The Management of Diabetic Foot

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Current Diabetes Reviews, 2012, 9, 000-000 1

1573-3998/13 $58.00+.00 © 2013 Bentham Science Publishers

The Management of Diabetic Foot

Carlo Caravaggi1 *

, Adriana Sganzaroli1, Paolo Galenda

1, Matteo Bassetti

2, Roberto Ferraresi

3 and

Livio Gabrielli4

1Diabetic Foot Clinic, Istituto Clinico Città Studi, Milan, Italy

*University Vita-Salute Milan Italy

2Clinica Malattie Infettive dell’Azienda Ospedaliera Universitaria Santa Maria della Misericordia di Udine.

3Interventional Cardiovascular Unit, Istituto Clinico Città Studi, Milan, Italy;

4Division of Vascular Surgery, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy

Abstract: Diabetes is a chronic disease with a worldwide increasing trend. Foot complications, closely related to neuropa-

thy and obstructive peripheral vascular disease, are responsible for more than 1 million of leg amputations every year.

Foot infection can dramatically increase the risk of amputation. Although many ulcer classification systems have been

proposed to stratify the severity of the infectious process, the definition of a specific therapeutic approach still remains an

unsolved problem. A Diabetic Foot Triage and an Integrated Surgical Protocol are proposed to identify a diagnostic flow-

chart and a step-by-step surgical protocol that can be applied in the treatment of diabetic foot infection. Considering the

rapid climbing of multidrug resistant strains it is very important to rationalize the use of antibiotics utilizing them only for

the treatment of true infected ulcers. PAD is widely considered the most important factor conditioning the outcome of a

diabetic foot ulcer. Currently no randomized control trials are reported in the international literature directly comparing

open versus endovascular revascularisation in diabetic patients with CLI. Insufficient data are available to demonstrate

whether open bypass surgery or endovascular interventions are more effective in these patients. A decisional flow chart in

choosing the best revascularization strategy in diabetic patients with CLI is proposed.

Goals and technical aspects of emergency and elective surgical procedures in diabetic foot are analysed to evaluate critical

aspects and to suggest proper surgical choices.

Keywords: Charcot Neuroarthropaty, Diabetic foot, Diabetic foot infection, Diabetic foot surgery, Diabetic foot ulcer, Ischemic diabetic foot.

INTRODUCTION

Diabetes is a worldwide common chronic disease caused both by genetic and environmental factors with an epidemic evolution in developing countries. It is estimated that ap-proximately 346 million people worldwide (6.5%) have dia-betes and this trend is expected to increase to some 440 mil-lion (7.8%) by 2030 [1]. Every year more than 1 million people undergo a lower-limb amputation as a consequence of diabetes and 85% of all amputations are preceded by a foot ulcer [2]. Prevalence of lower-extremity amputations in peo-ple with diabetes ranges from 0.2 to 4.8% while annual inci-dence ranges from 46 to 936 for 100.000 diabetic patients [3]. Differences in prevalence and incidence are mainly re-lated to demographic factors, local prevalence of diabetes and different data collection criteria.

Diabetic people are 25 times more likely to lose a leg than non-diabetic and throughout the world up to 70% of leg

*Address correspondence to this author at the Diabetic Foot Clinic, Istituto

Clinico Città Studi, Via Ampère 47, 20131 Milano, Italy; Tel: +39 02

23933020; Fax: +39 02 23933050; E-mail: [email protected]

amputations are performed in people with diabetes [4]. Dia-betic foot complications result in huge costs for diabetics, their families and society and foot problems consume from 15% to 40% of the healthcare resources for diabetes [1,2,5].

DEFINITION, CHARACTERISTICS AND PATHO-PHYSIOLOGY

Diabetic foot has been defined as an infection, ulceration

or destruction of deep tissues of the foot associated with

neuropathy and/or peripheral arterial disease [4]. Ulcers may

involve any part of the foot: approximately 50% are located

on the plantar surface of the foot while remaining 50% may

involve other areas. Diabetic foot lesions frequently result

from a combination of many risk factors occurring together

as listed in Table 1 [6]. Diabetic foot ulcers can be divided

into neuropathic, neuro-ischemic and pure ischemic lesions

[7].

Neuropathy

Diabetic peripheral neuropathy is characterized by the involvement of all fibers (sensory, motor and autonomic). Motor neuropathy results in atrophy and weakness of the

2 Current Diabetes Reviews, 2013, Vol. 9, No. 1 Caravaggi et al.

muscles of foot and leg and joint rigidity with consequent abnormal walking pattern resulting in increase of peak pres-sure on the plantar aspect of the foot. Foot deformities as consequence of muscle impairment and joint rigidity may cause ulcer on both plantar and dorsal side of the foot [8,9].

Autonomic neuropathy results in reduced or absent sweating leading to dry skin with cracks and fissures. The involvement of sympathetic nerve fibers causes increased arteriovenous shunting which leads to a warm and edema-tous foot with distended dorsal foot veins [10].

Sensory neuropathy may reduce pain perception, increas-ing the risk of ulceration secondary to repetitive trauma dur-ing walking [11-13]. Insensitive callus on plantar foot sur-face, caused by peak of pressure, frequently anticipates the onset of a neuropathic plantar ulcer [8,9,11].

Charcot neuro-osteoarthropathy is a devastating compli-cation of diabetic foot syndrome. Acute Charcot usually pre-sents with a hot, inflamed, swollen and sometimes painful foot without skin lesions. Clear differentiation from infection is essential to ensure appropriate management. Progression is often rapid with bone fragmentation and joints destruction followed by exuberant periosteal reaction. Collapse of the medial longitudinal arch of the foot is a common evolution leading to typical 'rocker bottom' deformity with a high risk of deep infected ulcer [14-16].

Peripheral Arterial Disease

PAD is the most important factor conditioning the out-come of a diabetic foot ulcer and is the only independent prognostic factor for amputation [7]. PAD can be approxi-mately found in 50% of the patients presenting a foot ulcer [17]. In diabetics PAD is more common, affects younger individuals, is equally divided between genders, has a mul-tisegmental and more distal localization with a faster pro-gression [4].

Less than 25% of diabetic patients affected by PAD re-ports intermittent claudication due to the concomitant sensory neuropathy [4,18]. Diagnostic procedures include ankle and toe pressure measurements and ankle-brachial index. The cut off for diagnosis of CLI in patients with ulcers or gangrene is considered an ankle pressure less than 70 mmHg or a toe pressure less than 50 mmHg [18]. High

or a toe pressure less than 50 mmHg [18]. High incidence of arterial wall calcification in diabetic patients renders ankle and toe pressure often unreliable due to overestimation of the intravascular pressure [19]. TcPO2 measurement is more valuable in diabetic patients, the critical level of TcPO2 for the diagnosis of CLI is considered < 30 mmHg; however Faglia et al. demonstrated that TcPO2 levels < 34 mmHg indicate the need for revascularization, while for values rang-ing from 34 to 40 mmHg it appears less pressing, although there remains a considerable probability of amputation. TcPO2 levels greater than 40 mmHg suggest that the revas-cularization is dependent on the severity of the tissue loss and on the possible morbidity caused by the procedure [20].

Infection

Foot infection is a common complication in patients with diabetes and is associated with a dramatic increase of the risk of lower extremity amputation. Patients with diabetes are particularly susceptible to foot infection [21] because of neu-ropathy, vascular insufficiency and diminished neutrophil function [22-24]. Several studies have demonstrated that in diabetic subjects there was a consistent reduction in apopto-sis and consequently neutrophils failed to down regulate the production of TNF over time. The failure to limit the pro-duction of mediators potentially causing tissue injury might contribute to the extensive tissue damage observed during infections in diabetic patients. DFIs are classified as mild, moderate, or severe (Table 2) [4,25].

Osteomyelitis

Osteomyelitis is a frequent and serious complication of diabetic foot ulcers and infection. Bone infection may be difficult to detect on a clinical basis [26]. A delay in the di-agnosis of osteomyelitis increases the risk of amputation considering that imaging techniques are not enough specific and sensitive [27-29]. Diagnostic criteria for the diagnosis of osteomyelitis have been recently proposed (Table 3) [30].

Diabetic Foot Triage: A New Therapeutic Approach to Diabetic Foot Problems

In case of a foot ulcer in a diabetic patient, the assess-ment of the extent and depth of the lesion, of the presence of PAD and infection is crucial for the diagnosis, the therapeu-tic approach and the prognosis. Many staging systems have been proposed, currently the most widespread and vali-dated system is the University of Texas Wound Classifica-tion System that combines the depth of the lesion and the presence or absence of ischemia and infection (Fig. 1) [31, 32]. TUC stages demonstrate a positive correlation between ulcer size, ischemia and infection and the increase of the relative amputation risk. Although this classification permits to stratify accurately the severity of the infectious process, the problem of defining a correct therapeutic approach for different clinical conditions remains unsolved. From a clini-cal point of view it is clear that the severity of an infectious process indicates the need for immediate treatment, but un-fortunately there are few data in the literature that specify which treatment is appropriate according to the different degrees of infection and ischemia. In 2004 Van Baal et al.

Table 1. Risk Factors for Foot Ulcers in Diabetes.

• Previous amputation

• Past foot ulcer history

• Peripheral neuropathy

• Foot deformity

• Peripheral vascular disease

• Visual impairment

• Diabetic nephropathy (especially patients on dialysis)

• Poor glycaemic control

• Cigarette smoking

From Boulton AJM et al. [6]

Diabetic Foot Management Current Diabetes Reviews, 2013, Vol. 9, No. 1 3

Table 2. Clinical Classification of Diabetic Foot Infection.

Clinical Manifestations of Infection Infection

Severity

PEDIS

Grade*

Wound lacking purulence or any manifestations of inflammation. Uninfected 1

Presence of 2 manifestations of inflammation (purulence, or erythema, pain,

tenderness, warmth, or induration), but any cellulitis/erythema extends <2

cm around the ulcer, and infection is limited to the skin or superficial subcutaneous

tissues; no other local complications or systemic illness.

Mild 2

Infection (as above) in a patient who is systemically well and metabolically stable

but which has 1 of the following characteristics: cellulitis extending >2

cm, lymphangitic streaking, spread beneath the superficial fascia, deep-tissue

abscess, gangrene, and involvement of muscle, tendon, joint or bone

Infection in a patient with systemic toxicity or metabolic instability (e.g., fever,

chills, tachycardia, hypotension, confusion, vomiting, leukocytosis, acidosis,

severe hyperglycemia, or azotemia)

Severe 4

From Lipsky BA et al. [25]

*PEDIS: perfusion, extension/size, depth/tissue loss, infection, and sensation [4]

Table 3. Proposed Criteria for Diagnosing Osteomyelitis in the Diabetic Foot.

Category Probability

Osteomyelitis

Management

Advice Criteria Comments

Definite >90% Treat for

osteomyelitis

• Bone sample with positive culture AND positive

histology OR

• Purulence in bone found at surgery OR

•

• Atraumatically detached bone fragment removed

from ulcer by podiatrist/surgeon OR

• Intraosseous abscess found on MRI OR

• Any two probable criteria OR one probable and two

possible criteria OR, any four possible criteria be-

low

Sample must be obtained

at surgery or through

uninvolved skin

Definite purulence

identified by experienced surgeon

Definite bone fragment

identified by experienced

surgeon/podiatrist

Probable

51-90%

Consider

treating, but

further inves-

tigation may

be needed

• Visible cancellous bone in ulcer OR

• MRI showing bone oedema with other signs of

osteomyelitis OR

• Bone sample with positive culture but negative or

absent histology OR

• Bone sample with positive histology but negative or

absent culture OR

• Any two possible criteria below

Sinus tract; sequestrum,

heel or metatarsal head involved;

cloaca


Table 3. contd….

Category Probability

Osteomyelitis

Management

Advice Criteria Comments

Possible

10-50%

Treatment

may be justi-

fiable, but

further inves-

tigation usu-

ally advised

• Plain X-rays show cortical destruction OR

• MRI shows bone oedema OR cloaca, OR

• Probe to bone positive OR, Visible cortical bone OR

• ESR >70mm/h with no other plausible explanation

OR

• Non-healing wound despite adequate offloading and

perfusion for >6 weeks OR

• Ulcer of >2 weeks duration with clinical evidence of

infection

Unlikely

<10%

Usually no

need for fur-

ther investiga-

tion or treat-

ment

• No signs or symptoms of inflammation AND normal

X-rays AND ulcer present for <2 weeks or absent

AND any ulcer present is superficial OR

• Normal MRI OR

• Normal bone scan

From Berendt AL et al. [30]

Fig. (1). University of Texas Wound Classification System Adapted from Armstrong DG et al. [32]. Colors were inserted to create a link with

figure 2 “Diabetic Foot Triage”.

demonstrated that the delay in the radical surgical treatment is correlated with an high percentage of major and minor amputations because it allows the infection to proliferate and destroy the tissues [33]. Faglia et al. demonstrated that, in case of CLI, an early surgical treatment of a severe infection followed by an early revascularization procedure, is able to achieve limb salvage or a more distal level of foot amputa-tion [34]. The International Guidelines on Diabetic Foot Treatment have clearly indicated which is the treatment of choice to be applied in different situations to achieve the best clinical outcome [4]. Unfortunately these guidelines have been applied in only a few specialized Centres and have re-mained unknown and not enforced by most physicians who deal occasionally with diabetic foot lesions. Patients with an

infected diabetic foot are often sent to an Emergency De-partment where only rarely they can be subjected to an evaluation by a diabetic foot specialist for proper diagnosis and treatment. In our clinical experience anything resulting in a dramatic delay in the diagnosis and treatment of DFI increases not only the risk of amputation but also the risk of death. We therefore considered appropriate, based on a ten-year experience in emergency medicine and surgery of dia-betic foot, to propose a specific “diabetic foot triage” (Fig. 2) envisaged as a codified set of procedures that allows the evaluation of the priorities of patient care. We think that this diagnostic approach could be of great therapeutic utility not only for the diabetic foot specialists but also for all physi-cians who have to deal, even occasionally, with diabetic foot problems.


ANTIBIOTIC THERAPY FOR DIABETIC FOOT

INFECTIONS

Etiology

DFI is one of the most frequent complications of diabetes mellitus and represents a major cause of morbidity and mor-tality; it is the first cause of diabetes-related admission to the hospital and one of the primary causes of lower limb ampu-tations [2, 25,35- 38]. The commonest etiology of infection is actually represented by Gram-positive bacteria, such as Staphylococci and Streptococci, but the isolation of Gram-negative strains is not unusual in chronic ulcers and in pa-tients previously treated with antimicrobials. The most fre-quent isolated bacterial strains resulting from a seven-year study of an European and American surveillance were: S. aureus, P. aeruginosa, E. coli and Enterococcus spp [39]. During the observation period it was noticed a growth in the incidence of multi-resistant bacteria, especially MRSA. However, recent data demonstrate a decreasing trend in the prevalence of MRSA in several European countries, except in Italy, where an increasing trend has been noted probably related to an inadequate hospital infection control policy; Gram-negative bacteria with a warning resistance pattern represented the 30% of isolates in the same study [40].

Rationale of Antibiotic Therapy

Compared to the climbing of multidrug resistant strains,

there are no new antimicrobials, especially active against

Gram-negatives [40], consequently, it is very important to

rationalize the use of antibiotics which have to be used only

for the treatment of true infected ulcers, that must be differ-

entiated from colonized ulcers (Table 2). An ulcer can be

defined as infected when there are at least two signs: sur-

rounding cellulitis and inflamed wound and/or drainage. In

fact, the antibiotic treatment is mandatory only if there is

clinical and microbiological evidence of infection (local or

systemic). Bacteriological sampling is only indicated if the

DFI is clinically confirmed, corresponding to grade 2-4 in-

fections (3). Microbiological samples must be collected prior

to the initiation of the antimicrobial therapy, by cutaneous

biopsy, ulcer curettage or deep aspiration of pus. Superficial

swabs must be discouraged, because of the low diagnostic

accuracy of this technique [41]. The imaging studies (ultra-

sounds and MRI) are useful to evaluate deph of the infection

and can also demonstrate the involvement of the bone (CT,

MRI, FDG-PET, bone scintigraphy with technetium-99m-

labeled diphosphonates or leucocyte scanning with radiola-beled blood cells).

Fig. (2). Diabetic Foot Triage Lesions code refers to figure 1; colors were inserted to create a link with figure 1 “University of Texas Wound Classification System”.


Antimicrobial Treatment

The appropriate antimicrobial treatment must be chosen

on the basis of the type of infection (deepness of the infec-

tion, presence of ischemia, systemic symptoms, metabolic

alterations). Usually the commonest isolates in patients who

have not been treated in the past and whose ulcer’s TUC

grade is 2-3 are single Gram-positive pathogens. Patients

with severe ulcers (TUC grade 4), or previously exposed to

antimicrobial therapy, frequently have more than one patho-

gen responsible of the infection (either Gram positive or

negative pathogens), potentially drug-resistant. Anaerobic

bacteria must be suspected in every case of ischemic lesions

[35]. In mild to moderate DFI (grade 2-3), the therapy spec-

trum must be targeted against Gram-positive bacteria strains

(Staphylococci and Streptococci). We recommend in difficult

to treat cases, a collaboration with infectious diseases spe-

cialists can that can help in increasing microbiology labora-

tory facilitations usage and sufficient and improving the di-

agnosis and treatment of DFI.If the patient has not been pre-

viously exposed to any antibiotic therapy, the best treatment

option is represented by amoxicillin/clavulanic acid (1-2 g

q8 hours). The therapy can be taken orally, given the high

bioavailability of this drug. Alternative regimens can be rep-

resented by fluoroquinolones (moxifloxacin 400 mg q24

hours or levofloxacin 500 mg q12 hours or 750 mg q24

hours), cotrimoxazole (900 mg q8 hours) or ceftriaxone (2 g

q24 hours). If MRSA infection is suspected, the choice is

among linezolid (600 mg q12 hours), daptomycin (6-8

mg/kg/ q24 hours), or vancomycin (2g q24 hours). In severe

DFI (grade 4), the therapy must cover a broader spectrum of

pathogens (both gram positive and gram negative strains)

and be administrated intravenously. The appropriate treat-

ment can be one of the following:

• Piperacillin/tazobactam (4,5 g q6hours) + daptomycin (6-8 mg/kg q24 hours) / linezolid (600 mg q12 hours) /vancomycin (2 g q24 hours).

• Ciprofloxacin (400-mg q8 hours) / levofloxacin (500 mg q 12 hours or 750 mg q24 hours) + daptomycin (6-8 mg/kg q24 hours) / linezolid (600 mg q12 hours) / van-comycin (2 g q24 hours).

• Ertapenem (1 g q24 hours) + daptomycin (6-8 mg/kg q24 hours) / linezolid (600 mg q12 hours) / vancomycin (2 g q24 hours).

• Meropenem (1 g q6 hours) + daptomyicin (6-8 mg/kg q24 hours) / linezolid (600 mg q12 hours) / vancomycin (2g q24 hours).

• Tigecycline (100 mg q24 hours)

An MRSA infection must always be considered on the basis of the local epidemiology and the previous antibiotics exposure. Although vancomycin and teicopanin are consid-ered the first choices in case of MRSA infection, failure with these options occurs due to the growing number of strains with higher MIC to glycopeptides [42-44]. The main disad-vantages of old glycopeptides are the renal toxicity and the need of monitoring blood levels to obtain the most favorable ratio between toxicity and effectiveness: blood levels must be kept between 15-20 μg/ml.

New molecules active on MRSA and useful in DFI are

linezolid and daptomycin (both active only on Gram positive

strains) and tigecycline (active even against gram negative

bacteria). Linezolid is an oxazolidone, has a bacteriostatic

effect against all Gram-positive bacteria and a very good

penetration in skin and bone tissue. The drug is available

both as intravenous and oral formulations, allowing the

planning of sequential therapies, even for prolonged time.

Daptomycin is a cyclic lipopeptide, characterized by a rapid

bactericidal and concentration-dependent activity against all

Gram positive bacteria. Daptomycin is approved at a dose of

4 mg/kg for the treatment of complicated skin and soft-tissue

infection and at a dose of 6 mg/kg for S. aureus bloodstream

infection, including treatment of right-sided endocarditis.

Although prospective randomized clinical studies have

claimed that these dosage regimens are safe and effective for

their respective indications, the optimal dose level has not

been firmly established yet. In recent years, reports of clini-

cal failures and emergence of resistant strains following dap-

tomycin treatment have raised great concern. As a result,

higher doses of daptomycin are being proposed as an alterna-

tive for some difficult-to-treat infections such as complicated

bacteremia and osteomyelitis [45-48]. On the basis of pub-

lished data and personal experience, daptomycin at higher

doses (> 8 mg/kg/day) seems safe and might be more effec-

tive than standard dosage in S. aureus infections.

Tigecycline is actually approved in complicated skin and

soft tissue and intra-abdominal infections, but not in the

therapy of DFI. It has a broad antimicrobial spectrum [49]

and its usage must be limited in cases of multi-resistant

strains [50]. In fact, its use in case of P.aeruginosa infections

is not adequate. In infections sustained by Gram-negative

multi-drug resistant bacteria, it may be mandatory the use of

colistin, a re-emerging antibiotic which use had been aban-

doned in the last years because of its high nephrotoxicity (Li

J, Nation RL, Turnidge JD, Milne RW, Coulthard K, Rayner

CR, Paterson DL.

Colistin: the re-emerging antibiotic for multidrug-

resistant Gram-negative bacterial infections. Lancet Infect

Dis. 2006;6(9):589-601). It has been rediscovered recently,

since it maintains an high activity versus P. aeruginosa, car-

bapenemase- producers K. pneumoniae and A. baumannii.

It is difficult to establish the best treatment duration of

colistin, however at least of 1-2 weeks appear appropriate for

mild to moderate infections and 2-4 weeks for severe infec-

tions. In some cases longer treatment times are needed, de-

pending on the site of infection and local vascularization.

In conclusion, in view of the growing prevalence of

multi-resistant bacteria, the correct and appropriate use of

antimicrobials and the knowledge of the local resistance pat-

tern must always be taken into consideration. There is also a

need for continuous microbiological surveillance of resistant

bacteria to provide the basis for empirical therapy and reduce

the risk of complications.The best way to stem the phenome-

non of multidrug resistance is the use of molecules with low

selective pressure and high efficacy and the planning of rea-

sonable combination therapies.


REVASCULARIZATION APPROACH TO THE

ISCHEMIC DIABETIC FOOT

Pattern of Disease and Clinical Manifestation of CLI in

Diabetics

The obstructive atherosclerotic pattern of CLI in diabetic patients is characterized by a multilevel disease, specific

involvement of BTK arteries, calcifications and prevalence of CTOs over stenosis [18,51,52]. The majority of diabetic patients with CLI have a femoro-popliteal obstruction asso-ciated with BTK vessels disease and less than 20% of the patients present pure BTK vessels disease [51,53]. Iliac and common femoral arteries obstruction is generally related to other associated cardiovascular risk factors such as smoking and hypercholesterolemia [54]. The first manifestation of CLI can be caused by the natural progression of the vascular obstructive disease, leading to an unbearable ischemic condi-tion of the distal tissues evolving in necrosis. In most cases, the initial lesion follows a mechanical trauma: neuropathy and bones deformity cause recurring trauma, burns and ul-cerations [13]. When the tissue loss is established in an ischemic foot, the treatment becomes a challenge because healing is a blood flow dependent process.

Targets of the Revascularization Therapy

Peregrin et al. analyzed the clinical success of PTA in

diabetic patients with CLI considering the number of BTK

vessels successfully treated [55]. The emerging concept is

that “complete” revascularization is better than “partial” re-

vascularization: limb salvage rate at one year was 56% with-

out direct blood flow to the foot (0 BTK vessels open), and,

respectively, 73%, 80% and 83% with 1, 2 or 3 BTK vessels

open (Fig. 3). Faglia et al. also found that PTA of tibial ar-

teries had a better outcome than PTA of the peroneal artery

alone [56]. Another emerging concept is the “wound related

artery” revascularization: following the angiosome concept

[57], the revascularization of the artery directly feeding the

wound region leads to higher rate of limb salvage and wound

healing [58,59]. Figure 4 summarizes the concept of com-

plete and WRA revascularization. Also in the case of distal

bypass surgery, Neville demonstrated that revascularization

of the artery directly feeding the ischemic angiosome leads

to a higher rate of healing and limb salvage [60]. Complete

and WRA revascularization must not be uncritically pursued:

the procedure must be tailored on technically realistic strate-

gies and on the general patient status.

Fig. (4). Targets in BTK vessel revascularization.

Fig. (3). Diffuse disease of BTK vessels A: basal angiogram: ante-rior and posterior tibial arteries occlusion; faint visualization of the foot circle B: after a successful angioplasty: direct blood flow to the pedal and plantar arteries.


Type of Revascularization

There are currently no randomized control trials directly comparing open versus endovascular revascularisation in diabetic patients with CLI, therefore, there are insufficient data to demonstrate whether open bypass surgery or endo-vascular interventions are more effective in these patients [61]. Pedal bypass grafting is generally considered the gold standard therapy for CLI in diabetics, providing good out-comes in terms of limb salvage and patency rate [62,63]. Nevertheless an increasing number of studies propose an “angioplasty first strategy”, advocating the minor invasive-ness of percutaneous procedures and the possibility to revas-cularize patients that cannot be treated surgically due to poor general status, extensive foot tissue damage, unavailability of an adequate vein conduit or of a target vessel for distal anastomosis [64-73]. To achieve a long-term benefit, how-ever, multiple revascularization procedures may be required in diabetic patients, and a dedicated interdisciplinary surveil-lance program is mandatory; while the choice of the initial revascularization modality (surgical or endoluminal) seems not to influence the clinical success [74]. Figure 5 summa-rizes the decisional flow chart in choosing the best revascu-larization strategy in diabetic patients with CLI. While wait-

ing for future studies to better clarify the selection criteria for surgical or percutaneous revascularization according to the clinical and anatomical variables, the personal expertise plays a key role in the decision making [61].

Surgical Revascularization

If the decision to revascularize is in favor of the open

surgical procedure, there are some key points to be consid-

ered: the graft inflow and outflow, the availability of autolo-

gous material for grafting [75], the absence of contamination

at the surgical incision sites and the forecast of possible ad-

verse events for a long procedure in a fragile patient [76].

Choice of the Anastomosis Site

The optimal bypass graft starts from an healthy artery and ends in an artery which must be less diseased as possi-ble. To approach such condition when atherosclerosis in-volves proximal arteries it is sometimes necessary to perform an endoarterectomy of the donor artery (common femoral, less frequently profunda or superficial femoral artery), on the contrary it is better to avoid the endoarterectomy of the distal site due to the general poor result. One must find the seg-ment of artery relatively spared from calcium, with an ade-

Fig. (5). Revascularization flow-chart in diabetics CLI.


quate lumen and a direct flow line to the ankle (peroneal artery) or to the foot (anterior and posterior tibial arteries). Due to the disease pattern in diabetic patients, the distal anastomosis is rarely performed in the proximal popliteal artery (above the knee graft). In the majority of the cases, the anastomosis site is chosen on the distal popliteal, tibial or pedal arteries. BTK bypass grafts have significantly inferior patency rates than above the knee grafts [77], whereas distal and ultradistal BTK bypass have comparable outcomes [78].

Choice of Bypass Graft Material

It is generally accepted that an autologous vein should be

used wherever possible; there are observations that autolo-

gous vein bypass grafts in patients with diabetes have better

30-day limb salvage rates than in patients without diabetes

[79]. The vein must be free of disease (varicosis, fibrosis)

with a diameter > 3 mm; if the caliber is not uniform (dis-

tally smaller) it is better to graft it “in situ”; anyway there is

no significant difference between in situ and reversed saphe-

nous vein bypass at any time interval [80]. In case of un-

availability of an autologous vein, a prosthetic Dacron or

PTFE bypass can be performed in, possibly with a distal cuff

[81].

A trend towards an improved primary patency using

PTFE versus Dacron bypass was observed. Ac significant

benefit for a PTFE bypass with a vein cuff when compared

with PTFE alone [was underlined [82].

Surveillance of the Graft

Vigilant ongoing surveillance of infrainguinal grafts may be resource-demanding but it is essential to obtain a high graft patency in order to obtain an good limb salvage rate. Revision of graft stenoses identified by duplex scanning is required in up to 40% of diabetic patients [83]. For venous grafts acetylsalicylic acid treatment is preferred; clopidogrel

in association with acetylsalicylic acid confers benefit in patients receiving prosthetic grafts [84].

Percutaneous Revascularization

The Approach

In the majority of diabetic patients with CLI, the obstruc-tive disease involves below-the-groin vessels, sparing the iliac and the common femoral artery and enables the ante-grade femoral approach. In diabetic CLI this is the favored approach because it provides adequate device control, maximizes angiographic resolution, and enables access to foot vessels to achieve complete and WRA revascularization [53,56,66]. However, the antegrade access is more techni-cally demanding, it is fraught by an increased risk of access site failure or complications and it requires an adequate learning curve [85-87].

CTOs Crossing Strategy

The first step in percutaneous recanalization is to cross the long CTOs typical of diabetics CLI. Different techniques are now available: endoluminal approach, subintimal, trans-collateral, pedal-plantar loop technique and retrograde punc-ture of the vessel beyond the CTO [88-98]. Figure 6 summa-rizes the role of these different techniques in a step-by-step approach.

Acute Result Optimization

Long, thin-profiled, high pressure balloons are the key point in BTK vessel PTA [64-70,99]. Traditionally a 1- 2 minutes inflation is recommended, longer time in case of dissection, but there are not studies comparing results using different inflation times in BTK vessel PTA. Bailout stenting in case of flow limiting dissection or poor result is recom-mended [18]. Atherectomy, cryoplasty, laser, scoring bal-loons, cutting balloons, are all promising devices which

Fig. (6). Step-by-step approach in CTOs crossing strategies.


value have to be clarify, especially regarding the cost-to-benefit ratio [100,101].

Prevention of Restenosis

Restenosis remains the Achille’s heel of percutaneous re-vascularization. Restenosis is higher for small arteries and long lesion [18], reaching a 69% rate in BTK vessel three month after PTA [102]. Figure 7 shows the length of treated lesions in studies regarding the patency after BTK an-gioplasty performed with balloon expandable stents, nitinol self expandible stents and plain old uncoated and drug-coated angioplasty balloons [103]. The good results in terms of prevention of restenosis by stenting, particularly DES, are confined to short BTK lesions (<5cm) that are a minority of the lesions seen in diabetic CLI patients. In long, diffuse lesions (majority of CLI patients) the optimal endovascular treatment remains the balloon angioplasty with dedicated BTK balloons and bailout stenting. In these type of lesions DEBs are promising devices in the prevention of restenosis [104]. Apart from these data, it is well known that patency after BTK PTA and limb salvage are not strongly correlated [105,106] therefore further studies are needed to clarify the importance of BTK vessels patency in terms of wound heal-ing time, reulceration rate, time-to-walking, target vessel revascularization and cost-to-benefit ratio.

THE SURGICAL TREATMENT OF AN INFECTED DIABETIC FOOT INJURY

Surgical Classification of Diabetic Foot Infection

The diabetic foot infections can be classified, from a sur-gical point of view, as superficial, intermediate and deep. A specific diagnostic and therapeutic approach with a different risk of amputation corresponds to each of these clinical con-ditions.

Superficial infections are those that affect epidermis and dermis and that have no tendency to spread by contiguity or by the lymphatic and venous network. The amputation risk is extremely low. Such infections are mostly supported by Gram-positive pyogenic cocci, with a prevalence of Staphy-lococcus aureus. Intermediate infections are those that affect the dermis up to the external muscular fascia with tendency to spread locally by contiguity and by active transport through the lymphatic network of the district, without in-volvement of deep structures but being associated with a risk of minor amputations. Intermediate infections are supported mostly by pyogenic cocci but they can also be associated with Gram-negative bacteria such as Pseudomonas aerugi-nosa. The most frequent clinical forms of intermediate infec-tions are the deep infected ulcer and the phlegmon. These two forms are in fact the clinical evolution of one into the other, due to first the spread of infection in the subcutaneous tissue and then through the lymphatic vessels.

Deep infections (Fig. 8) are those that extend beyond the muscle fascia surface, involving muscles, tendons, joints and bones. They tend to spread proximally along the deep anat-omic structures resulting in extended involvement of the leg compartments while haematogenous spread of infection is extremely rare. Deep infection may be accompanied by fe-ver, malaise, and leucocytosis. Deep infections are the main cause of major amputations in diabetic patients; due to the aggressiveness they have to be considered an absolute surgi-cal emergency condition. A deep, infected ulcer is frequently associated with deep localized abscesses, subfascial abscess, septic arthritis, osteomyelitis and necrotizing fasciitis of the foot or leg. In the case of deep infections, the pathogenesis is very often polymicrobial, with the simultaneous presence of Gram-positive cocci, Gram-negative bacteria,anaerobes and frequent association with fungi. The combination of different microbial species has a potentiating effect on the aggressive-

Fig. (7). Length of BTK treated lesion.


ness of each strain, creating a true pathogenetic synergy. The evolution of the clinical condition is abruptly progressive, spontaneously turning into wet gangrene, with putrefactive phenomena if proteolysic strains predominate.

Necrotizing fasciitis is the most severe infective clinical condition in the diabetic population, very often it is highly correlated to previous incorrect surgical procedures. In these patients the risk of major amputation is up to 50%

Surgical Approach to the Treatment of Infected Diabetic

Foot Lesions

As previously pointed out, the extent and depth of infec-tion correlates with an increased risk of amputation. A rapid control of the early infective process is the cornerstone of treatment of infected diabetic foot lesions. In 2003 Arm-strong and Frykberg [107] have classified the diabetic foot surgery into 4 groups showing increasing risks of surgical failure and amputation when surgical procedures are per-formed in emergency clinical conditions. The objective of emergency surgery in an infected diabetic foot is to gain a rapid control of local and systemic effects of infection. It should be stressed that the time factor must be considered of paramount importance in the surgical treatment approach of the infected diabetic foot. Faglia et al. [36] have recently

shown that the early treatment of both the infection by emer-gency surgery and the CLI by endoluminal or surgical revascularization procedures, , are able to obtain a tremendous increase in limb salvage or a distalization of the amputation level of the foot.

Surgical Treatment of Infected Superficial Ulcers of the

Foot

The goal of surgical treatment of infected superficial ul-cers is the debridement of the lesions and their management until healing. Debridement of the ulcer consists in the re-moval of all necrotic or non vital tissue with exposure of an healthy and bleeding wound bed. The ulcer debridement methods basically surgically remove by physical means (scalpels, scissors, curette) dead, infected or necrotic tissue and openi all sinuses that may be present. The advantages of this approach are its speed, direct control by the operator, versatility on different anatomical sites and cost-effectiveness. The need to perform local anaesthesia often and the risk of surgical complications like bleeding and in-jury to deep structures are the main disadvantages. In any case, the surgical debridement should always be performed by skilled operators in a suitable environment. Surgical de-bridement can be performed by an ultrasound debrider. This technique allows to modulate the aggressiveness of the sur-gical intervention therefore sparing as much as possible the viable tissue Another surgical debridement tool is repre-sented by the Hydrosurgery system, which employs the "Venturi" effect. Thanks to a jet of saline solution at very high speed it is possible to obtain the removal of the necrotic or infected tissue with very high selectivity (Fig. 9). By vir-tue of its highly aggressiveness, the hydrosurgery system can be used only by specially trained medical and nursing staff (109).

Once the infected and/or necrotic tissue has been re-moved, NPWT is generally used to guarantee the cleansing of the wound bed and the quick removal of all exudates which could be still be contaminated by residual deep bacte-rial colonies. The primary treatment goal in the application of NPWT to DFU is to progress towards a wound closure either by secondary intention or by surgical closure (109). Once the control of infection by surgical means has been obtained (110), the NPWT therapy is a useful aid in the preparation of the wound bed, either in case of a chronic or surgical lesion The application of NWPT may be considered as a bridge to obtain a healthy wound bed suitable for a sur-gical closure by suture, flaps or skin graft) or by secondary healing in combination with a dermal substitute or an ad-vanced dressings.

Surgical Treatment of Deep Infection of the Foot

Phlegmon

The complications of a superficial ulcer incorrectly treated can be the collection of purulent material in the der-mis and in deeper tissues. The clinical signs that point to the presence of a phlegmon of the deep tissues are the classic signs of local infection (rubor, tumor, calor, dolor and func-tio laesa) accompanied by an area of fluctuation interesting the skin and the subcutaneous tissues. In the most favourable case, the infection progresses to a spontaneous drainage of the purulent material through a skin ulcer with partial remis-

Fig. (8). Deep infection of forefoot-midfoot.

Fig. (9). Ulcer debridement by Hydrosurgery.


sion of local and systemic signs of inflammation. In case of spread of the infection into other deep foot compartments, a clinical evolution into an infective compartmental syndrome can be observed, which places patients at risk of sepsis and major limb amputation. The surgical treatment includes inci-sion of the skin and deep tissues with drainage of purulent material and removal of all infected tissues (Fig. 10). When the infective process involves skeletal structures, it is manda-tory to remove the infected bone exposing the vital subcuta-neous tissues and the bone which are macroscopically healthy. Frequently, an open forefoot or midfoot amputation has to be performed in order to allow the daily cleaning and dressing of the wound (Fig. 11). It is recommended not to expose the cancellous bone until the infection is under con-trol, to prevent the resorption of the infected material with a consequent risk of bacteraemia and sepsis.

Infective Compartmental Syndrome

A deep foot infections in a diabetic patient is a disaster both in terms of local and systemic effects. Infact, the foot structure consists of four main compartments: medial, central (superficial and deep), lateral and interosseous, which are

separated by fascial structures. This division into compart-ments is strictly independent and is responsible for the onset of the infective compartmental syndromes. The increase of pressure inside the compartments, caused by tissue oedema due to the infective process, causes the compression of the small arteries resulting in tissue ischemia and worsening of tissue blood perfusion. From a clinical point of view, pa-tients may present with systemic signs of infection (fever, leucocytosis, elevated erythrocyte sedimentation rate) ac-companied by signs of inflammation and pain of varying intensity.

The surgical approach to deep wound infection of the

foot requires a careful inspection of foot compartments. It

should be underlined that, although the different compart-

ments of the foot are anatomically separated, the infective

process can disseminate with the involvement of the adjacent

compartment, particularly if the infection is not quickly

treated. Frequently a phlegmon of the central compartment of the foot, originating from a dorsal ulcer, deepens through

the intermetatarsal area, reaching the plantar compartments.

A floating and painful plantar area in the midfoot often rep-

resents the only clinical sign of a plantar involvement (Fig.

12). From the surgical point of view, the infective compart-

mental syndromes of the foot is treated by performing a de-

compression fasciotomy. It very important to follow such

decompression fasciotomy with an accurate inspection of the deep tissues. It is mandatory to check carefully the integrity

of the adjacent anatomical compartments to exclude their

involvement in the infectious process. After opening the in-

fected compartment and performing a meticulous debride-

ment, cleansing of wound bed should be done with hydrogen

peroxide and povidone iodine solution. After wound bed

rinsing, a biopsy of the deep tissue should be performed to

obtain a suitable specimen for the microbiological examina-tion and culture. The residual tissue cavity obtained after

surgical debridement should be dressed with iodoform

gauze. The edges of the surgical incision must be approached

with stitches to avoid retraction of the skin, which may com-

plicate the surgical wound closure at a later time. The dress-

ing should be replaced once or twice a day to achieve a com-

plete control of the infective process.

Fig. (10). Post surgical drainage of forefoot-midfoot infection.

Fig. (11). Open midfoot amputation.

Fig. (12). Phlegmon of plantar side of the foot.


Necrotizing Fasciitis

Necrotizing fasciitis is a frequent complication of the surgical treatment of a severe diabetic foot infection. It is characterized by a particular aggressiveness and devastating evolution of the infective process (111). In the initial stage, the infection tends not to involve the underlying muscular structures. Given the rapid evolution of the infective process, the surgical treatment has to be applied as soon possible.

A careful examination of all infected tissues must be per-formed, followed by an extensive fasciotomy and open mi-nor amputation to allow the drainage of all infected materi-als. The result of the surgical debridement must be moni-tored daily as it may be necessary to carry out further de-bridements to achieve the full infection control.

Gangrene

Wet gangrene is often the final evolution of a superficial

ulcer in presence of CLI not underwent to a correct diagnos-

tic and treatment approach (Fig. 13). Although an antibiotic

treatment can sometimes gain control of the infection turning

a wet gangrene into a non infected dry one, the evolution

toward the auto amputation of a necrotic segment is abso-

lutely not indicated due to the high risk of subsequent infec-

tion, unless the patient is confined to bed for a chronic ill-ness.

A proper surgical treatment involves removing the ne-crotic tissueincluding the infected bone segment. The demo-lition of part of the foot can result in an open amputation of the forefoot, midfoot, or rear foot at different levels depend-ing on the spread of the infective process. As previously no-ticed, the extent of the surgical debridment does not depend on the vascular condition but only on the severity of the in-fection. The objective remains the complete removal of the infected tissue. Obviously, in case of critical ischemia of the

foot, following the surgical debridement the patient will be immediately subjected to the most appropriate revasculariza-tion procedure (surgical or endoluminal).

RECONSTRUCTIVE SURGERY OF THE INFECTED DIABETIC FOOT

While the goal of emergency surgery is the control of the local and systemic infection, the role of elective surgery is primarily the reconstruction of the foot and the correction of foot deformity and joint instability (107). It is extremely im-portant to underline that the objective of the diabetic foot surgery, both in emergency and elective conditions, is to allow the patient to return to walk with an improved quality of life. On deciding which surgical approach has to be ap-plied on a patient, some questions have to be answered be-forehand.

First of all, it should be considered whether the patient has maintained its residual walking attitude. Patients often come to clinical observation after a long period of chronic infection of the foot that has greatly undermined the possibil-ity of a functional recovery. The peripheral vascular disease in diabetes populations is frequently associated with heart disease which greatly reduces the workload of the heart, while the cerebrovascular disease puts the major limitations to the recovery due to the residual functional deficits of the lower limbs. These patients, after a long period of bed rest, frequently have an irreducible flexion of the knee on the thigh, which undermines any attempt of limb salvage. In this clinical situation the choice of major amputations (mostly above the knee) can be the best option as it allows a rapid healing thus avoiding further risks of infection. The choice of the definitive surgical treatment is completely different if the patient has a good chance to return to walk. No doubt that the main goal of reconstructive surgery of the foot is obtaining a foot or a stump useful for a proper gait and for easy fitting. From the biomechanical point of view, the re-sidual foot or the stump should have some basic features: 1) a lever long enough in order to maintain stability during the boost phase of the gait cycle, 2) proper alignment of the foot with the leg, 3) proper motion of pronation and supination of the forefoot and dorsiflexion of the ankle joint, 4) a suitable subcutaneous tissue in the plantar region of the foot that can withstand pressure trauma on the plantar surface of the foot during walking. These biomechanical and functional charac-teristics are often present after minor surgery of the forefoot (toe or ray ampautation) and of the midfoot (Transmetatarsal amputation). Having to decide the definitive surgical treat-ment in a patient with good residual ability to walk, the re-constructive surgery of the forefoot and the midfoot is indi-cated. Several precautions must always be taken into ac-count. From a biomechanical and functional point of view, amputation of the hallux and of the 5th toe does not pose any serious problems unless after surgical treatment the patient wears a protective shoe with an unloading insole. These shoes are characterized by a rigid rocker bottom sole and a moulded insole with the aim to control the redistribution of pressure level on the plantar surface (Fig. 14).

The amputation of the intermediate toes (2nd

, 3rd

, 4th

) poses serious problems both in terms of functional and biomechanical aspects. Amputation of the 2

nd, 3

rd or 4

th toe

Fig. (13). Forefoot wet gangrene.


will cause unequivocally a varus or valgus deviation of the other toes with severe metatarsal head loading and subse-quent serious risk of insensitive plantar ulcer. When possi-ble, it is better to perform a partial amputation of the toe. In the case of an ulcer with osteomyelitis of the phalanges, in-stead of performing a toe amputation it is advisable to try to remove the infected bone thus saving part of the toe. Ampu-tation of a single ray (in the proximal third metatarsal) is also a correct surgical choice that allows to have a foot with re-maining 4 fairly symmetrical and stable rays (Fig. 15). From a biomechanical point of view amputation of the 5

th ray

doesn’t create any problem while 1th

ray may be responsible for walking impairment. Even in this case it is essential to wear proper protective shoes.

In recent years the availability of different kinds of der-mal substitutes has greatly changed the reconstructive surgi-cal approach of severe diabetic foot infection. The massive loss of soft tissue after demolitive surgery for the control of infection can now be restored using a Hyaluronic acid de-rived dermal substitute that is able to stimulate the process of

soft tissue reconstruction ((Fig. 16). The final closure of the surgical wound may ultimately be obtained by secondary intention or by a skin graft (Fig. 17). However, the need for a stable foot, well aligned with the leg and functionally valid must be pointed out.

Transmetatarsal amputations are certainly the surgical

procedures most frequently performed in cases of severe

infection of the forefoot. To reduce dramatically the risk of a

relapsing ulcer, a metatarsal amputation must be performed

at the base of the metatarsals (very proximally) to obtain a

stable and symmetrical forefoot stump. A more distal resec-

tion of the metatarsals may cause an increase of pressure on

the plantar surface of the stump because of its tendency to

the equinus deformity with a high risk of ulcer recurrences

(Fig. 18).

Lisfranc amputation is performed disarticulating the fore-foot at the base of the metatarsals (Lisfranc joint) saving only the cuneiform. Although, from a surgical point of view, Lisfranc Amputation can be considered an “elegant” amputa-

Fig. (14). Custom-made protective shoe with rocker-bottom sole and moulded unloading sole.

Fig. (15). Ray Amputation.

Fig. (16). New Tissue developed after Hyalurionic acid derived

dermal substitute application.

Fig. (17). Skingraft on new tissue developed after Hyalurionic acid derived dermal substitute application.


tion, from a biomechanical point of view it poses serious problems of stability and alignment of the forefoot. The re-moval of the base of the 5th metatarsal, and the consequently loss of the peroneus brevis insertion, leads to a supination deformity of the forefoot causing serious problems of gait. To avoid the deviation of the forefoot, the base of 5

Th meta-

tarsal must be spared and fixed to the cuboid bone with a screw when performing Lisfranc Amputation.

Chopart Amputation, which saves only the talus and cal-caneus, is the most proximal midfoot amputation (Fig. 19). This surgical option is sometimes the only alternative to leg amputation in case of severe infection of the forefoot and midfoot.

The question that arises when suggesting this surgical choice to the patient is whether, from biomechanical and functional points of view, the Chopart amputation can be considered a good solution. From a functional point of view, the Chopart Amputation shows some disadvantages : 1) a very short residual lever; 2) the boost phase of the walking cycle is completely lost; 3) the deviation of the stump in

equinovarus is frequent. Prostheses also pose serious prob-lems because the neck of the foot is completely lost and con-sequently the stump tends to turn into the shoe with a high risk of ulceration. Chopart amputation can be considered a good surgical choice in elderly patients because in these pa-tients the ability to use a prosthesis in case of major amputa-tion is very low. Great part of elderly patients submitted to leg amputation frequently lose the ability to walk with total loss of autonomy in daily living activities. In elderly diabetic patients with important comorbidities such as heart disease, kidney disease and visus impairment, the Chopart amputa-tion should be considered a rescue choice that allows an ac-ceptable walking ability with discrete autonomy in daily ac-tivities. In particular patients with severe dysfunction of heart may not tolerate the increase in load on cardiovascular system correlated with the use of a prosthesis for major am-putation (BKA-AKA) The risk of ulceration of the stump can be dramatically reduced by replacing the protective shoe with a custom-built brace that is inserted into a dedicated shoe thus avoiding any twisting and bending of the stump (Fig. 20). Since, from a functional point of view, the Chopart amputation does not allow a valid gait, it may be appropriate to suggest a below-the-knee amputation to a young patient because modern prostheses provide a high level of physical activities. In any case, the choice of the amputation level must be always agreed with the patient.

LIST OF ABBREVIATIONS

AMS = absorbable metal stent

BMS = bare metal stent

BTK = below-the-knee

CABG = coronary artery bypass graft

CLI = critical limb ischemia

CT = computed tomography

CTO = chronic total occlusion

DEB = drug eluting balloon

DES = drug eluting stent

DFC = diabetic foot center

Fig. (18). Transmetatarsal amputation.

Fig. (19). Chopart ampuuation.

Fig. (20). Custom-built brace for prosthesis of Chopart Amputation.


DFI = diabetic foot infection

DFU = diabetic foot ulcer

ESR = eritrosedimentation rate

PET = positron emission tomography

LMWH = low molecular weight heparin

MIC = minimum inhibitory concentration

MRI = magnetic resonance imaging

MRSA = methicillin-resistant Staphylococcus aureus

NPWT = negative pressure wound therapy

PAD = peripheral arterial disease

POBA = plain old balloon angioplasty

PTA = percutaneous transluminal angioplasty

PTFE = polytetrafluoroethylene

TcPO2 = transcutaneous oxygen pressure

TUC = Texas University wound classification system

UB = uncoated balloon

WRA = wound related artery

CONFLICT OF INTEREST

Dr. Roberto Ferraresi has a consultant agreement with Medtronic Invatec, Abbott, EV3.

ACKNOWLEDGEMENTS

None

REFERENCES

[1] World Health Org. Fact sheet N°312, August 2011

www.who.int/mediacentre/factsheets/fs/312/en/ [2] Boulton AJM, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J.

The global burden of diabetic foot disease. Lancet 2005;336:1719–24

[3] Johannesson A, Larsson GU, Ramstrand N, Turkiewicz A, Wirehn AAtroshi Incidence of lower-limb amputation in the Diabetic e

Non diabetic general population. A 10-year population-based co-hort study of initial unilateral and contralateral amputation and

reamputation Diabetes Care February 2009; Vol. 32 no.2:275-280 [4] International Working Group on the Diabetic Foot. International

consensus on the diabetic foot. 2011. In: International Diabetes Foundation; Brussels. http://www.iwgdf.org

[5] Jeffcoate WJ, van Houtum WH. Amputation as a marker of the quality of foot care in diabetes. Diabetologia 2004; 47: 2051-8.

[6] Boulton AJM, Armstrong DG, Albert FA, Frykberg RG, Hellman R, Kirkman MS, Lavery LA, LeMaster JW, Mills JL, Mueller MJ

Sheenhan P, Wukich DK.Comprehensive foot examination and risk assessment. Diabetes Care 2008;31:1679–85

[7] Prompers, L, Shaper N, Apelquist J, Edmonds M, Jude E, Mauricio D, Uccioli L, Urbancic V, Bakker K, Holstein P, Jirkoska A, Piag-

gesi A, Ragnarson-Tennvall G, Reike H, Sparul M, Van Acker K, Van Baal J, Van Merode F, Ferreira I, Hijberts M. Prediction of

outcome in individuals with diabetic foot ulcers: focus on the dif-ferences between individuals with and without peripheral arterial

disease. The EURODIALE Study. Diabetologia 2008;51:747 [8] Andreassen CS, Jakobsen J, and Andersen H. Muscle weakness: a

progressive late complication in diabetic distal symmetric polyneu-ropathy. Diabetes 2006;55:806-12

[9] Lavery LA, Armstrong DG, Wunderlich RP, Tredwell J, Boulton

AJM. Predictive value of foot pressure assessment as part of a population-based diabetes disease management program. Diabetes

Care 2003;26:1069-73 [10] Greenman RL, Panasyuk S, Wang X, Lyons TE, Dinh T, Longoria

L, Giurini JM, Freeman J, Khaodhiar L, Veves A. Early changes in the skin microcirculation and muscle metabolism of the diabetic

foot. Lancet 2005;366:1711-7 [11] Litzelman DK, Marriott DJ, Vinicor F. Independent physiological

predictors of foot lesions in patients with NIDDM. Diabetes Care 1997;20:1273–8

[12] Macfarlane RM, Jeffcoate WJ. Factors contributing to the presenta-tion of diabetic foot ulcers. Diabet Med 1997;14:867–70

[13] Reiber GE, Vileikyte L, Boyko EJ, Del Aguikla M, Smith DG, Lavery LA, Boulton AJM. Causal pathways for incident lower ex-

tremity ulcers in patients with diabetes from two settings. Diabetes Care 1999;22:157–62

[14] Armstrong DG, Todd WF, Harkless LB, Bushman TR. The natural history of acute Charcot's arthropathy in a diabetic foot specialty

clinic. Diabet Med 1997;14:357-63 [15] Schon LC, Easley ME, Weinfeld SB. Charcot neuroarthropathy of

the foot and ankle. Clin Orthop 1998;349:116-31 [16] Sanders LJ, Frykberg RG. Charcot neuroarthropathy of the foot. In:

Levin ME, O'Neal LW, U Rajbhandari SM, Jenkins RC, Davies C, Tesfaye S. Charcot neuroarthropathy in diabetes melli-

tus. Diabetologia 2002;45:1085-96 [17] Prompers L, Huijberts M, Apelqvist J, Jude E, Piaggesi A, Bakker

K, Edmonds M, Holstein P, Jirkovska A, Mauricio D, Ragnarson Tennvall G, Reike H, Spraul M, Uccioli L, Urbancic V, Van Acker

K, van Baal J, van Merode F, Schaper N. High prevalence of ischaemia, infection and serious comorbidity in patients with dia-

betic foot disease in Europe. Baseline results from the Eurodiale study. Diabetologia 2007;50:18-25

[18] Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG; on behalf of the TASC II Working Group. Inter-

Society Consensus for the Management of Peripheral Arterial Dis-ease (TASC II). J Vasc Surg 2007;45:S5-S67

[19] Faglia. E, Clerici G, Caminiti M, Quarantiello A, Curci V, So-malvico F. Evaluation of Feasibility of Ankle Pressure and Foot

Oxymetry Values for the Detection of Critical Limb Ischemia in Diabetic Patients. Vascular and Endovascular Surgery 2010;44

(3):184-9 [20] Faglia E, Clerici G, Caminiti M, Quarantiello A, Curci V, Morabito

A. Predictive values of transcutaneous oxygen tension for above-the-ankle amputation in diabetic patients with critical limb ische-

mia. Eur J Vasc Endovasc Surg 2007;33:731-6 [21] Shah B, Hux J. Quantifying the risk of infectious diseases for peo-

ple with diabetes. Diabetes Care 2003;26:510–3 [22] Sato N, Shimizu H, Susa K, Shimomura Y, Kobayashi I, Mori M.

MPO activity and generation of active O2 species in leukocytes from poorly controlled diabetic patients. Diabetes Care

1992;15:1050–2 [23] Marhoffer W, Stein M, Maeser E, Federlin K. Impairment of poly-

morphonuclear leukocyte function and metabolic control of diabe-tes. Diabetes Care 1992;15:256–60

[24] Muchová J, Liptáková A, Országhová Z, Garaiova I, Tison P, Car-sky J, Durackova Z.Antioxydant system in polymorphonuclear leu-

cocytes of type 2 diabetes mellitus. Diabet Med 1999;16:74–8 [25] Lipsky BA, Berendt AR, Deery HG, Embil JM, Karchmer AW,

LeFrock JL,Lew DP, Mader JT, Norden C, Tan JS. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2004;39:885–

910 [26] Shone A, Burnside J, Chipchase S, Game F, Jeffcoate W. Probing

the validity of the probe-to-bone test in the diagnosis of osteomye-litis of the foot in diabetes. Diabetes Care 2006;29:945

[27] Delcourt A, Huglo D, Prangere T, Benticha H, Devemy F, Tsirt-sikoulou D, Fontain P, Steinling M. Comparison between Leu-

koscan (Sulesomab) and Gallium-67 for the diagnosis of osteomye-litis in the diabetic foot. Diabetes Metab 2005;31:125–33

[28] Maugendre D, Poirier JY. Nuclear medicine in the diagnosis of diabetic foot osteomyelitis. Diabetes Metab 2001;27:396–400

[29] Poirier JY, Garin E, Derrien C, Devillers A, Moisan A, Bourguet P, Maugendre D. Diagnosis of osteomyelitis in the diabetic foot with

a 99mTc-HMPAO leucocyte scintigraphy combined with a 99m-Tc-MDP bone scintigraphy. Diabetes Metab 2002;28:485–90


[30] Berendt AR, Peters EJ, Bakker K, Embil JM, Eneroth M, Hinch-

liffe RJ, Jeffcoate WJ, Lipsky BA, Senneville E, Teh J, Valk GD. Diabetic foot osteomyelitis: a progress report on diagnosis and a

systematic review of treatment. Diabetes Metab Res Rev 2008;24 Suppl 1:S145-61

[31] Lavery LA, Armstrong DG, Harkless LB. Classification of diabetic foot wounds. J Foot Ankle Surg 1996;35:528–31

[32] Armstrong DG, Lavery LA, Harkless LB. Validation of a diabetic wound classification system. The contribution of depth, infection,

and ischemia to risk of amputation. Diabetes Care 1998;21:855–9 [33] Van Baal JG. Surgical treatment of the infected diabetic foot. Clin

Infect Dis 2004;39 Suppl 2:S123-8 [34] Faglia E, Clerici G, Caminiti M, Quarantiello A, Gino M, Morabito

A. The role of early surgical debridement and revascularization in patients with diabetes and deep foot space abscess: retrospective

review of 106 patients with diabetes. J Foot Ankle Surg 2006;45:220-6

[35] Lavery LA, Armstrong DG, Wunderlich RP, Mohler MJ, Wendel CS, Lipsky BA. Risk factors for foot infections in individuals with

diabetes. Diabetes Care 2006;29:1288-93 [36] Prompers L, Huijberts M, Schaper N, Apelqvist J, Bakker K,

Edmonds D, Holstein P, Jude E, Jirkovska A, Mauricio D, Piaggesi A, Reike H, Spraul M, Van Acker K, Van Baal S, Van Merode F,

Uccioli L, Urbancic V, Ragnarson Tennvall G. Resource utilisation and costs associated with the treatment of diabetic foot ulcers. Pro-

spective data from the Eurodiale study. Diabetologia 2008;51:1826–34

[37] Lavery LA, Armstrong DG, Wunderlich RP, Boulton AJM, Tred-well JM. Diabetic foot syndrome: evaluating the prevalence and in-

cidence of foot pathology in Mexican Americans and non-Hispanic whites from a diabetes disease management cohort. Diabetes Care

2003;26:1435–8 [38] Jeffcoate WJ, Lipsky BA, Berendt AR, Cavanagh PR, Bus SA,

Peters EJ, van Houtum WH, Valk GD, Bakker K; International Working Group on the Diabetic Foot. Unresolved issues in the

management of ulcers of the foot in diabetes. Diabet Med 2008;25:1380–9

[39] Moet GJ, Jones RN, Biedenbach DJ, Stilwell MG, Fritsche TR. Contemporary causes of skin and soft tissue infections in North

America, Latin America, and Europe: report from the SENTRY Antimicrobial Surveillance Program (1998-2004). Diagn Microb

and Infect Dis 2007;57:7-13 [40] Gagliotti C, Balode A, Baquero F, Degener J, Grundmann H, Gür

D, Jarlier V, Kahlmeter G, Monen J, Monnet DL, Rossolini GM, Suetens C, Weist K, Heuer O; EARS-Net Participants (Disease

Specific Contact Points for AMR). Escherichia coli and Staphylo-coccus aureus: bad news and good news from the European Antim-

icrobial Resistance Surveillance Network (EARS-Net, formerly EARSS), 2002 to 2009. Euro Surveill 2011;17:16(11)pii: 19819

[41] Spellberg B, Guidos R, Gilbert D, Bradley J, Boucher HW, Scheld WM, Bartlett JG, Edwards J Jr; Infectious Diseases Society of

America. The epidemic of antibiotic-resistant infections: a call to action for the medical community from the Infectious Diseases So-

ciety of America. Clin Infect Dis 2008;46:155-64 [42] El Solh N, Davi M, Morvan A, Damon HA, Marty N; GISA group,

RAISIN subgroup. Characteristics of French methicillin-resistant Staphylococcus aureus isolates with decreased susceptibility or re-

sistance to glycopeptides. J Antimicrob Chemother 2003;52:691-4 [43] Sancak B, Ercis S, Menemenlioglu D, Colakoglu S, Hasçelik G.

Methicillin-resistant Staphylococcus aureus heterogeneously resis-tant to vancomycin in a Turkish university hospital. J Antimicrob

Chemother 2005;56:519-23 [44] Wang G, Hindler JF, Ward KW, Bruckner DA. Increased vanco-

mycin MICs for Staphylococcus aureus clinical isolates from a university hospital during a 5-year period. J Clin Microbiol.

2006;44:3883-6 [45] Katz DE, Lindfield KC, Steenbergen JN, Benziger DP, Blackerby

KJ, Knapp AG, Martone WJ. A pilot study of high-dose short dura-tion daptomycin for the treatment of patients with complicated skin

and skin structure infections caused by gram positive bacteria. Int J Clin Pract 2008;62:1455–64

[46] Moise PA, Hershberger E, Amodio-Groton MI, Lamp KC. Safety and clinical outcomes when utilizing high-dose (> or =8 mg/kg)

daptomycin therapy. Ann Pharmacother 2009;43:1211-9 [47] Figueroa DA, Mangini E, Amodio-Groton M, Vardianos B,

Melchert A, Fana C, Wehbeh W, Urban CM, Segal-Maurer S.

Safety of high-dose intravenous daptomycin treatment: three-year

cumulative experience in a clinical program. Clin Infect Dis 2009;49:177-8

[48] Bassetti M, Nicco E, Ginocchio F, Ansaldi F, de Florentiis D, Vis-coli C. High-dose daptomycin in documented Staphylococcus

aureus infections. Int J Antimicrob Agents 2010;36:459-61 [49] Peterson LR. A review of tigecycline-the first glycylcycline. Int J

Antimicrob Ajents 2008;32,S4:215-222. [50] FDA. FDA Drug Safety Communication: Increased Risk of Death

with Tygacil (Tigecycline) Compared to Other Antibiotics Used to Treat Similar Infections.

http://www.fda.gov/Drugs/DrugSafety/ucm224370.htm (1 Septem-ber 2010)

[51] Graziani L, Silvestro A, Bertone V, Manara E, Andreini R, Sigala A, Mingardi R, De Giglio R. Vascular involvement in diabetic sub-

jects with ischemic foot ulcer: a new morphologic categorization of disease severity. Eur J Vasc Endovasc Surg 2007;33:453-60

[52] Jude EB, Oyibo SO, Chalmers N, Boulton AJM. Peripheral Arterial Disease in Diabetic and Nondiabetic Patients. Diabetes Care

2001;24:1433–7 [53] Ferraresi R, Centola M, Ferlini M, Da Ros R, Caravaggi C, Assalo-

ni R, Sganzaroli A, Pomidossi G, Bonanomi C, Danzi GB. Long-term outcomes after angioplasty of isolated, below-the-knee arter-

ies in diabetic patients with critical limb ischaemia. Eur J Vasc En-dovasc Surg 2009;37:336-42

[54] Diehm N, Shang A, Silvestro A, Do DD, Dick F, Schmidli J, Mahler F, Baumgartner I; Association of cardiovascular risk factors

with pattern of lower limb atherosclerosis in 2659 patients under-going angioplasty. Eur J Vasc Endovasc Surg 2006;31:59-63

[55] Peregrin JH, Koznar B, Kovác J, Lastovicková J, Novotn J, Ved-lich D, Skibová J. PTA of infrapopliteal arteries: long-term clinical

follow-up and analysis of factors influencing clinical outcome. Cardiovasc Intervent Radiol 2010;33:720-5

[56] Faglia E, Clerici G, Clerissi J. Mantero M, Caminiti M, Quaran-tiello A, Curci V, Lupattelli T, Morabito A. When is a technically

successful peripheral angioplasty effective in preventing above-the-ankle amputation in diabetic patients with critical limb ischaemia?

Diabetic Med 2007;24;823–9 [57] Attinger CE, Evans KK, Bulan E, Blume P, Cooper P. Angiosomes

of the foot and ankle and clinical implications for limb salvage: re-construction, incisions, and revascularization. Plast Reconstr Surg

2006;117:261S-293S [58] Iida O, Nanto S, Uematsu M, Ikeoka K, Okamoto S, Dohi T, Fujita

M, Terashi H, Nagata S. Importance of the angiosome concept for endovascular therapy in patients with critical limb ischemia.

Catheter Cardiovasc Interv 2010;75:830-6 [59] Alexandrescu V, Vincent G, Azdad K, Hubermont G, Ledent G,

Ngongang C, Filimon AM. A reliable approach to diabetic neu-roischemic foot wounds: below-the-knee angiosome-oriented an-

gioplasty. J Endovasc Ther 2011;18:376-87 [60] Neville RF, Attinger CE, Bulan EJ, Ducic I, Thomassen M, Sidawy

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

[61] International consensus on the diabetic foot and practical guidelines on the managenet and prevention of the diabetic foot. A Systematic

Review of the Effectiveness of Revascularisation of the Ulcerated Foot in Patients with Diabetes and Peripheral Arterial Disease. In-

ternational working group on the diabetic foot. 6th International Symposium on the Diabetic Foot (ISDF). 11-14 May 2011,

Noordwijkerhout, The Netehrlands [62] Aulivola B, Pomposelli FB. Dorsalis pedis, tarsal and plantar artery

bypass. J Cardiovasc Surg 2004;45:203 [63] Pomposelli FB, Kansal N, Hamdan AD, Belfield A, Sheahan M,

Campbell DR. A decade of experience with dorsalis pedis artery bypass: analysis of outcome in more than 1000 cases. J Vasc Surg

2003;37:307 [64] Dorros G, Jaff MR, Dorros AM, Mathiak LM, He T. Tibioperoneal

(outflow lesion) angioplasty can be used as primary treatment in 235 patients with critical limb ischemia: five-year follow-up. Cir-

culation 2001;104:2057-62 [65] Nasr MK, McCarthy RJ, Hardman J, Chalmers A, Horrocks M.

The increasing role of percutaneous transluminal angioplasty in the primary management of critical limb ischaemia. Eur J Vasc Endo-

vasc Surg 2002;23:398-403 [66] Faglia E, Dalla Paola L, Clerici G, Clerissi J, Graziani L, Fusaro M.

Peripheral angioplasty as the first-choice revascularization proce-


dure in diabetic patients with critical limb ischemia: prospective

study of 993 consecutive patients hospitalized and followed be-tween 1999 and 2003. Eur J Vasc Endovas Surg 2005;29:620-7

[67] Bosiers M, Hart JP, Deloose K, Verbist J, Peeters P. Endovascular therapy as the primary approach for limb salvage in patients with

critical limb ischemia: experience with 443 infrapopliteal proce-dures. Vascular 2006;14:63-9

[68] Tefera G, Turnipseed W, Tanke T. Limb salvage angioplasty in poor surgical candidates. Vasc Endovascular Surg 2003;37:99-104

[69] Jämsén T, Manninen H, Tulla H, Matsi P. The final outcome of primary infrainguinal percutaneous transluminal angioplasty in 100

consecutive patients with chronic critical limb ischemia. J Vasc In-terv Radiol 2002;13:455-63

[70] Tan M, Pua U, Wong DE, Punamiya SJ, Chua GC, Teo N. Critical limb ischaemia in a diabetic population from an Asian Centre: an-

giographic pattern of disease and 3-year limb salvage rate with per-cutaneous angioplasty as first line of treatment. Biomed Imaging

Interv J 2010;6:33 [71] Uccioli L, Gandini R, Giurato L, Fabiano S, Pampana E, Spallone

V, Vainieri E, Simonetti G. Long-term outcomes of diabetic pa-tients with critical limb ischemia followed in a tertiary referral dia-

betic foot clinic. Diabetes Care 2010;33:977-82 [72] Markose G, Bolia A. Below the knee angioplasty among diabetic

patients. J Cardiovasc Surg (Torino) 2009;50:323-9 [73] Apelqvist J, Elgzyri T, Larsson J, Löndahl M, Nyberg P, Thörne J.

Factors related to outcome of neuroischemic/ischemic foot ulcer in diabetic patients. J Vasc Surg 2011;53:1582-8

[74] Dick F, Diehm N, Galimanis A, Husmann M, Schmidli J, Baumgartner I. Surgical or endovascular revascularization in pa-

tients with critical limb ischemia: influence of diabetes mellitus on clinical outcome. J Vasc Surg 2007;45:751-61

[75] Eidt D, Roll S, Kulp W, Müller-Nordhorn J, Vauth C, Greiner W, Willich SN, and von der Schulenburg JM. Bypass materials in vas-

cular surgery. GMS Health Technol Assess. 2006 Mar 28;2:Doc06 [76] Flu HC, Ploeg AJ, Marang-van de Mheen PJ, Veen EJ, Lange CP,

Breslau PJ, Roukema JA, Hamming JF, Lardenoye JW. Patient and procedure-related risk factors for adverse events after infrainguinal

bypass. J Vasc Surg 2010;51:622-7 [77] Pereira CE, Albers M, Romiti M, Brochado-Neto FC, Pereira CA.

Meta-analysis of femoro-popliteal bypass grafts for lower extrem-ity arterial insufficiency. J Vasc Surg 2006;44:510–7

[78] Slim H, Tiwari A, Ahmed A, Ritter JC, Zayed H, Rashid H. Distal versus ultradistal bypass grafts: amputation-free survival and

patency rates in patients with critical leg ischaemia. Eur J Vasc En-dovasc Surg 2011;42:83-8

[79] Weis-Müller BT, Römmler, V, Lippelt I, Porath M, Godehardt E, Balzer K, Sandmann W. Critical Chronic Peripheral Arterial Dis-

ease: Does Outcome Justify Crural or Pedal Bypass Surgery in Pa-tients With Advanced Age or With Comorbidities? Ann Vasc Surg

2011;25:783-95 [80] Watelet J, Soury P, Menard J-F, Plissonnier D, Peillon C,Lestrat J-

P, et al. Femoropopliteal bypass: in situ or reversed vein grafts? Ten-year results of a randomized prospective study. Ann Vasc Surg

1997;11:510–19 [81] Twine CP, McLain AD. Graft type for femoro-popliteal bypass

surgery. Cochrane Database Syst Rev 2010;5:CD001487 [82] Griffiths GD, Nagy J, Black D, Stonebridge PA. Randomized clini-

cal trial of distal anastomotic interposition vein cuff in infraingui-nal polytetrafluoroethylene bypass grafting. Br J Surg

2004;91:560–2 [83] Nguyen LL, Conte MS, Menard MT, Gravereaux EC, Chew DK,

Donaldson MC, Whittemore AD, Belkin M. Infrainguinal vein by-pass graft revision: factors affecting long-term outcome. J Vasc

Surg 2004;40:916-23 [84] Belch JJF, Dormandy J and the CASPAR Writing Committee.

Results of the randomized, placebo-controlled clopidogrel and ace-tylsalicylic acid in bypass surgery for peripheral arterial disease

(CASPAR) trial. J Vasc Surg 2010;52:825-33 [85] Nice C, Timmons G, Bartholemew P, Uberoi R. Retrograde vs.

antegrade puncture for infra-inguinal angioplasty. Cardiovasc In-tervent Radiol 2003; 26:370–374

[86] Biondi-Zoccai GG, Agostoni P, Sangiorgi G, Dalla Paola L, Armano F, Nicolini S, Alek J, Fusaro M. Mastering the antegrade

femoral artery access in patients with symptomatic lower limb ischemia: learning curve, complications, and technical tips and

tricks. Catheter Cardiovasc Interv 2006;68:835-42

[87] Wheatley BJ, Mansour MA, Grossman PM, Munir K, Cali RF,

Gorsuch JM, Cuff RF, Wong PY, Chambers CM. Complication rates for percutaneous lower extremity arterial antegrade access.

Arch Surg 2011;146:432-5 [88] Bown MJ, Bolia A, Sutton AJ. Subintimal angioplasty: meta-

analytical evidence of clinical utility. Eur J Vasc Endovasc Surg 2009;38:323-37

[89] Fusaro M, Agostoni P, Biondi-Zoccai G. "Trans-collateral" an-gioplasty for a challenging chronic total occlusion of the tibial ves-

sels: a novel approach to percutaneous revascularization in critical lower limb ischemia. Catheter Cardiovasc Interv 2008;71:268-72

[90] Fusaro M, Dalla Paola L, Biondi-Zoccai G. Pedal-plantar loop technique for a challenging below-the-knee chronic total occlusion:

a novel approach to percutaneous revascularization in critical lower limb ischemia. J Invasive Cardiol 2007;19:34-7

[91] Manzi M, Fusaro M, Ceccacci T, Erente G, Dalla Paola L, Brocco E. Clinical results of below-the knee intervention using pedal-

plantar loop technique for the revascularization of foot arteries. J Cardiovasc Surg (Torino) 2009;50:331-7

[92] Fusaro M, Dalla Paola L, Biondi-Zoccai GG. Retrograde posterior tibial artery access for below-the-knee percutaneous revasculariza-

tion by means of sheathless approach and double wire technique. Minerva Cardioangiol 2006;54:773-7

[93] Zhu YQ, Zhao JG, Li MH, Liu F, Wang JB, Cheng YS, Wang J, Li J. Retrograde transdorsal-to-plantar or transplantar-to-dorsal in-

traluminal re-entry following unsuccessful subintimal angioplasty for below-the-ankle arterial occlusion. J Endovasc Ther

2010;17:712-21 [94] Marinescu V, Mirowska KK, Schreiber T, Elder M, Petrina M.

Insights into endovascular revascularization in limb salvage proce-dures: "antegrade-retrograde" technique in chronic total occlusion.

Rev Cardiovasc Med 2011;12:42-7 [95] Hansen A, Krawzcynski H, Lacher F. Retrograde transpedale reca-

nalisation of tibial artery occlusion. Vasa 2009;38:249-53 [96] Graziani L, Silvestro A, Monge L, Boffano GM, Kokaly F,

Casadidio I, Giannini F. Transluminal angioplasty of peroneal ar-tery branches in diabetics: initial technical experience. Cardiovasc

Intervent Radiol 2008;31:49-55 [97] Graziani L, Morelli LG. Combined retrograde-antegrade arterial

recanalization through collateral vessels: redefinition of the tech-nique for below-the-knee arteries. Cardiovasc Intervent Radiol

2011;34 Suppl 2:S78-82 [98] Gandini R, Pipitone V, Stefanini M, Maresca L, Spinelli A, Colan-

gelo V, Reale CA, Pampana E, Simonetti G. The "Safari" technique to perform difficult subintimal infragenicular vessels. Cardiovasc

Intervent Radiol 2007;30:469-73 [99] Gandini R, Volpi T, Pampana E, Uccioli L, Versaci F, Simonetti G.

Applicability and clinical results of percutaneous transluminal an-gioplasty with a novel, long, conically shaped balloon dedicated for

below-the knee interventions. J Cardiovasc Surg (Torino) 2009;50:365-71

[100] Peeters P, Keirse K, Verbist J, Deloose K, Bosiers M. Other endo-vascular methods of treating the diabetic foot. J Cardiovasc Surg

(Torino) 2009;50:313-21 [101] Zeller T, Sixt S, Rastan A. New techniques for endovascular treat-

ment of peripheral artery disease with focus on chronic critical limb ischemia. Vasa 2009;38:3-12

[102] Schmidt A, Ulrich M, Winkler B, Klaeffling C, Bausback Y, Bräunlich S, Botsios S, Kruse HJ, Varcoe RL, K um S, Scheinert

D. Angiographic patency and clinical outcome after balloon-angioplasty for extensive infrapopliteal arterial disease. Catheter

Cardiovasc Interv 2010;76:1047-54 [103] Ferraresi R. Advanced techniques for optimal interventional reca-

nalisation in complex below the knee disease. EuroPCR,17-20 May 2011, Paris - France

[104] Schmidt A, Piorkowski M, Werner M, Ulrich M, Bausback Y, Bräunlich S, Ick H, Schuster J, Botsios S, Kruse HJ, Varcoe RL,

Scheinert D. First experience with drug-eluting balloons in in-frapopliteal arteries restenosis rate and clinical outcome. J Am Coll

Cardiol 2011;58:1105-9 [105] Kudo T, Chandra FA, Ahn SS. The effectiveness of percutaneous

transluminal angioplasty for the treatment of critical limb ischemia: a 10-year experience. J Vasc Surg 2005;41:423-35

[106] Romiti M, Albers M, Brochado-Neto FC, Durazzo AE, Pereira CA, De Luccia N. Meta-analysis of infrapopliteal angioplasty for

chronic critical limb ischemia. J Vasc Surg 2008;47:975-981


[107] Armstrong DG, Frykberg Rg. Classifying diabetic foot surgery:

toward rational definition. Diabetic Medicine 2003 Ap;2084).329-31

[108] Caputo WJ, Beggs DJ, DeFede JL, Simm L, Dharma H. A prospec-tive randomised controlled clinical trial comparing hydrosurgery

debridement with conventional surgical debridement in lower ex-tremity ulcers. Int Wound J. 2008;5:288-94

[109] Armstrong DG, Lavery LA. Diabetic Foot Study Consortium. Negative pressure wound therapy after partial diabetic foot amputa-

tion: a multicentre, randomised controlled trial. Lancet 2005;12;366(9498):1704-10

[110] Birke-Sorensen H, Malmsjo M, Rome P, Hudson D, Krug E, Berg L, Bruhin A, Caravaggi C, Chariker M, Depoorter M, Dowsett C,

Dunn R, Duteille F, Ferreira F, Martínez JM, Grudzien G, Ichioka S, Ingemansson R, Jeffery S, Lee C, Vig S, Runkel N; (Interna-

tional Expert Panel on Negative Pressure Wound Therapy [NPWT-

EP]), Martin R, Smith J. Evidence-based recommendations for negative pressure wound therapy: Treatment variables (pressure

levels, wound filler and contact layer) - Steps towards an interna-tional consensus. J Plast Reconstr Aesthet Surg. 2011;64 Suppl:S1-

S16 [111] Espandar R, Sibdari SY, Rafiee E, Yazdanian S. Necrotizing fasci-

itis of the extremities: a prospective study. Strategies Trauma Limb Reconstr 2011 Nov; 6(3):121-5

[112] Carlo Caravaggi, MD; Francesco Grigoletto, ScD; Nicolò Scuderi, MD Wound Bed Preparation With a Dermal Substitute (Hyaloma-

trix® PA) Facilitates Re-epithelialization and Healing: Results of a Multicenter, Prospective, Observational Study on Complex Chronic

Ulcers (The FAST Study) Wounds 2011;23(8):228–235

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The Management of Diabetic Foot