatments, spread worldwide
and was also routinely used for the treatment of vesical dysfunctions from multiple
sclerosis, extrapyramidal-type motor disorders, and spasticity secondary to spinal
cord lesions.
The rationale at the basis of SCS is primarily represented by the attempt to modulate
the neural transmission of pain impulses
from the periphery to the brain at the spinal cord.
According to Gate Control theory, which
is still one of the most accredited, since the
transmission of pain would be correlated
to the balance of information that passes
the spinal cord through the large-diameter
Ap fibers (non-nociceptive) and the smalldiameter A5 and C ones (nociceptive), if the
activity in the large Ap fibers prevails, the
pain will be mild or absent (gate closed),
but if transmission prevails along the thin
A5 and C fibers, the pain will be perceived
(gate open).32
Even if Gate Control theory is still the
main hypothesis to explain the operation
of SCS, in reality, the mechanisms of action
implicated in spinal cord stimulation are
multiple and therefore the exact mechanism
remains unknown.
With regard to the effectiveness of the
use of SCS in the treatment of chronic pain
of an ischemic nature from serious peripheral arteriopathies, in 1976 it was postulated
for the first time, following some observations of Cook et al. that noted, in patients
subjected to SCS for neurogenic vesical, an
increase of local temperature and an improvement of the tissue trophism of the
lower limbs.33 The authors, therefore, extended the indication of SCS to the chronic
arteriopathies that had not previously responded favorably to conventional medical
treatments, traditional revascularization surgery or to sympathectomy, and thus highlighted how the disappearance of ischemic
pain, the instrumental improvement of the
rheological and plethysmographic indices,
and finally the healing of distal trophic le-
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sions were contextually observed. Also in
subsequent studies relative to patients with
serious peripheral arteriopathies, the authors reported an excellent control of pain,
observed an increase in healing of ulcerous
trophic lesions, a decreased need for oral
analgesics, and an improvement in the daily
activities of the patients.34-39
In clinical practice the fundamental prerequisite for the proposal of a treatment
with SCS in serious arteriopathies consists of
the absolute or relative impossibility in these
patients of a surgical and/or endovascular
revascularization therapy, and of the more
or less complete failure of previous invasive,
pharmacological, or conservative treatments,
and is based on the intent to correct the microcirculatory damage from low perfusion
pressure secondary to the macroangiopathic
hemodynamic lesions of an atherosclerotic
nature that occurred upstream of the small
vessels in time and in sequence.
Since, in critical lower limb ischemia
(CLLI), the treatment of revascularization
with invasive practices, including angioplasty or reconstructive surgery, is feasible
only in 60% of cases, while another 20% of
patients are obliged to undergo a primary
amputation surgery at the time of diagnosis,
the role of SCS can theoretically be carved
out of the remaining 20% of subjects that, in
the absence of alternatives, are subjected to
temporary conservative adjuvant therapies
which, while not mechanically modifying
the hemodynamic lesions of the macrocirculation upstream, are often able to limit
the microcirculatory damage from altered
perfusion pressure.40
In reality, given the high economic and
professional cost of the method, the indications for the use of SCS should be restricted
to only CLLI patients with limited trophic lesions (less than 3 cm in diameter), to subjects
who are theoretically operable but at a high
risk of failure of revascularization, or at a high
operatory risk due to the presence of serious
concomitant comorbidities, while the absolute contraindications are tied to the presence
of extended trophic lesions (greater than 6
cm in diameter), of concomitant pathologies with short life expectancy (e.g., tumors)
194
or serious pathologies of the dorsal lumbar
spine (disc pathologies, vertebral schisis, serious kyphotic-scoliotic deformations, etc.).
Over the last decades, numerous clinical trials on the use of SCS were performed
in arteriopathic patients with critical lower
limb ischemia. Most of the work was carried
out starting from the mid-80s and has, overall, documented favorable short-term effects
of electrical stimulation on the salvage of
the symptomatic limb and, sometimes, even
a better long-term prognosis for patients in
terms of morbidity and mortality.41-51
A really valid contribution to the selection of patients appears to be linked to the
use of TCpO2 both in a supine position
and in declivity, allowing for a more precise identification of patients with a critical
limb ischemia who are theoretically more
responsive to therapy with SCS and are so
eligible to the said treatment.51-55
In the course of past years there has been
observed, both in our experience and in
that of other important medical and/or vascular surgery centers, a sharp decrease in
the number of patients with critical lower
limb ischemia which cannot be operated on
any longer and who so had to undergo an
SCS, following probably, at endovascular intervention level, a major aggressiveness by
doctors on distal arterial areas, previously
excluded from procedures, and, at a medical
level, of a wider use of infusion therapy with
prostanoids in patients on whom, in co-administration with important comorbidities,
vascular rehabilitation intervention could be
immediately or absolutely contraindicated.56
Finally, on the basis of literature data and
of our experience, epidural medullary electrical stimulation still seems to constitute to
the present day a methodical alternative in
treating critical lower limb ischemia turning out to be valid, scarcely invasive and
reversible, but which to be successful requires suitable specialist competence by a
medical multi-specialist team taking charge
of the patient, not only in the performance
stage of the procedure but also and above
all in that of selecting patients and remotely
following them up.
Although there has been a considerable
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reduction in the use of the treatment method for critical lower limb ischemia occurring
during past years, our data confirm the validity of recurring to epidural medullary electrical stimulation in those patients who can no
longer receive the traditional medical and/
or surgical therapeutic benefits, notwithstanding that the evaluation of its effectiveness has been established not only clinically,
but also, and above all, instrumentally.
The use of microvascular metabolical indices, such as the transcutaneous oxygen and
carbon dioxide tensiometry, actually constitutes the most valid criterion for the selection and monitoring of patients undergoing
chronic medullary electrical stimulation.56
In conclusion, based on literature data
and our experience, epidural spinal cord
electric stimulation still appears to be an alternative method in the treatment of critical
lower limb ischemia that is effective, minimally invasive and reversible, but which requires for its success an adequate specialist competence by a polyspecialist medical
team that takes charge of the patient not
only in the execution of the procedure, but
also and above all in the selection of patients and long-term follow-up. Despite a
significant reduction in the use of the technique for the treatment of critical lower
limb ischemia that has occurred in recent
years, our data confirm the validity of the
use of epidural spinal cord electrical stimulation in patients that are no longer susceptible to traditional medical and/or surgical therapeutic benefits, provided that the
evaluation of its effectiveness is carried out
not only clinically, but also, and above all,
instrumentally.
The use of metabolic microvascular indices such as transcutaneous oxygen and
carbon dioxide tensiometry is currently the
most valid criterion for the selection and
monitoring of patients subjected to chronic
spinal cord electrical stimulation.
Hyperbaric oxygen therapy
Hyperbaric oxygen therapy would find
its treatment rationale in critical lower limb
Vol. 10 - No. 4
ischemia and the ulcers connected to it, as
the ischemic tissues would benefit from
hyperoxygenation with an improvement
of the metabolism and a reduction of edema. Other effects that can be ascribed to
hyperbaric oxygen therapy in the healing
of ischemic ulcers would be: the stimulation of the proliferation and differentiation
of fibroblasts, the increase in the formation
and cross-linking of collagen, the stimulus
for neovascularization, and the leukocytemediated bactericidal action.57
As a matter of fact, there are not many
works on hyperbaric oxygen therapy in this
indication while there are many reports of
a good effect on the healing of ulcers with
arteriopathy and diabetes, as is also shown
by the Cochrane review.58
It is also interesting to note how, however, not all critical ischemia ulcers would
be susceptible to improvement with hyperbaric oxygen therapy, but only those that
show an increase in the O2 tension equal
to or greater than 10 torr while the patient
breathes pure oxygen.59
In conclusion, as recommended by the
Cochrane review 58 and TASC II,48 some selected patients with an ulcer from critical
ischemia are likely to benefit from hyperbaric oxygen therapy, but more rigorous studies
are needed before a definitive confirmation
of generalized efficacy can be made.
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44. Klomp HM, Spincemaille G, Steyerberg EW, Habbema JD, van Urk H for the ESES study. Efficacy of
spinal cord stimulation (SCS) in critical limb ischemia.
Lancet 1999;353:1040-4.
45. Claeys L, Horsch S. Transcutaneous oxygen pressure
as predictive parameter for ulcer healing in endstage
vascular patients treated with spinal cord stimulation.
Int Angiology 1996;15:344-9.
46. Spincemaille GH, de Wet HCW, Ubbink DT, Jacobs
MJ. The results of spinal cord stimulation in critical
limb ischemia: a review. Eur J Vasc Endovasc Surg
2001;20:99-105.
47. Ubbink DT, Vermeulen H. Spinal cord stimulation
for non-reconstructable chronic critical leg ischaemia
(Review). The Cochrane Collaboration in The Cochrane Library 2006;4.
48. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG; on behalf of the TASC II Working
Group: Inter-Society Consensus for the Management
of Peripheral Arterial Disease (TASC II). J Vasc Surg
2007;45(Suppl S):S5-S67.
49. Ubbink DT, Spincemaille GH, Prins MH, Reneman
RS, Jacobs MJ. Microcirculatory investigations to determine the effect of spinal cord stimulation for critical limb ischemia: the Dutch multicenter randomized
controlled trial. J Vasc Surg 1999;30:236-44.
50. Amann W, Berg P, Gersbach P, Gamain J, Raphael
JH, Ubbink DT for the SCS-EPOS Study Group: Spinal Cord Stimulation in the treatment of Non-reconstructable stable Critical Leg Ischaemia: Results of the
European Peripheral Vascular Disease Outcome Study
(SCS- EPOS). Eur J Vasc Endovasc 2003;26:280-6.
51. Ubbink DT, Vermeulen H. Spinal cord stimulation
for Critical Leg Ischemia: a Review of effectiveness
and optimal patient selection. J Pain Sympt Manag
2006;31:S30-S5.
52. Gersbach PA, Argitis V, Gardaz JP, von Segesser LK,
Haesler E. Late Outcome of Spinal Cord Stimulation
for Unreconstructable and Limb-threatening Lower
Limb Ischemia. Eur J Vasc Endovasc 2007;33:717-24.
53. Iabichella ML, Melillo E, Mosti G. A review of microvascular measurements in wound healing. Lower
Extremity Wounds 2006;5:181-99.
54. Melillo E, Cocciaro A, Lutzemberger L, Ferrari M, Rossi
G, Pedrinelli R. Transcutaneous oxygen tension during long-term spinal cord stimulation as a treatment
for critical leg ischemia. In: Galley D, Illis LS, Kranig
JU, Meglio M, Sier JC, Staal MJ, editors. First International Congress of the International Neuromodulation
Society. Bologna: Monduzzi Editore; 1992. p. 81-5.
55. Melillo E, Giannini D, Buttitta F, Menegato A, Nuti M,
Ferrari M et al. Long-term follow-up of Critical Limb
Ischemia (CLI) treated by spinal cord stimulation. Eur
Heart J 2002;23:99.
56. Melillo E, Nuti M, Pedrinelli R, Buttitta F, Balbarini A.
Is transcutaneous oxygen and carbon dioxide monitoring indispensable in short and long-term therapeutic management of non-reconstructable lower critical
limb ischemia? Minerva Cardioang 2006;54:481-98.
57. Fife CE. Hyperbaric oxygen therapy applications in
wound care. In: Sheffield PJ, Fife CE, Smith APS, editors. Wound Care Practice. 2nd ed. Flagstaff, AZ: Best
Publishing Company; 2004. p. 661-76.
58. Kranke P, Bennett M, Roeckl-Wiedmann I, Debus S.
Hyperbaric oxygen therapy for chronic wounds. Co��
chrane Database Syst Rev 2004;2:CD004123.
59. Grolman RE��
, ��
Wilkerson DK��
, ��
Taylor J��
, ��
Allinson P��
, ��
Zatina MA. Transcutaneous oxygen measurements predict
a beneficial response to hyperbaric oxygen therapy
in patients with nonhealing wounds and critical limb
ischemia. Am Surg 2001;67:1072-9; discussion 1080.
Vol. 10 - No. 4
TREATMENT OF
SCLERODERMA ULCERS
The first and earliest clinical manifestation of scleroderma vascular disease is
Raynaud’s phenomenon, the change in the
color of the fingers (but also feet, ears, nose,
and tongue) mainly in relation to exposure
to low temperatures, or, as is commonly described “a white finger, as if it were dead”
as an expression of a phase of transient
complete acute ischemia and spontaneous
remission (Figure 12).1
The naifold videocapillaroscopy is a first
level examination that can identify a pattern
of alterations of the periungual capillary
circle that are absolutely characteristic of a
series of pathologies that constitute the socalled scleroderma spectrum, characterized
by dilatations of the capillary loops with the
formation of giant capillaries (megacapillaries) until the advanced forms where the
microcirculation is completely disordered,
with multiple avascular areas that constitute
the capillary desert.2-4
Digital ischemia is the most characteristic
aspect of scleroderma vascular disease and
is characterized by endothelial dysfunction
that evolves in the intimal proliferation and
is complicated by endoluminal thrombosis
in the capillaries and arteries.
If not recognized and treated early, scleroderma vascular disease leads to real acute
Figure 12.—Acute ischemic phase.
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Figure 13.—Scleroderma pattern.
Figure 14.—Pitting scar.
and chronic ischemia of the fingers and
toes with death of the tissues and formation of painful necrotic ulcers that are difficult to heal, and if not promptly recognized
and treated with systemic pharmacological
therapies and with local dressings, will inexorably evolve into gangrene.5-7
Scleroderma ulcers
Ulcers are a visible evidence of scleroderma vascular disease. They develop in
30-50% of patients with SSc but we can say
that they appear at least once in the course
of the disease in almost all, and it is not unusual that the lesions arise before a definite
diagnosis of systemic sclerosis has been
made, especially if the diagnosis is delayed.
Ulcers are not the most important complications quoad vitam of the patient, while
they represent the most debilitating complication for quality of life due to pain, func-
198
tional impairment, long healing times and
location with regard to the critical role that
the hands play in daily and relational life.
They occur relatively early in the course of
SSc and have a chronic relapsing trend with
devastating physical and personal, familial,
and social psychological effects.1-6
They are typically ischemic ulcers as they
are the result of a spasm and occlusion of
the arterial-capillary region of the fingers,
determining an ischemic and hypoxic damage that presents as a pitting scar, i.e., localized hyperkeratosis on the distal phalanges
up to dermohypodermic-muscular necrosis
and acroosteolysis. The infections can have
devastating consequences and evolve into
amputations and sepsis (Figures 17).
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of the calcinosis itself, which determines the
self-limitation of the inflammatory process
and the healing of the lesion without concomitant infective complications (Figure 18).
The knowledge of the different types of
scleroderma ulcers and of the different associated pathophysiological mechanisms
is a necessary and indispensable prerequisite for the choice of the different targeted
and effective therapeutic strategies; for example, the ulcer with underlying calcinosis
may not be responsive to vasodilators like
the ischemic ulcer should be.7
Figure 17.—Amputation.
A different aspect of scleroderma ulcers
are the atrophic ulcers, that arise on the
articular prominences, where the tissue is
thinner and subject to traction as an outcome of cutaneous sclerosis and tendon retraction, and where the slightest occasional
trauma inexorably results in trophic lesion
without any tendency toward healing in the
presence of atrophic sclerotic tissue and is
often mechanically ischemized in tension
on the articular surface (Figure 18).
Because of their slow tendency toward
healing and long duration, atrophic ulcers
are frequency exposed to infective phlogistic complications that further slow healing.
Finally, in the course of systemic sclerosis,
ulcers associated with an underlying calcinosis arise that trigger an intense inflammatory process like a reaction to a foreign
body, absolutely finalized to the expulsion
Primary prevention
The patient should be viewed in the familial context and should be educated and
informed on the known pathophysiological
mechanisms of his disease to guarantee a
greater adherence and compliance with the
directions given.
The patient must realize that he must
keep his entire body warm (not only his
hands) and avoid trauma to his fingers, he
must stop smoking and taking vasoconstrictors (e.g., beta-blockers, adrenergic nasal
decongestants) and caffeine,8 he must avoid
exposing his hands to direct heat sources,
he must constantly apply moisturizing and
emollient creams, he must wear insulated
gloves, even at night, he must know how to
recognize the initial periungual trophic suf-
Figure 18.—Atrophic ulcers.
Vol. 10 - No. 4
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fering and must have a priority, direct and
fast access to the care center dedicated to
scleroderma ulcers.9-11
Active ulcer therapies
The treatment’s objective is to promote the
healing of the ulcer and reduce the formation
of new ulcers. The optimal treatment should
obtain the reduction of pain, the functional
recovery of the hand, implement digital blood
circulation and prevent infectious complications. The framing of the medical history and
the careful evaluation of comorbidity are fundamental, as they can actively influence the
ulcer’s occurrence and complications such
as diabetes, obstructive arteriopathy, and
venous insufficiency due to the exponential
additive impact of microcirculatory damage
that requires a priority intervention on the
macrocirculatory pathology where possible.
Support therapy
Pain must absolutely be treated not only
as a primary and essential requirement of a
global therapeutic approach aimed at the improvement of the patient’s quality of life, but
also as an essential requirement for the healing process, as the state of anxiety associated
with pain evokes a vasoconstriction reaction
that worsens and aggravates Raynaud’s phenomenon and the consequent vasospastic
ischemic damage. It is preferable to use acetaminophen and opioids instead of NSAIDs
because of the pain’s chronic characteristics
and the need for prolonged treatments. Infection occurs frequently and the clinician must,
every time he accesses the dressing, evaluate
the occurrence of this feared complication,
especially if the patient reports an increase
in pain symptoms. If a purulent secretion
can be detected, it is necessary to carry out
a swab for culture and antibiogram examination, immediately starting an antibiotic coverage active against gram-positive bacteria, effective in most cases and possibly modified
with the outcome of the antibiogram. Always
ask for a radiological evaluation if you suspect that the infective phlogistic process may
200
have affected the bone. Scleroderma patients
may require further cycles of antibiotic therapy, particularly if an osteomyelitis process
is present that requires parenteral and prolonged systemic antibiotic therapy.
Pharmacologic therapy
After having controlled the pain and infection, it is necessary to promote the healing of the existing ulcers and prevent the
formation of new ulcers.
Despite the notable impact on the quality of life of the scleroderma patient, a defined therapeutic algorithm accepted by the
FDA (Food and Drug Administration) or the
EMA (European Medicines Agency) does
not currently exist.
The pharmacologic therapy starts from the
pathophysiological assumption that scleroderma ulcers are ischemic ulcers with endothelial dysfunction and obliterative vasculopathy
with medial intimal hyperplasia complicated
by endoluminal thrombotic processes and
progressive destruction and impoverishment
of the capillary bed and of the number of
capillaries per dermal papilla until there is a
desert with avascular areas. The therapeutic
algorithm should therefore first of all include
antiplatelet agents and vasodilators. The acquired implication of endothelial damage/
dysfunction and of platelet hyper aggregability in the pathogenesis of systemic sclerosis
as well as the very high prevalence of reflux
esophagopathy have led experts to use, in all
patients, even in the absence of digital ulcers,
a basic therapy based on the association between proton pump inhibitors, acetylsalicylic
acid and calcium antagonists.11
Antiplatelet
agents
The treatment of treating scleroderma patients with low doses of aspirin (75-100 mg/
day) even in the absence of digital ulcers
in virtue of the known pathophysiological
mechanisms described above has become a
common clinical practice. A fortiori, in the
presence of digital ulcers it is important to
administer to the patient an antithrombotic
therapy with antiplatelet agents or with low
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molecular weight heparin in the most significant pictures of acute ischemia.9
Vasodilator
drugs to counteract vasoconstriction and with indication for the
treatment of Raynaud’s phenomenon with
clinical evidence of efficacy in the treatment of scleroderma ulcers
—— Slow-release and prolonged coverage
(chrono form) calcium antagonists (nifedipine), already indicated as a basic therapy
in the presence of scleroderma Raynaud’s
even in the absence of digital ulcers.11, 12
—— Prostacyclin analogues, potent vasodilators that inhibit platelet aggregation and
the proliferation of smooth muscle cells in
the blood vessel wall. Iloprost is a stable
prostacyclin analogue, administrable intravenously, which plays an important therapeutic role in the treatment of ischemic scleroderma ulcers as well as other pathological
forms characterized by arterial hypoperfusion with consequent tissue ischemia. The
therapeutic indication is the treatment of
Raynaud’s phenomenon secondary to systemic sclerosis, which constitutes the most
typical and precocious form of scleroderma
ischemia. This therapy is therefore indicated
in patients who, while being treated with
the basic therapy with calcium antagonists,
present repeated and prolonged asphyxic
crises. Iloprost infusion therapy is the standard treatment for ischemic scleroderma digital ulcers. Iloprost has been the subject of
controlled studies that have endorsed its
effectiveness for the aforementioned indications. In a multicenter controlled double-blind clinical study versus placebo in
patients with scleroderma Raynaud’s, the
intravenous administration of iloprost for 6
hours per day for 5 days at doses of 0.5-2
ng/kg/min showed a significant reduction
of digital ulcers and highlighted the persistence of effects at 9 weeks of follow-up, indicating a potential effect of the molecule
of functional reset on the endothelium, and
showed a potential trend of prevention of
new ulcers.13 All the more so in virtue of the
pleiotropic effects of iloprost on the circulatory system shown in a randomized control-
Vol. 10 - No. 4
Figure 19.—Atrophic ulcers exposed to infective phlogistic complications.
led clinical trial, the infusional cyclical therapy and prolonged effect on the endothelial
wall during the therapeutic interval period
reinforce the potential role of the molecule
in modifying the natural evolution of scleroderma vascular disease (Figures 19, 20).14
—— Phosphodiesterase inhibitors: induce
vasodilation by increasing the levels of bioavailability of endogenous nitric oxide (NO).
The utility of using these drugs is based on
the pathophysiological assumption that systemic sclerosis is a typical pathology of endothelial activation/dysfunction with imbalance between vasoconstrictor factors and
vasodilator factors (including NO) in favor
of the former and that tissue damage is established subsequent to this dysfunction.
Raynaud’s phenomenon is the typical clinical manifestation that testifies to how the
vasospasm, with consequent peripheral hypoperfusion, is one of the pathology’s typical markers. The positive effect of sildenafil
and tadalafil on Raynaud’s phenomenon is
shown by two randomized controlled clinical trials.15, 16 Numerous case reports and
pilot studies showed efficacy of sildenofil in
the treatment of scleroderma ulcers.17
Prevention of relapse
Scleroderma ulcers, in addition to being difficult to treat, slow healing, intensely
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lls
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ILOPROST
Vascular cells
• Proliferation regulation and vascular leiomyocyte
phenotype
• Vascular anti-remodeling effects
• Reduction of the increase in vasal permeability
in phlogosis
• ICAM-1 reduction (on the endothelium)
• Reduction of the “reflow-paradox” phenomen
on (damage from ischemia/reperfusion)
• Reduction of the expression of metalloproteases
(MMP-9)
• Neoangiogenesis ( VEGF
via PPAR-α)
• Increase of circulating
endothelial progenitor cells
Platelets
• Aggregation
• Activation
• Release
Miscellaneous
• Indirect anticoagulant effect:
PA; PAI-1; F 1+2
• Reduction of the hematic viscosity
• Inhibitory action on oxidation of
native and glycated LDL
• Ischemic preconditioning
• …
Monocytes and neutrophils
• Reduction of αMβ2 integrin
(on neutrophils and monocytes)
• Modulation of cytokine production
• Adhesion
• Chemotaxis
• Production of free radicals
Figure 20.—Pleiotropic effects of iloprost on the circulatory system: some examples.
painful and disabling, have a natural tendency to recur.
The scleroderma patient who has already
presented scleroderma ulcers, in addition to
the antiplatelet and vasoactive therapy indicated above, is indicated to be treated with
non-selective endothelin receptor inhibitors
(Bosentan).
This indication has emerged from the results of two double-blind randomized controlled clinical trials with placebo, RAPIDS
1 and 2, that have shown the efficacy of
bosentan in significantly reducing the onset of new digital ulcers in patients that are
already affected by digital ulcers while the
effectiveness in promoting the healing of
active ulcers did not emerge.18, 19
The endothelial damage that characterizes
digital ischemic ulcers is associated with increased endothelin-1 levels. Endothelin-1 is
a potent vasoconstrictor and an important
pathogenic mediator that carries out its effects through two receptors called ETA and
ETB, expressed in various cell types. The
primary targets of endothelin’s activity are
smooth muscle cells, endothelial cells, fibroblasts and macrophages that, in response
to the stimulus, activate a vascular remod-
202
eling process and the deposition of extracellular matrix. The phenomenon is driven by
excessive vasoconstriction and hyperproliferation by the myocytes of the tunica media
of the arteriolar component, by a proliferation of endothelial cells, and by an excessive
production of profibrotic mediators by the fibroblasts, which can generate the thickening
of the tunica adventitia. Endothelin-1 is also
linked to an increased production of PDGF
and overexpression of adhesion proteins.18-21
From a clinical standpoint, the earliest
and most common manifestation of this
pathological process is Raynaud’s phenomenon and the formation of digital ulcers.21, 22
By blocking the effects of ET-1, one aims
to slow the progression of the vascular remodeling that underlies the ulcerative manifestations (Figure 21).21-24
Surgical therapy
Surgical therapy is essentially reserved for
extreme cases of vasospastic ischemization
during the nearly continuous or subcontinuous cyanotic phase. Recourse to sympathectomy is intended to reduce the number and
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duration of the digital asphyxiation crises and
finds indication in severe digital ulcers and
recurrent ulcers refractory to the combined
medical therapy.25 While the long-term results of cervical sympathectomy have been
rather disappointing, better results are derived from digital sympathectomy associated
with techniques of resection and removal of
the fibrotic adventitia (microsurgical arteriolysis).26 This procedure has promoted healing of the lesions, and has reduced pain and
the recurrence of digital ulcers.27
In the case of an indication to carry out
amputation procedures, common experience advises conservative procedures
limited to eliminating the necrotic material, also carrying out extra-anatomic procedures aimed at the conservation of the
perilesional ischemic tissue. Where this has
not been carried out, driven by the natural
conviction to eliminate all of the ischemic
tissue in addition to the necrotic tissue to
reach a resolving if demolishing solution,
the result has been very disappointing, with
an exacerbation of the ischemic damage of
the tissue presumed healthy and further extension of the necrotizing process. Alternatively, the removal of the necrotic material
and the treatment of perilesional ischemic
tissue with vasoactive, antithrombotic and
vasodilatory therapy allows results to be
obtained that are sufficient to guarantee the
recovery of a dignified relational life with
conservative scarring.
Dressing of the scleroderma ulcer
A careful evaluation of the ulcer according to the principles of the TIME acronym
is necessary for an optimal dressing; this
acronym summarizes the essential characteristics of the ulcer by considering T (devitalized tissue), I (infection), M (maceration),
and E (perilesional epithelium).
Microangiopathic ulcers in general and
scleroderma ulcers in particular, in the activity phase, are extremely painful, very
reactive and rather unwilling to accept aggressive local treatments of a mechanical
type or surgical cleansing, which can pro-
Vol. 10 - No. 4
INFLAMMATION
SMOOTH
MUSCLE
CELLS
NF-KB and the
release of
cytokines
Increase of
vascular
permeability
Vasoconstriction
Hypertrophy and
proliferation
Extracellular matrix
ENDOTHELIN
ENDOTHELIUM
Dysfunctionproliferation
apoptosis
Fibroblast
Collagen,
proteoglycans
Figure 21.—Mechanisms of endothelin’s action in vascular remodeling process.
mote an abnormal phlogistic response with
a necrotizing evolution. The elimination of
devitalized tissue is necessary to promote
autolytic or enzymatic debridement.
Wherever signs of infection show it is
important, besides systemic antibiotic treatment, to drain any local purulent collection,
following delicate removal of the sclerotic
cap, to obtain an immediate reduction in
the pain caused by the subcutaneous collection. Bandaging should be ample at the
lesion stage, with an aim of favoring the
granulation stage re-epithelization.
All this requires having dedicated staff,
particularly trained and knowledgeable
about the disease.
Conclusions
These are difficult ulcers whose therapeutic success is contingent upon the promptness and appropriateness of the intervention.
At the time of their onset, the modest
sizes induce the clinician to make an optimistic and conservative wait-and-see type
evaluation, given the small dimensions
that are similar to a pinhole or the slit of
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a cut, which is absolutely the appropriate
behavior for any lesion of this type in a
non-scleroderma patient. Unfortunately, in
many patients, the trophic lesion is the first
clinical manifestation that leads the patient
to medical attention before he is diagnosed
with disease, with a consequent delay in
the proper treatment of lesions initially approached traditionally as described above. It
is exactly the rapidly worsening evolution of
the lesions as well as the intense pain that is
little responsive to analgesic therapies that
should lead to clinical suspicion and diagnostic completion. Nevertheless, the evolution times of the scleroderma lesion are
so fast that when the targeted intervention
is implemented, while it often ensures the
demarcation and limitation of the lesion, it
does not succeed in avoiding the loss of areas of tissue already in the necrotic phase.
That said, it is evident that the optimal,
economic and ideal treatment of the scleroderma ulcer starts with primary prevention,
which requires the early diagnosis of scleroderma even in the early and preclinical
forms when the reversible and paroxysmal
phases of ischemia, represented by Raynaud’s phenomenon, manifest themselves,
treating the patient with nifedipine and
acetylsalicylic acid, and where prolonged
and recurrent asphyxiated crises persist
nevertheless, turning to the infusional cyclic treatment with iloprost. In the presence
of active ulcers, the systemic treatment of
the acute ischemia with an infusional therapy of iloprost, an anti-thrombotic therapy,
associated with the appropriate pain management and antibiotic therapy in the case
of infection, is important. In the case of
recurrent ulcers, despite the optimization
of the vasoactive and antithrombotic therapy, it is important to subject the patient
to therapy with the non-selective endothelin-1 receptor inhibitor drug (bosentan),
and, where resistant ulcers and severe Raynaud’s are present, to add the phosphodiesterase inhibitor drug (sildenafil/tadalafil).
Although an antifibrotic therapy that heals
systemic sclerosis is not yet available, and
while ignoring if the early scleroderma syndromes will all evolve into definite system-
204
BOX
— Ischemic ulcers typically require
privileged and priority clinical audit
— Primary prevention: treating Sclerodermic Raynaud’s phenomenon with
living standards, calcium antagonists, antiplatelet, iloprost; clinical follow up in
the context of a dedicated multidisciplinary path.
— Secondary prevention: recurrent ulcers are indicated to be treated with non
selective endothelin receptor inhibitor
(bosentan).
— Active ulcer: systemic treatment
of the acute ischemia with an infusional
therapy of iloprost, an anti-thrombotic
therapy, associated with the appropriate
pain management and antibiotic therapy
in the case of infection; resistent ulcers
and severe Rynaud phenomenon are indicated to be treated adding the phosphodiesterase 5 inhibitor drug.
— Surgical indication limited and selected.
— Conservative surgery and Amputation limited to necrotic area
ic sclerosis, with regard to the treatment
of scleroderma ulcers, the medical history
evidence of the early scleroderma finding
by itself puts the patient in the conditions
to promptly direct the clinic, at the first appearance of the lesions, toward the most
appropriate and effective therapeutic directives with less healing time, conservative
outcomes, and minor impairment of the
quality of life.28-30 It is, therefore, necessary,
in the presence of Raynaud’s phenomenon
with confirmation upon the capillaroscopy
examination of the “scleroderma pattern”,
that the patient carries out the diagnostic
completion examinations, where possible
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guided in the context of a dedicated multidisciplinary path.28-31
The close clinical follow-up of the patient with early diagnosis allows the same a
privileged and priority clinical audit at the
first occurrence of any trophic lesion of any
dimensions, which can be promptly treated
and rapidly resolved.28
Since there is no therapeutic algorithm officially accepted by the FDA for the treatment of scleroderma ulcers, the current
knowledge of pathogenetic mechanisms
and the results of clinical trials should guide
therapeutic interventions, indicating useful
principals to contrast the major known pathogenic phases of ischemic damage. Similarly
to the treatment of other clinical manifestations of scleroderma vascular disease such
as pulmonary hypertension, the therapeutic
algorithm for the prevention and treatment
of scleroderma ulcers should indicate, as described above, a combination of therapies
that, starting from the earliest stages of scleroderma vascular disease, exploits the targets of activity of different molecules to have
a sequential, synergistic and additive effect.
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