position document - aiuc · head of vascular disease master azienda ospedaliera s....

ACTA VULNOLOGICA 2012VOLUME 10, N. 4

POSITION DOCUMENT

ISCHEMIC ULCER ANDCRITICAL ISCHEMIA

P. E. MOLLO, M. M. DI SALVO, G. FAILLA, A. MARCOCCIA, G. MOSTI, G. GUARNERA

ITALIAN WOUND CARE ASSOCIATION(ASSOCIAZIONE ITALIANA ULCERE CUTANEE - AIUC)

Vol. 10 - No. 4 ACTA VULNOLOGICA 173

ACTA VULNOL 2012;10:173-205

POSITION DOCUMENTAssociazione Italiana Ulcere Cutanee – AIUC

Ischemic ulcer and critical ischemiaP. 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, Italy2Unit 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, Italy5Vascular 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 repre-sent 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 Guarn-era 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 some-thing 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 aware-ness 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 MasterAzienda 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 Angiol-ogy, Policlinico Vittorio Emanuele, Catania, Italy; F. Mugno, Unit of Angiology, Policlinico Vittorio Emanuele, Catania, Italy.

Anno: 2012Mese: DecemberVolume: 10No: 4Rivista: ACTA VULNOLOGICACod Rivista: ACTA VULNOL

Lavoro: titolo breve: Ischemic ulcer and critic ischemiaprimo autore: MOLLOpagine: 173-205

174 ACTA VULNOLOGICA December 2012

MOLLO ISCHEMIC ULCER AND CRITIC ISCHEMIA

DEFINITION OF CRITICAL ISCHEMIA

The definition of critical lower limb ischemia (CLLI) indicates the clinical

picture characterized by rest pain and/or trophic lesions of different degrees and ex-tents (see the Lériche-Fontaine and Ruther-ford classifications reported in Table I) such as ulcers and/or gangrene, having arisen over 15 days prior, secondary to arteriopa-thy 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 micro-circulatory 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 anal-gesic treatment;

— acral focal skin lesions (Lériche-Fon-taine 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 ad-jective, 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 ampu-tation and death, criticalities that also char-acterize the finding of severe claudication. The incidence of critical limb ischemia in Europe is approximately 450 cases/million inhabitants with a relative risk of amputa-tion 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 surger-ies are burdened by a very poor progno-sis; 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 dur-ing longitudinal studies, resulting, unfor-

Table i.—�Clinical staging of chronic obliterative arteriopathy of the lower limbs according to Lériche-Fon-taine and according to Rutherford.

- Lériche-Fontaine classificationStage Symptomatology Clinical examinationI AsymptomaticII Intermittent claudication Manifestation of skin and skin adnexa dystrophy

III Rest pain Pallor - cyanosisIV Trophic lesions Focal ulcers - gangrene

- Rutherford classificationDegree Category Clinical0 0 AsymptomaticI 1 Mild claudicationI 2 Moderate claudicationI 3 Severe claudicationII 4 Rest painIII 5 Minor tissue lesionsIII 6 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.


ISCHEMIC ULCER AND CRITIC ISCHEMIA MOLLO

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 nosologi-cal 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 cas-es 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 consid-ered or only active ones?); 2) the special-ist 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 investi-gations on all types of skin ulcers, it is es-sential 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 estab-

tunately, in an incompleteness of the data collected.

The diagnosis of CLLI should be based on the ABI, the systolic pressure measure-ment at the big toe, or on the measure-ment 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 obstruc-tive-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 natu-ral 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 oblitera-tive arterial disease). CLLI primarily due to peripheral chronic obliterative arteriopathy leads to an expectation of the risk of cer-ebrovascular events with an adverse course in at-risk individuals including people with diabetes, dyslipidemia, and heart disease, smokers, and people with congenital or ac-quired coagulation disorders, with respect to the control population. The unexpected preponderance of asymptomatic individu-als (55%), essentially the absence of the “claudication” symptom as the main clinical manifestation of hypoperfusion with a con-sequent 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 signifi-cant reduction of the possibilities for saving the limb, in a manner that is directly pro-portional 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 im-possible due to its asymptomaticity or pau-cisymptomaticity in the initial clinical action stages (I-IIA). Often the symptoms are non-specific, and the patient does not consult the specialist but treats himself with self-dressings that are sometimes inappropriate.

Table ii.—�Prevalence of ischemic ulcer.

Author Country Prevalence

Cornwall, 1986 UK 9%Callam, 1987 Scotland 22%Baker, 1991 Australia 22%Salaman, 1995 UK 9%Nelzen, 1996 Sweden 9%O’Brien, 2000 Ireland 10.5%

From G. Guarnera.3



rial hypertension, heart failure, arrhythmias, diabetes mellitus, chronic renal failure, cer-ebral vasculopathies, neural radiculopa-thies, etc.) that condition and/or aggravate the peripheral vascular disease.

The observation of the skin of an ischem-ic limb, of its coloring (pallor, cyanosis, erythrosis), of possible variations in relation to posture (acral pallor in decubitus), of tro-phism 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 palpa-tion 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 abdo-men, the detection through auscultation of “indigenous” murmurs in correspondence with the anatomical auscultation sites such as the lateral-cervical regions, the supracla-vicular fossae, the inguinal regions, Scarpa’s triangle, the popliteal compartment, etc. confirm the suspected diagnosis of arterio-pathy.

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 Win-sor Index), which precisely expresses the relationship between the systolic pressure value measured at the ankle and the systo-lic 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

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):S5-S67.

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: Mo-mento Medico; 2011.

CLINICAL EXAMINATION

If well conducted, the clinical examina-tion is generally sufficient to make a di-agnosis of ischemic ulcer and critical limb ischemia. A proper clinical examination is not possible without an accurate and com-plete medical history which, naturally, must not be limited to the study and evaluation of the vascular situation, but must be ori-ented 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 pa-thology, respiratory diseases, polycythemia, renal failure, etc.

A careful medical history must be fol-lowed by an equally accurate physical ex-amination that must include a systematic passage through the classical portions of physical symptomatology, with particular regard to inspection, auscultation and pal-pation.

It is fundamental, before the regional clinical examination, to carry out a general physical examination and a physical exami-nation of the individual organs and systems, aimed at excluding clinical pictures attrib-utable to cardiac, internal medicine, meta-bolic, renal or neurological pathology (arte-



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 super-ficial femoral and deep femoral segments and as an evaluation prior to angiography in cases in which a revascularization sur-gery is hypothesized. After angiography it provides useful details for the surgical treat-ment, since it can give useful information such as the caliber, characteristics of the ar-terial 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 surgi-cal option. The use of color-Doppler ultra-sound as a replacement for the angiograph-ic investigation does not seem rational, as the ultrasound method lacks homogeneous execution criteria and still has operator-de-pendent reporting (Figure 2).

Radiological examinations

As known, angiography is an invasive con-trast investigation that is moreover burdened by a significant rate of morbidity (serious re-actions to contrast media in 0.1%) and mor-tality (0.15%), even if the use of non-ionic contrast materials, the quality of the devices for the introduction of the media, and digital

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 re-quired accuracy, the ABI reading can have rather high “intraobserver” variability.

Paradoxical ABI results (values greater than 1.3) can emerge in patients with in-compressibility of the arterial walls, as in the case of diabetics or in those with me-dial calcinosis (Monckeberg’s disease). The continuous wave Doppler examination still retains its validity for diagnostic purposes for the measurement of the segmental pres-sures 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 preva-lences 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 respon-sible for the clinical manifestation and to exclude a possible ectasia pathology borne

Figure 1.—Continuous wave (bidirectional) Doppler de-vice.

Figure 2.—Color-Doppler ultrasound machine.



mental systolic pressures provides quantita-tive information on the hemodynamic sig-nificance of the arterial lesions.

The detection of the transcutaneous oxy-gen (TcPO2) and carbon dioxide (TcPCO2) tensions offers useful data for a metabolic evaluation of the ischemic tissue. These parameters represent an important instru-ment for the prediction of the healing of an ischemic ulcerative lesion; partial oxy-gen 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 specifical-ly mentioned elsewhere in this document, finds a unique indication in the diagnostic confirmation of ischemic trophic lesions during scleroderma (Figure 3).

Oscillography and plethysmographic in-vestigations 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 di-agnostic 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 exami-nation of the lesion allows the confirmation of the diagnostic direction through the eval-uation 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 back-ground with little granulation tissue, irregu-lar margins and edges that are often necrot-ic, inserted in a context of perilesional skin with marked dystrophic manifestations (loss of the normal pilifer assets and ungual alter-ations). The regional and perilesional skin looks pale, and is often characterized by ec-chymotic marbling and/or diffuse cyanosis.

image subtraction techniques have contrib-uted to significantly reducing complications. However, for these reasons, angiography is only indicated in those patients with criti-cal limb in which there is an indication for surgery, and maintains the role of the intrap-rocedural method of choice during invasive therapy, of both the traditional and above all endovascular types, in a completely preju-diced and codified way.

CT angiography and MR angiography are invaluable investigations in the study of pa-tients in which a dilatative and/or desiccat-ing pathology is associated with the sten-otic-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 meth-od that allows a very accurate definition of complex pictures.

Complementary investigations

In the clinical-instrumental course of eval-uation of patients with critical limb, there are other complementary investigations that are extremely useful due to their predictive sig-nificance 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.



Role of the clinical pathology laboratory

In the clinical-diagnostic path of the pa-tient with a critical limb and ischemic ul-cerative lesion, the laboratory represents a precious support for the clinical monitor-ing 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 rou-tine laboratory parameters to show any in-fections (leukocytosis, sedimentation rate), alterations in glucose metabolism, protein levels, renal function and myocytolysis pa-rameters.

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, lym-phangitic involvement, extension of the le-sion or delay in scarring, coloring of the background, and worsening olfactory mod-ifications must be orienting towards this complication, particularly in lesions with a primitively ischemic genesis. In these cases it is extremely important from the patho-physiological point of view to identify the responsible microbial agent through tar-geted 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

Edema from the forced antalgic declivous position frequently coexists, and is particu-larly feared in the arteriopathic patient with regional insufficiency because it triggers a vicious cycle of tissue suffering that pro-gressively aggravates the perfusion deficit and the metabolic exchanges on the micro-circulation. The site of the ischemic ulcera-tive 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 “vascu-lar” disposition in the sense that it can local-ize 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 man-ner 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 rea-sons described previously, the shape and the number, the background (coloring, presence of signs of bacterial contamination or coloni-zation, 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 ol-factory peculiarities related to tissue necrosis.

The clinical-diagnostic approach to pa-tients 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) labora-tory-instrumental study (Figure 4).

Figure 4.—Ischemic ulcer.



PHYSIOPATHOLOGY

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 togeth-er with arterial pressure. The endothelium performs a basic role in the microcirculato-ry 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 regu-lating 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 regula-tion 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 pro-duced by the endothelium, but above all by the circulating cells (leukocytes and plate-lets), in a broad reply to a “threat” which can disturb the microcirculatory homeosta-sis, which on the whole activate the platelet aggregation and promote vasoconstriction (DCF, thromboxane A2, serotonin, coagu-lation factors, PAI, endothelin). These two regulatory systems are normally in home-ostatic balance between activators and re-

of the infection on the basis of an antibi-ogram, thereby reducing possible empiri-cism margins (Figure 5).

The role of histopathology in ulcera-tive lesions in the course of critical limb ischemia is marginal due to intuitive rea-sons 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;203:611-20.

2. Dormandy J, Stock G. Critical legs ischaemia: its pathophysiology and management. Berlin: Springer-Verlag; 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. [Ital-ian: Le ulcere vascolari degli arti inferiori]. Testo At-lante. Salerno: Ed. Momento Medico; 2011.

5. Koelemay MJ, Denhang D et al. Diagnosis of arterial disease of the lower extremities with duplex ultra-sonography. 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 is-chaemia. J Wound Care 2010;19:202-6.

8. Rutherford RB, Baker JD et al. Recommended stand-ards for reports dealing with lower extremity ischae-mia: 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 arte-rial occlusive disease in general practice. A multivari-ate 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.

Figure 5.—Infection and in vivo evaluation.



with ischemic skin lesions be they ulcers or gangrene, with symptoms and indications being present for at least two weeks, as at-tributed to a demonstrated arteriopathy.3

A subgroup of patients does not fall with-in this definition, in that it comes with a se-rious 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 microtrauma-tisms and could interest the distal extrem-ity 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 fis-sures of the dry skin, an increase of arte-riovenous 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 arteriopa-thy. 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

spective inhibitors. The reduction of macro-circulatory 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 proag-gregatory and vasoconstrictor activity.1 This mechanism contributes to activating the “endothelial dysfunction”,2 being the main cause of the altered control of the fibrino-lytic-coagulative balance and of the haemo-dynamics 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 claudica-tion, critical ischemia) the hypoperfusion causes persistent hypoxia, prevalence of the MDS on the MFRS, intense activity of leukocytes, major endothelial pain, micro-vascular 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 mecha-nisms (formation of collateral circulations, activations of vasodilatory and antiaggre-gant factors), the nutritional needs of pe-ripheral microcirculation could not be en-sured, even at rest.

In its classical definition the CLI is a man-ifestation of the chronic peripheral obstruc-tive arteriopathy inflicted on patients with chronic ischemic pain at rest or patients

Figure 6.—Peripheral arteriopathy. Figure 7.—Diabetic foot ulcer.



be more efficient if the analgesic is adminis-tered 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 antidepres-sants (Figure 8).

Although revascularization constitutes the best option, where indicated, it could not overlook an intensive medical treat-ment preceding, accompanying and follow-ing the said revascularization to guarantee better results in terms of healing ulcers, of amputations and of survival.

The drugs which are recognised and vali-dated for the treatment of critical ischemia are the prostanoids, iloprost (a stable ana-logue 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 leu-kocytes and platelet, while its more evident and more immediate action lies in vasodil-atation. 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-lym-phocytes and cytokines, reduces the lev-els of ICAM-1, reduces blood viscosity and lastly takes part in the angiogenesis mecha-nisms 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

contributes to the occurrence of the typi-cal osteoarticular deformities of the diabetic foot.4 Clinically the opening of several ar-teriovenous shunts could be the cause of objective evidence of a warm foot, while caring for the distal arteries and the micro-circulatory 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 localisa-tion of the atherothrombosis, of associated comorbidities, of possible therapeutic op-tions (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 abil-ity, 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

Figure 8.—Limb that requires 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 spe-cific rehabilitation programmes, in which controlled physical activity constitutes the main methodology used. Rehabilitation pro-grammes are adopted according to deam-bulation 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 spe-cific track, under controlled speed and in-

(ESC, European Society of Cardiology, EASD, European Association for the Study of Diabetes, CHEST 2012) have recom-mended with an “A” level of evidence treat-ing patients with critical limb ischemia who are not susceptible to revascularization with prostacyclin infusion.11

A retrospective Italian study of the Soci-età Italiana di Angiologia e Patologia Vasco-lare – 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 pro-cedure 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 indis-pensable in “intensive” CLI treatment: an-tiaggregant platelet (ASA and ticlopidine)

13, 14 and anticoagulants (heparins and di-coumarols) which are useful in reducing the risk of major cardiovascular events, in reducing the progression of atherosclero-sis 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 painkill-ers by systemic route and/or epidurally (or SCS). Support drugs are considered to be antihypertensives and congestive heart fail-ure 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 indi-cated, would allow stabilisation of the pa-thology in 61.8% of the cases, clinical im-provement 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

Figure 9.—Limb that requires revascularization.

Figure 10.—Results associated with drug intensive treat-ment and revascularization.

150

120

90

60

30

0

107

5738 32

6 2 9

Pazienti stabilizzati AOCP da IIB a IIAAOCP IV ulcere stabilizzate AmputazioniTIA



clination, or, if they can attend at a vascu-lar rehabilitation outpatients’department, to perform deambulation exercises on a tread-mill. Some protocols envisage 15 control-led physical exercise sessions each lasting about 30 minutes. The distance to be run equals about 70% of the patient’s deambu-latory 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 recov-ery period, after maximum exercise, nec-essary 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 circula-tion. For the same purpose exercises could also be undertaken for the improvement of walking techniques, deambulatory capacity and posture.

Patients who instead present trophic le-sions such as to prevent proper deambu-lation, should undertake the rehabilitation even if enticed by the performance of spe-cific 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 al-low the patient, during the various stages of the disease, to overcome specific psycho-logical blocks which could influence the therapeutic effects of the given therapy.

The purpose is that of developing an in-tegrated system of therapy/rehabilitation, by minimising the effects of the cure’s frag-mentation. Moreover, the identification of some psychological factors could be use-ful to increase adherence to treatment by drugs, through psycho-educational inter-ventions and by psychologically sustaining the patient.

Since some psychological variables are strictly connected with amputation inter-ventions, the treatment of the psychological component assumes a fundamental posi-tion in favour of interventions which sustain

BOX 2

— Revascularization should be con-sidered in therapeutic strategy, taking into account the risks linked with the in-tervention, be they surgical or endovas-cular, the anatomical-functional nature of the altered vessels, run off, comorbid-ity, 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-rehabili-tation treatment.

— The association of several thera-peutic options determines a synergic ef-fect 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 micro-circulation system (prostanoids, antiag-gregants, anticoagulants, haemorheolog-ics) associated with analgesic treatments (pharmacological painkiller or by using SCS) and with ongoing clinical and in-strumental monitoring, to be performed in a specialist environment.

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.

the patient in adapting oneself to the loss of a limb.



7. Jivegard LE, Augustinsson LE, Holm J, Risberg B, Or-tenwall P. Effects of spinal cord stimulation in pa-tients 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 mi-crocirculation is independent of nitric oxide metabo-lites 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 mol-ecules 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 Angiol-ogy 2000;19:358-65.

11. Guidelines on diabetes, pre-diabetes, and cardiovas-cular 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, To-dini AR, of Salvo MM. Il management intensivo dell’arteriopatia periferica in fase avanzata (Intensive management of advanced stage periferal arteriopa-thy). 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 infarc-tion and stroke in high risk patients. BMJ 2002.

14. Clagett P, Sobel M, Jackson MR, Lip GYH, Tangelder M, Verhaeghe R. Thrombolytic Therapy Confer-ence on Antithrombotic and Occlusive Disease: The Seventh ACCP Antithrombotic Therapy in Periph-eral 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 ther-apy 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 intrave-nous 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 ilo-prost in the treatment of patients with critical limb ischemia. Therapie 1991;46:319-22.

20. Staben P, Albring M. Treatment of patients with pe-ripheral occlusive disease Fontaine stage III and IV with intravenous iloprost: an open study in 900 pa-tients. 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 consec-utive cases Diabetes & Metabolism 2003.

22. Loosemore TM, Chalmers TC, Dormandy JA. A meta-analysis of randomized placebo control trials in Fon-taine stages III and IV peripheral occlusive arterial disease. International Angiology 1994;13:133-42.

23. Hied WR, Hirsch AT, Regensteiner JG, Brass EP. Clini-cal trials for claudication: assessment of exercise per-formance, functional status, and clinical end points. Circulation 1995;92:614-21.

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):IV1-IV26.

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 elec-tro-stimulation midollare in the ischemia of the limb). Minerva Cardioang 1996;44:663-7.

— Personalised intensive treatment should be established as early as pos-sible.

— A correction of risk factors should be performed (smoking, diabetes melli-tus, arterial hypertension, dyslipidemia, hyperhomocysteinemia, hypercoagula-bility syndromes etc.).

— A primary and secondary pre-vention of cerebro- and cardiovascular events should be performed (with an-tiaggregants, statines, ace-inhibitors).

— Association of accompanying co-morbid vascular therapy (carotidopa-thies, aortic abdominal aneurysms, ischemic heart disease etc.) and other-wise (chronic respiratory and renal in-sufficiency etc.).

— Intensive angiological treatment in specialist structures dedicated to patients suffering from chronic critical ischemia constitutes an alternative to early ampu-tation.

— In a chosen sample of patients who cannot be revascularized evalu-ate the neo-angiogenic therapy op-tion, above all by using the progenitor cells of the endothelial cells through in situ differentiation of autologous stem cells.



ing the surgical intervention of revasculari-zation selectively towards the vessel which supplies the angiosome where the lesion is located (Figure 11).2

A high percentage of trophic lesion heal-ing 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 cas-es ).3-6 Such data are confirmed by a re-cent 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 af-ter a revascularization intervention of a sin-gle vessel. After twelve months of follow-up

SURGICAL TREATMENT

The basic treatment of critical limb ischemia consists in surgical or endovascu-lar revascularization, with the main aim of saving the limb.

In therapeutic strategy one need consider the angiosome concerned and collateral ar-eas.

The angiosome concept was introduced towards the end of the eighties to identify anatomical units with their own specific vas-cularization. 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; ante-rior tibial artery no. 1; peroneal [fibular] ar-tery no. 2), with a possibility of anastomosis and connections between adjacent areas.1 These anatomical studies have allowed cor-relating the localisation of ulcers with the stenotic or obstructed vessel and address-

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).



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. Revasculariza-tion of a specific angiosome for limb salvage: does the target artery matter? Ann Vasc Surg 2009;23:367-73.

4. Soderstrom M, Aho P-S, Lepantalo M, Alback A. The influence of the characteristics of ischemic tissue le-sions 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. Se-lective 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;15:580-93.

6. Iida O, Nanto S, Uematsu M et al. Importance of the angiosome concept for endovascular therapy in pa-tients with critical limb ischemia. Catheter Cardiovasc Interv 2010;75:837.

7. Varela C, Aci NF, Bleda S et al. The role of foot col-lateral vessels on ulcer healing and limb salvage after successful endovascular and surgical distal proce-dures according to an angiosome model. Vasc En-dovascular 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 an-giosome 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, Mi-yashita Y et al. Long-term results of direct and in-direct endovascular revascularization based on the angiosome concept in patients with critical limb ischemia presenting with isolated below-the-knee le-sions. 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

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, suffer-ing from limb ischemic lesions and who un-derwent a distal bypass, a total percentage of healing of ischemic ulcers was obtained of 84.7%, with lower values in cases of indi-rect revascularization, only in patients with chronic kidney failure.

In this study the localisation and the ex-tension of the ulcers and the comorbidities appear to be more important than the angi-osome 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 revasculat-ing 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 revas-cularization could take place with an en-dovascular procedure or with a surgical bypass intervention. The TransAtlantic Inter-Society Consensus has identified the profile and the extension of the vessel le-sions 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 le-sions of the aortoiliac area, of the common femoral and superficial femoral arteries and the endovascular treatment of isolated le-sions of the iliac arteries, of the superficial femoral artery and of the subpopliteal ves-sels.

For the purposes of lesion healing, one should finally consider that it is often neces-sary to adopt a series of post-revasculariza-tion procedures (debridement surgery, mi-nor amputations, VAC therapy, skin grafts).

BOX

— The main aim of the surgical treat-ment is limb saving

— In the therapeutic strategy account need to be taken of the involved angio-some and collateral areas

— Endovascular procedure should be the first-choice method, while tradition-al surgery could be reserved for lesions which are technically not appropriate for angioplasty

— The endovascular procedure and revascularization surgery are often com-plementary



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 foot-wear. Without such devices one would take the risk of jeopardizing the beneficial ef-fects 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 proto-cols, the possibility of choice of technology becomes a resource in itself for the contain-ment of health expenses as long as there would be, on the part of users, an in-depth awareness of the clinic, techniques and ma-terials.

The basic technologies sustaining proper management of the skin lesion, further to its etiology, could be thus, partially, sum-marised:

— fast and selective debridement; — topical antimicrobials for the preven-

tion 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 cadav-

er skin; — preservation of the perilesional skin.

The possibility that the clinician can make use of available advanced technolo-gies widens the clinician’s possibility of in-terventions and improves the patient’s heal-ing expectancy.

Fast and selective debridement

While the debridement of neuropathic ulcers in a diabetic person could be surgi-cally performed without any hesitation, in ischemic ulcers and critical ischemia ulcers, particularly, it should be assessed whether

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 ul-cers of the skin and it should be supple-mented to systemic drug and surgical treat-ment. Actually, any improper action might compromise the healing of an ischemic ulcer rendering useless proper therapeutic medical/surgical management.

A mistaken local treatment could how-ever determine amputation as a result, even if a technically perfect revascularization intervention has been performed. Aware-ness of the principle regulating the local management of chronic skin lesions would allow a further improvement of the clini-cal 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 them-selves as:

— ulcers localised in various, often mul-tiple, areas with variable impairment of sur-face and deep tissues;

— dry gangrene or moist gangrene; — ulcers as sequelae of revascularization

surgical interventions, or of amputation; — acral ischemic lesions in the sclero-

derma 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 ul-cers should be treated with a non-adherent gauze associating a reduction of the pres-sure load 1 which could be made, in the lower limbs, by altering the shoes, ortho-pedic shoes and plaster casting techniques



because they precede amputation in a per-centage 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 revas-cularization intervention. Wherever has al-ready 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 pres-sure, above all in the diabetic foot and in lesions after partial amputation.10

to proceed with enzymatic or autolytic de-bridement, 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 apply-ing, after irrigating with water, the most suit-able combined action advanced dressings, chosen on the score of local conditions.

There are no comparative studies on sur-gical cleansing, with respect to between en-zymatic or autolytic, but experts are unani-mous in retaining that cleansing is essential in case of callus and necrosis and that surgi-cal debridement represents the best choice when one can practise it.

In the most recent guidelines emphasis has been made on the precocity of debride-ment interventions with the removal of the tissue defined as “non active”, highlighting the time factor; debridement should be the fastest possible and performed the soon-est 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 ba-sic principles of the “Wound Bed prepara-tion”.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 au-reus 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,



characteristics to be able, in the short term, to be a treatment technique in aid of the re-covery 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 ob-tained 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 sur-faces (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 af-ter revascularization or in cases of stabilised critical ischemia which could not be revas-cularized 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 ap-pears that the repaired skin with this system is more elastic and functional with respect to the procedure with homologous skin.17, 18

Compression therapy

In patients with skin ulcers caused by critical ischemia associated with peripher-al oedema, the use of sequential pressure therapy at low pressure (20 mmHg) is as-sociated with an improvement of the troph-ic 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-

Unfortunately, a review of current litera-ture 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 wor-kers have shown that the use of these dress-ing 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 consid-ered to be useful to obtain any recommen-dation for use at a higher level.11

Pain

Pain control in patients with ischemic ul-cer is extremely difficult and is exasperat-ing 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 con-tribute 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 suf-ficient exudate component.13

FREMS and PESF

Pain control could be, in some patients, realised by using the FREMS therapy (Fre-quency Rhythmic Electrical Modulation Sys-tem), a comfortable methodology which is easy to apply and is well accepted by patients. Pain reduction, in responder pa-tients 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



Ubbink DT, Westerbos SJ. Topical silver for treat-ing infected wounds. Cochrane Database of Sys-tematic Reviews 2007;1. Art. No.: CD005486. DOI: 10.1002/14651858.CD005486.pub2

10. Armstrong DG, Lavery LA. Diabetic Foot Study Con-sortium. Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, rand-omized controlled trial. Lancet 2005;366:1704-10.

11. Ubbink DT, Westerbos SJ, Evans D, Land L, Ver-meulen H. Topical negative pressure for treat-ing 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 pa-tients 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 pain-ful 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 fluximen-tric patterns. 5th Conference of the European Study group on cardiovascular oscillations.

16. Pullar EC. The physiology of bioelectricity in devel-opment, 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’ ex-perience 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 thera-py in the treatment of skin ulcers. Acta Vul 2009;113-35.

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 revascu-larization surgery aimed at saving the limb.

Use of other types of treatment is justified only in case of contraindications to the sur-gery that can be general (patients in criti-cal 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-

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 deriva-tion (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 periph-eral ischemia show up as dry and dehy-drated. The use of softening creams is par-ticularly 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 ex-tracellular matrix, altering the repair proc-ess.22

References

1. TASC II (Documento di Consenso InterSocietario TransAtlantico per il trattamento dell’arteriopatia periferica – TransAtlantic InterCompany Agreed Doc-ument for the treatment of peripheral arteriopahy. G Ital Cardiol 2007;8 (Suppl 2-12):3S-71S.

2. ADA. Peripheral arterial disease in people with dia-betes. Diabetes Care 2003;26:3333-41.

3. Nabuurs-Franssen MH, Sleegers R, Huijberts MS, Wi-jnen W, Sanders AP, Walenkamp G et al. Total contact casting ofthe diabetic foot in daily practice: a prospec-tive follow-up study. Diabetes Care 2005;28:243-7.

4. Falanga V et al. European Wound Management As-sociation (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 arte-riopatia diabetica - Guidelines of the Italian Associa-tion 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 in-terattivo per affrontare le sfide del wound care – A dynamic and interactive approach to face the chal-lenges of wound care. Acta Vuln 2010;8(Suppl. 1 no. 4).

7. Lipsky B. International consensus group on diagnos-ing 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,



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, intermit-tent pneumatic compression therapy (IPC) has been shown to play a relevant role, be-ing able to increase the arterial flow not only in normal patients but also in arterio-pathic 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 an-other; the administration modality is, there-fore, very different from that generally used in IV-lymphatic pathology for edema reduc-tion. The first studies on IPC in the claudi-cating patient go back 20 years ago and re-ported 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 arterio-pathic patients, one is well-documented and is represented by the reduction in the ve-nous pressure that increases the arterial-ve-nous 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 in-crease 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 lev-el of TcPO2;24 the salvage of 9/14 ischemic limbs in inoperable patients.25

At three months 58% of the limbs were

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 electri-cal stimulation and hyperbaric oxygen ther-apy may number among these.

Compression therapy

The rationale of compression therapy in chronic obstructive arteriopathy is well known: the treatment of a possible coex-istent venous pathology, skin ulcers, and edema that aggravates the arteriopathy.

Compression therapy is possible in pa-tients 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 be-tween 0.5 and 0.8.1-12 In this clinical situa-tion, not only is the pressure at the big toe not reduced 13, 14 but an increase in the per-iulcerous blood flow below the compres-sive system may be encountered.14-18 In one of our works in patients with mixed-etio-pathogenesis 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 pres-sure 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 trans-mural 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



Subsequently the technique, first intro-duced into clinical practice in the man-agement of pain syndromes refractory to conservative treatments, spread worldwide and was also routinely used for the treat-ment of vesical dysfunctions from multiple sclerosis, extrapyramidal-type motor dis-orders, and spasticity secondary to spinal cord lesions.

The rationale at the basis of SCS is prima-rily represented by the attempt to modulate the neural transmission of pain impulses from the periphery to the brain at the spi-nal 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 small-diameter 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 periph-eral arteriopathies, in 1976 it was postulated for the first time, following some observa-tions of Cook et al. that noted, in patients subjected to SCS for neurogenic vesical, an increase of local temperature and an im-provement of the tissue trophism of the lower limbs.33 The authors, therefore, ex-tended the indication of SCS to the chronic arteriopathies that had not previously re-sponded favorably to conventional medical treatments, traditional revascularization sur-gery or to sympathectomy, and thus high-lighted how the disappearance of ischemic pain, the instrumental improvement of the rheological and plethysmographic indices, and finally the healing of distal trophic le-

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 criti-cal 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 ar-tery 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 attrib-utable to the increase of the arterial-venous gradient and production of vasodilating substances by the endothelial cells conse-quent to the increase in shear stress.

Spinal cord stimulation

The electrical stimulation of the spinal cord, defined by the Anglo-Saxons as spi-nal 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 intro-duction of the stimulator electrode in the vertebral medullary epidural space in the treatment of various pain syndromes.31



or serious pathologies of the dorsal lumbar spine (disc pathologies, vertebral schisis, seri-ous kyphotic-scoliotic deformations, etc.).

Over the last decades, numerous clini-cal 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, over-all, 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 selec-tion of patients appears to be linked to the use of TCpO2 both in a supine position and in declivity, allowing for a more pre-cise 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 vas-cular 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 in-tervention 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-ad-ministration 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 elec-trical stimulation still seems to constitute to the present day a methodical alternative in treating critical lower limb ischemia turn-ing out to be valid, scarcely invasive and reversible, but which to be successful re-quires 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

sions were contextually observed. Also in subsequent studies relative to patients with serious peripheral arteriopathies, the au-thors 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 pre-requisite 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 mi-crocirculatory 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 angi-oplasty 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 macrocir-culation 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 indica-tions for the use of SCS should be restricted to only CLLI patients with limited trophic le-sions (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 abso-lute contraindications are tied to the presence of extended trophic lesions (greater than 6 cm in diameter), of concomitant patholo-gies with short life expectancy (e.g., tumors)



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 ede-ma. Other effects that can be ascribed to hyperbaric oxygen therapy in the healing of ischemic ulcers would be: the stimula-tion of the proliferation and differentiation of fibroblasts, the increase in the formation and cross-linking of collagen, the stimulus for neovascularization, and the leukocyte-mediated 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, how-ever, not all critical ischemia ulcers would be susceptible to improvement with hyper-baric 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 se-lected patients with an ulcer from critical ischemia are likely to benefit from hyperbar-ic oxygen therapy, but more rigorous studies are needed before a definitive confirmation of generalized efficacy can be made.

References

1. Humphreys ML, Stewart AH, Gohel MS, Taylor M, Whyman MR, Poskitt KR. Management of mixed arte-rial and venous leg ulcers. Br J Surg 2007;94:1104-7

2. Cornwall JV, Doré CJ, Lewis JD. Leg ulcers: epidemi-ology and aetiology. Br J Surg 1986;73:693-6.

3. Callam MJ, Harper DR, Dale JJ, Ruckley CV. Arterial disease in chronic leg ulceration: an underestimated hazard? Lothian and Forth Valley leg ulcer study. BMJ 1987;294:929-31.

4. Andersson E, Hansson C, Swanbeck G. Leg and foot ulcer prevalence and investigation of the peripheral arterial and venous circulation in a randomised eld-erly population: an epidemiological survey and clini-cal investigation. Acta Derm Venereol 1993;73:57-61.

5. Nelzén O, Bergqvist D, Lindhagen A. Venous and non-venous leg ulcers: clinical history and appear-ance in a population study. Br J Surg 1994;81:182-7.

6. Morrell CJ, Walters SJ, Dixon S, Collins KA, Brereton LM, Peters J, Brooker CG. Cost effectiveness of com-munity leg ulcer clinics: randomised controlled trial. BMJ 1998;316:1487-91.

reduction in the use of the treatment meth-od for critical lower limb ischemia occurring during past years, our data confirm the valid-ity of recurring to epidural medullary electri-cal stimulation in those patients who can no longer receive the traditional medical and/or surgical therapeutic benefits, notwith-standing that the evaluation of its effective-ness has been established not only clinically, but also, and above all, instrumentally.

The use of microvascular metabolical indi-ces, such as the transcutaneous oxygen and carbon dioxide tensiometry, actually consti-tutes the most valid criterion for the selec-tion 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 al-ternative method in the treatment of critical lower limb ischemia that is effective, mini-mally invasive and reversible, but which re-quires for its success an adequate special-ist 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 pa-tients and long-term follow-up. Despite a significant reduction in the use of the tech-nique 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 stim-ulation in patients that are no longer sus-ceptible to traditional medical and/or surgi-cal 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 in-dices 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



26. Louridas G, Saadia R, Spelay J, Abdoh A, Weighell W, Arneja AS et al. The ArtAssist Device in chronic lower limb ischemia. A pilot study. Int Angiol 2002;21:28-35.

27. Kavros SJ, Delis KT, Turner NS, Voll AE, Liedl DA, Gloviczki P et al. Improving limb salvage in critical ischemia with intermittent pneumatic compression: a controlled study with 18-month follow-up. J Vasc Surg 2008;47:543-9.

28. Sultan S, Hamada N, Soylu E, Fahy A, Hynes N, Taw-fick W. Sequential compression biomechanical device in patients with critical limb ischemia and non re-constructable peripheral vascular disease. J Vasc Surg 2011;52:440-6.

29. Labropoulos N, Leon LR Jr, Bhatti A, Melton S, Kang SS, Mansour AM et al. Hemodynamic effects of inter-mittent pneumatic compression in patients with criti-cal limb ischemia. J Vasc Surg 2005;42:710-6.

30. Shealy CN, Mortimer JT, Reswick JB. Electrical inhibi-Electrical inhibi-i-tion of pain by stimulation of the dorsal columns: preliminary clinical report. Anesth Analg (Cleve) 1967;46:489-91.

31. Dooley DM, Kasprak M. Modification of blood flow to the extremities by electrical stimulation of the nervous system, South Med J 1976;69:1309-11.

32. Melzack R, Wall PD. Pain mechanism: a new theory. Science 1965;150:971-9.

33. Cook AW, Oygar A, Baggenstos P, Pacheco S, Klerig E. Vascular disease of extremities. Electrical stimula-tion of spinal cord and posterior roots. NY State J Med 1976;76:366-8.

34. Ubbink DT, Vermeulen H, Spincemaille GH, Gersbach PA, Berg P, Amann W. Systematic review and meta-analysis of controlled trials assessing spinal cord stimulation for inoperable critical leg ischaemia. Br J Surg 2004;91:948-55.

35. Brümmer U, Condini V, Cappelli P, Di Liberato R, Scesi M, Bonomini M et al. Spinal cord stimulation in hemodialysis patients with critical lower limb isch-isch-emia. Am J Kidney Dis 2006;47:842-7.

36. Hilton S, Marshall J. Dorsal root vasodilatation in cat skeletal muscle. J Physiol 1980;299:277-88.

37. Linderoth B, Fedorcsak I, Meyerson B. Peripheral vasodilatation after spinal cord stimulation: animal studies of putative effect or mechanisms. Neurosur-gery 1991;28:187-95.

38. Linderoth B, Herregodts P, Meyerson B. Sympathetic medication of peripheral vasodilatation induced by spinal cord stimulation: animal studies of the role of cholinergic and adrenergic receptor subtypes. Neuro-surgery 1994;35:711-9.

39. Cui JG, O’Connor WT, Ungerstedt U, Linderoth B, Meyerson B. Spinal cord stimulation attenuates aug-mented dorsal horn release of excitatory amino ac-ids in mononeuropathy via a GABAergic mechanism. Pain 1997;73:87-95.

40. Transatlantic Inter-Society Consensus (Tasc): Man-agement of peripheral arterial disease. Suppl J Vasc Surg 2000;31:1-296.

41. Augustinson L, Carlson C, Holm J, Jivegard I. Epidural electric stimulation in severe limb ischemia. pain re-stimulation in severe limb ischemia. pain re-lief, increased blood flow and a possible limb-saving effect. Ann Surg 1985;202:104-10.

42. Jacobs MJ, Jorning PJ, Beckers RCY, Ubbink DT, Van Kleef M, Slaf DW et al. Foot salvage and improvement of microvascular blood flow as a result of epidural spi-nal electrical stimulation. J Vasc Surg 1990;12:354-60.

43. Jivegard LE, Augustinsson LE, Holm J, Risberg B, Or-tenwall P. Effects of spinal cord stimulation (SCS) in patients with inoperable severe lower limb ischemia: a prospective randomised controlled study. Eur J Vasc Endovasc Surg 1996;9:421-5.

7. Zimmet SE. Venous leg ulcers: modern evaluation and management. Dermatol Surg 1999;25:236-41.

8. O’Meara S, Cullum NA, Nelson EA. Compression for venous leg ulcers. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD000265. DOI: 1 0.1002/14651858.CD000265.pub2.

9. Gohel MS, Barwell JR, Taylor M, Chant T, Foy C, Earn-shaw JJ et al. Long term results of compression thera-py alone versus compression plus surgery in chronic venous ulceration (ESCHAR): randomised controlled trial. BMJ 2007;335:83.

10. Grey JE, Enoch S, Harding KG. ABC of wound healing: venous and arterial leg ulcers. BMJ 2006;332:347-50.

11. Hopf HW, Ueno C, Aslam R, Burnand K, Fife C, Grant L et al. Guidelines for the treatment of arterial insuffi-ciency ulcers. Wound Repair Regen 2006;14:693-710.

12. World Union of Wound Healing Societies’ Initiative (WUWHS) Compression in venous leg ulcers. A con-sensus document. London MEP Ltd 2008.

13. Top S, Arveschoug AK, Fogh K. Do short-stretch band-ages affect distal blood pressure in patients with mixed aetiology leg ulcers? J Wound Care 2009;18:439-42.

14. Mosti G, Partsch H. Compression therapy in mixed ulcers: search for a safe pressure range not affecting arterial inflow. JVS 2012;55:122-8.

15. Mayrovitz HN, Larsen PB. Effects of compression bandaging on leg pulsatile blood flow. Clin Physiol 1997;17:105-17.

16. Mayrovitz HN. Compression-induced pulsatile blood flow changes in human legs. Clin Physiol 1998;18:117-24.

17. Mayrovitz HN, Macdonald JM. Medical compres-sion: effects on pulsatile leg blood flow. Int Angiol 2010;29:436-41.

18. Mayrovitz HN, Sims N. Effects of ankle-to-knee ex-ternal pressures on skin blood perfusion under and distal to compression. Adv Skin Wound Care 2003;16:198-202.

19. Mehlsen J, Himmelstrup H, Himmelstrup B, Winther K, Trap-Jensen J. Beneficial effects of intermittent suction and pressure treatment in intermittent claudi-cation. Angiology 1993;44:16-20.

20. Delis KT, NicolaidesAN. Effect of intermittent pneu-matic compression of foot and calf on walking dis-tance, hemodynamics, and quality of life in patients with arterial claudication: a prospective randomized controlled study with 1-year follow-up. Ann Surg 2005;241:431-41.

21. Delis KT, Nicolaides AN, Wolfe JH, Stansby G. Im-proving walking ability and ankle brachial pressure indices in symptomatic peripheral vascular disease with intermittent pneumatic foot compression: a pro-spective controlled study with one-year follow-up. J Vasc Surg 2000;31:650-61.

22. Delis KT, Husmann MJ, Cheshire NJ, Nicolaides AN. Effects of intermittent pneumatic compression of the calf and thigh on arterial calf inflow: a study of nor-mals, claudicants, and grafted arteriopaths. Surgery 2001;129:188-95.

23. Montori VM, Kavros SJ, Walsh EE, Rooke TW. Inter-mittent compression pump for nonhealing wounds in patients with limb ischemia. The Mayo Clinic experi-ence (1998-2000). Int Angiol 2002;21:360-6.

24. Vella A, Carlson LA, Blier B, Felty C, Kuiper JD, Rooke TW. Circulator boot therapy alters the natural history of ischemic limb ulceration. Vasc Med 2000;5:21-5.

25. van Bemmelen PS, Gitlitz DB, Faruqi RM, Weiss-Olmanni J, Brunetti VA, Giron F et al. Limb salvage using high-pressure intermittent compression arterial assist device in cases unsuitable for surgical revascularization. Arch Surg 2001;136:1280-5.



TREATMENT OF SCLERODERMA ULCERS

The first and earliest clinical manifesta-tion 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 de-scribed “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 so-called scleroderma spectrum, characterized by dilatations of the capillary loops with the formation of giant capillaries (megacapil-laries) 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, scle-roderma vascular disease leads to real acute

44. Klomp HM, Spincemaille G, Steyerberg EW, Habbe-ma 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 Co-chrane Library 2006;4.

48. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Har-ris 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 de-termine the effect of spinal cord stimulation for criti-cal 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: Spi-nal Cord Stimulation in the treatment of Non-recon-structable 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 mi-crovascular 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 dur-ing 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 Interna-tional 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 moni-toring indispensable in short and long-term therapeu-tic 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, edi-tors. 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-Co-chrane Database Syst Rev 2004;2:CD004123.

59. Grolman RE, Wilkerson DK, Taylor J, Allinson P, Zati-, Wilkerson DK, Taylor J, Allinson P, Zati-Wilkerson DK, Taylor J, Allinson P, Zati-, Taylor J, Allinson P, Zati-Taylor J, Allinson P, Zati-, Allinson P, Zati-Allinson P, Zati-, Zati-Zati-na 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. Figure 12.—Acute ischemic phase.



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 dam-age that presents as a pitting scar, i.e., local-ized 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).

and chronic ischemia of the fingers and toes with death of the tissues and forma-tion of painful necrotic ulcers that are diffi-cult to heal, and if not promptly recognized and treated with systemic pharmacological therapies and with local dressings, will in-exorably evolve into gangrene.5-7

Scleroderma ulcers

Ulcers are a visible evidence of sclero-derma 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 un-usual 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 compli-cations quoad vitam of the patient, while they represent the most debilitating compli-cation for quality of life due to pain, func-

Figure 14.—Pitting scar.

Figure 13.—Scleroderma pattern.





of the calcinosis itself, which determines the self-limitation of the inflammatory process and the healing of the lesion without con-comitant infective complications (Figure 18).

The knowledge of the different types of scleroderma ulcers and of the different as-sociated pathophysiological mechanisms is a necessary and indispensable prerequi-site for the choice of the different targeted and effective therapeutic strategies; for ex-ample, the ulcer with underlying calcinosis may not be responsive to vasodilators like the ischemic ulcer should be.7

Primary prevention

The patient should be viewed in the fa-milial 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 vasoconstric-tors (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-

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 out-come of cutaneous sclerosis and tendon re-traction, 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 phlogis-tic complications that further slow healing. Finally, in the course of systemic sclerosis, ulcers associated with an underlying calci-nosis arise that trigger an intense inflam-matory process like a reaction to a foreign body, absolutely finalized to the expulsion

Figure 18.—Atrophic ulcers.

Figure 17.—Amputation.



have affected the bone. Scleroderma patients may require further cycles of antibiotic ther-apy, particularly if an osteomyelitis process is present that requires parenteral and pro-longed systemic antibiotic therapy.

Pharmacologic therapy

After having controlled the pain and in-fection, it is necessary to promote the heal-ing of the existing ulcers and prevent the formation of new ulcers.

Despite the notable impact on the qual-ity of life of the scleroderma patient, a de-fined 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 scleroder-ma ulcers are ischemic ulcers with endothe-lial 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 ac-quired implication of endothelial damage/dysfunction and of platelet hyper aggregabil-ity 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 be-tween proton pump inhibitors, acetylsalicylic acid and calcium antagonists.11

anTiPlaTeleT agenTs

The treatment of treating scleroderma pa-tients 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

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 complica-tions. The framing of the medical history and the careful evaluation of comorbidity are fun-damental, 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 im-provement of the patient’s quality of life, but also as an essential requirement for the heal-ing process, as the state of anxiety associated with pain evokes a vasoconstriction reaction that worsens and aggravates Raynaud’s phe-nomenon and the consequent vasospastic ischemic damage. It is preferable to use aceta-minophen and opioids instead of NSAIDs because of the pain’s chronic characteristics and the need for prolonged treatments. Infec-tion 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 examina-tion, immediately starting an antibiotic cover-age active against gram-positive bacteria, ef-fective in most cases and possibly modified with the outcome of the antibiogram. Always ask for a radiological evaluation if you sus-pect that the infective phlogistic process may



led clinical trial, the infusional cyclical ther-apy 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 scle-roderma vascular disease (Figures 19, 20).14

— Phosphodiesterase inhibitors: induce vasodilation by increasing the levels of bioa-vailability of endogenous nitric oxide (NO). The utility of using these drugs is based on the pathophysiological assumption that sys-temic sclerosis is a typical pathology of en-dothelial activation/dysfunction with imbal-ance between vasoconstrictor factors and vasodilator factors (including NO) in favor of the former and that tissue damage is es-tablished subsequent to this dysfunction. Raynaud’s phenomenon is the typical clini-cal manifestation that testifies to how the vasospasm, with consequent peripheral hy-poperfusion, is one of the pathology’s typi-cal markers. The positive effect of sildenafil and tadalafil on Raynaud’s phenomenon is shown by two randomized controlled clini-cal 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 be-ing difficult to treat, slow healing, intensely

molecular weight heparin in the most sig-nificant pictures of acute ischemia.9

VasodilaTor drugs To CounTeraCT VasoCon-sTriCTion and wiTh indiCaTion for The TreaTmenT of raynaud’s Phenomenon wiTh CliniCal eVidenCe of effiCaCy in The TreaT-menT of sCleroderma ulCers

— Slow-release and prolonged coverage (chrono form) calcium antagonists (nifed-ipine), 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 vasodi-lators that inhibit platelet aggregation and the proliferation of smooth muscle cells in the blood vessel wall. Iloprost is a stable prostacyclin analogue, administrable intra-venously, which plays an important thera-peutic role in the treatment of ischemic scle-roderma ulcers as well as other pathological forms characterized by arterial hypoper-fusion with consequent tissue ischemia. The therapeutic indication is the treatment of Raynaud’s phenomenon secondary to sys-temic 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 stand-ard treatment for ischemic scleroderma dig-ital ulcers. Iloprost has been the subject of controlled studies that have endorsed its effectiveness for the aforementioned indi-cations. In a multicenter controlled dou-ble-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 persist-ence of effects at 9 weeks of follow-up, in-dicating 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 circula-tory system shown in a randomized control-

Figure 19.—Atrophic ulcers exposed to infective phlogis-tic complications.



eling process and the deposition of extracel-lular matrix. The phenomenon is driven by excessive vasoconstriction and hyperprolif-eration by the myocytes of the tunica media of the arteriolar component, by a prolifera-tion of endothelial cells, and by an excessive production of profibrotic mediators by the fi-broblasts, 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 phenom-enon and the formation of digital ulcers.21, 22

By blocking the effects of ET-1, one aims to slow the progression of the vascular re-modeling that underlies the ulcerative man-ifestations (Figure 21).21-24

Surgical therapy

Surgical therapy is essentially reserved for extreme cases of vasospastic ischemization during the nearly continuous or subcontinu-ous cyanotic phase. Recourse to sympathec-tomy is intended to reduce the number and

painful and disabling, have a natural ten-dency to recur.

The scleroderma patient who has already presented scleroderma ulcers, in addition to the antiplatelet and vasoactive therapy indi-cated above, is indicated to be treated with non-selective endothelin receptor inhibitors (Bosentan).

This indication has emerged from the re-sults of two double-blind randomized con-trolled clinical trials with placebo, RAPIDS 1 and 2, that have shown the efficacy of bosentan in significantly reducing the on-set 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 in-creased endothelin-1 levels. Endothelin-1 is a potent vasoconstrictor and an important pathogenic mediator that carries out its ef-fects 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, fi-broblasts and macrophages that, in response to the stimulus, activate a vascular remod-

Figure 20.—Pleiotropic effects of iloprost on the circulatory system: some examples.

Vascular cells Vascular cells

Vascular cells

Monocytes and neutrophils

ILOPROST

• Reduction of αMβ2 integrin (on neutrophils and monocytes)• Modulation of cytokine production• Adhesion• Chemotaxis• Production of free radicals

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• …

• 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



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 treat-ment, 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 col-lection. 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 therapeu-tic success is contingent upon the prompt-ness and appropriateness of the intervention.

At the time of their onset, the modest sizes induce the clinician to make an op-timistic and conservative wait-and-see type evaluation, given the small dimensions that are similar to a pinhole or the slit of

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 re-sults of cervical sympathectomy have been rather disappointing, better results are de-rived from digital sympathectomy associated with techniques of resection and removal of the fibrotic adventitia (microsurgical arteri-olysis).26 This procedure has promoted heal-ing 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 expe-rience advises conservative procedures limited to eliminating the necrotic mate-rial, also carrying out extra-anatomic pro-cedures 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 ex-tension of the necrotizing process. Alterna-tively, 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 accord-ing to the principles of the TIME acronym is necessary for an optimal dressing; this acronym summarizes the essential charac-teristics of the ulcer by considering T (devi-talized tissue), I (infection), M (maceration), and E (perilesional epithelium).

Microangiopathic ulcers in general and scleroderma ulcers in particular, in the ac-tivity phase, are extremely painful, very reactive and rather unwilling to accept ag-gressive local treatments of a mechanical type or surgical cleansing, which can pro-

Figure 21.—Mechanisms of endothelin’s action in vascu-lar remodeling process.

VasoconstrictionHypertrophy and

proliferationExtracellular matrix

NF-KB and therelease ofcytokines

Increase ofvascular

permeability

INFLAMMATION SMOOTHMUSCLE

CELLS

FibroblastCollagen,

proteoglycans

ENDOTHELIN

ENDOTHELIUM

Dysfunction-proliferationapoptosis



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 ap-pearance of the lesions, toward the most appropriate and effective therapeutic direc-tives 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

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 ap-proached 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 diag-nostic completion. Nevertheless, the evo-lution 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 ar-eas of tissue already in the necrotic phase.

That said, it is evident that the optimal, economic and ideal treatment of the sclero-derma ulcer starts with primary prevention, which requires the early diagnosis of scle-roderma even in the early and preclinical forms when the reversible and paroxysmal phases of ischemia, represented by Ray-naud’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 cy-clic treatment with iloprost. In the presence of active ulcers, the systemic treatment of the acute ischemia with an infusional ther-apy of iloprost, an anti-thrombotic therapy, associated with the appropriate pain man-agement and antibiotic therapy in the case of infection, is important. In the case of recurrent ulcers, despite the optimization of the vasoactive and antithrombotic ther-apy, it is important to subject the patient to therapy with the non-selective endothe-lin-1 receptor inhibitor drug (bosentan), and, where resistant ulcers and severe Ray-naud’s are present, to add the phosphodi-esterase inhibitor drug (sildenafil/tadalafil). Although an antifibrotic therapy that heals systemic sclerosis is not yet available, and while ignoring if the early scleroderma syn-dromes will all evolve into definite system-

BOX

— Ischemic ulcers typically require privileged and priority clinical audit

— Primary prevention: treating Scle-rodermic Raynaud’s phenomenon with living standards, calcium antagonists, an-tiplatelet, iloprost; clinical follow up in the context of a dedicated multidiscipli-nary path.

— Secondary prevention: recurrent ul-cers 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 in-dicated to be treated adding the phos-phodiesterase 5 inhibitor drug.

— Surgical indication limited and se-lected.

— Conservative surgery and Amputa-tion limited to necrotic area



patients with Raynaud phenomenon secondary to systemic sclerosis: a multicenter placebo control-led double blind study. Annals of Internal Medicine 1994;120:199-206.

14. Scorza R et al. Effect of long term cyclic iloprost therapy in Systemic Sclerosis with Raynaud’s phe-nomenon. A randomized, controlled study. Clin Exp Rheumatol 2001;19:503-8.

15. Fries R et al. Sildenafil in the treatment of Raynaud’s phenomenon resistant to vasodilatory therapy. Circu-lation 2005;112:2980-5.

16. Shenoy PD et al. Efficacy of tadalafil in secondary Raynaud’s resistant to vasodilator therapy: a double blind randomized cross over trial. Reumatology (Ox-ford) 2010;49:2420-8.

17. Brueckner C et al. Effect of Sildenafil on digital ul-cers in Systemic sclerosis: analysis from a single centre pilot study. Annals of the Rheumatic Diseases 2010;69:1475-8.

18. Korn JH et al. Digital ulcers in systemic sclerosis. Pre-vention by treatment with bosentan, an oral endothe-lin receptor antagonist. Arthritis and Rheumatism 2004;50:3985-93.

19. Seibold J et al. Bosentan reduces the number of new digital ulcers in patients with systemic sclerosis. An-nals of Rheumatic Diseases 2006;65(Suppl. 2):90.

20. Abraham D, Disler O. How does endothelial cell inju-ry start? The role of endothelin in systemic sclerosis. Arthritis Res Ther 2007;9(Suppl 2):S2.

21. Shetty N. Endothelin receptor antagonista s disease modifiers in systemic sclerosis. Inflammation and Allergy-Drug Targets 2011;10:19-26.

22. Hachulla et al. Reumatology 2007;34:2423.23. Tsifetakin et al. Bosentan for digital ulcers in patients

with systemic sclerosis: a prospective 3-year follow-up study. Journal of Rheumatology 2009;36:550-1.

24. Marcoccia A, Salvucci C. Case report. Recurrence of digital ulcers after suspension of bosentan therapy in the patient affected by systemic sclerosis and gener-alized itching. [Italian: Recidiva di ulcere digitali dopo sospensione della terapia con bosentan in paziente affetta da sclerosi sistemica e prurito generalizzato]. Journal of Clinical Medicine 2011;10.

25. Bogoch ER, Gross DK. Surgery of the hand in pa-tients with systemic sclerosis: outcomes and consid-erations. Journal of Rheumatology 2005;32:642-8.

26. Ruch DS et al. Periarterial sympathectomy in sclero-derma patients: intermediate-term follow-up. Journal of Hand Surgery 2002;27:258-64.

27. Kotsis SV, Chung KC. A systematic review of the outcomes of digital sympathectomy for treatment of chronic digital ischemia. Journal of Rheumatology 2003;30:1788-92.

28. Marcoccia A et al. From Raynaud’s phenomenon to early systemic sclerosis: an operational model of early diagnosis, therapy, and follow-up [Italian: Dal fenomeno di Raynaud alla early sclerosi sistemica: modello operativo di diagnosi precoce, terapia e fol-low-up] Intern Emerg Med 2009;4:S 48.

29. Valentini G et al. Early systemic sclerosis: assessment of clinical and preclinical organ involvement in patients with different disease features. Rheumatology 2010.

30. Matucci Cerinic M et al. The challenge of early sys-temic sclerosis for the eular scleroderma trial and re-search group (EUSTAR community). It is time to cut the Gorgian Knot and develop a prevention or rescue strategy. Ann Rheumat Dis 2009;68:1377-80.

31. Avovac J et al. EUSTAR Group. Preliminary criteria for the very early diagnosis of Systemic Sclerosis: re-sults of a Delphi Consensus Study from Eular Sclero-derma Trials and Research Group. Ann Rheum Dis 2011;70:476-81.

guided in the context of a dedicated multi-disciplinary path.28-31

The close clinical follow-up of the pa-tient 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 of-ficially accepted by the FDA for the treat-ment 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 path-ogenic phases of ischemic damage. Similarly to the treatment of other clinical manifesta-tions of scleroderma vascular disease such as pulmonary hypertension, the therapeutic algorithm for the prevention and treatment of scleroderma ulcers should indicate, as de-scribed above, a combination of therapies that, starting from the earliest stages of scle-roderma vascular disease, exploits the tar-gets of activity of different molecules to have a sequential, synergistic and additive effect.

References

1. Valentini G. Early systemic sclerosis: diagnostic crite-ria and work up. Reumatismo 2002;54:9-11.

2. Maricq HR, LeRoy EC Diagnostic potential of in vivo capillary microscopy in scleroderma and related dis-orders. Arthritis Rheum 1980;23:183-9.

3. Grassi W, Del Medico P. Atlas of capillaroscopy. EDRA 2004.

4. Cutolo M. Atlas of capillaroscopy in rheumatic dis-ease. Elsevier 2010.

5. Schiopu E et al. Digital ischemia in scleroderma spec-trum of diseases. Int J Rheumatol 2010:pii923743.

6. Chung L, Fiorentino D. Digital ulcers in patients with systemic sclerosis. Autoimmun Rev 2006;5:125-8.

7. Matucci-Cerinic M, Seibold JR. Digital ulcers and out-comes assessment in scleroderma. Rheumatology 2008;47:46-7.

8. Harrison BJ et al. Cigarette smoking as a significant risk factor for digital vascular disease in patients with systemic sclerosis. Arthritis Rheum 2002;46:3312-6U.

9. Denton CP, Korn JH. Scleroderma Care Res 2003;1:12-20.

10. Marvi, Chung. Digital ischemic loss in systemic scle-rosis. Int J Rheumatol 2010:130717.

11. Valentini. The systemic sclerosis therapy. [Italian: La terapia della sclerosi sistemica.] Reumatismo 2004;56:1-8.

12. Steen V et al. Digital ulcers overt vascular disease in systemic sclerosis. Rheumatology 2009.

13. Wigley FM et al. Intravenous iloprost infusion in

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