Chronic Limb-Threatening Ischemia (CLTI) in Diabetic Patients: Looking at the Big Picture beyond Wound, Ischemia and Foot Infection (WIfI) Classification System

*Maria Pilar Vela-Orús and María Sonia Gaztambide-Sáenz*

## **Abstract**

During the 1990s, most diabetic ulcers were considered neuropathic, but the Eurodiale study showed that more than 50% of these were non-plantar (neuroischaemic and ischaemic). According to the International Guidelines, the neuroischaemic and ischaemic diabetic foot ulcer (DFU) outcomes are connected to factors related to the wound, leg-associated factors and patients' comorbidities. We used wound, ischaemia and foot infection (WIfI) classification system; Trans-Atlantic Inter-Society Consensus-II (TASC-II) arterial lesion score; and Kaiser Permanente pyramid (stratification of patients according to their complexity) for assessing these parameters. From February 2011 to June 2012, we collected 124 episodes of neuro-ischaemic and ischaemic active ulcer in 100 patients: 18 required major amputation, 14 of them were in WIfI stage 4 and 4 in WIfI stage 3. Ten patients (over 14 in WIfI stage 4) were classified as TASC-II D. Eight patients (over the same 14) were classified as the higher risk of Kaiser Permanente pyramid. In line with other studies, our data support that the WIfI classification correlates well regarding risk of amputation at 1 year. However, when adding TASC-II and Kaiser Permanente pyramid assessment, the outcome is even more accurate not only for limb salvage but also for patients'survival.

**Keywords:** critical limb ischaemia, chronic limb-threatening ischaemia, diabetic foot ulcers, diabetic foot ulcer classification systems, outcome predictors

## **1. Introduction**

Nowadays, diabetes is considered as a leading cause of non-traumatic amputation all around the world. Despite the high morbidity and mortality associated with diseases of the foot in diabetes and although it is costly to both healthcare providers and the patient and their families [1], it is a topic that has generally failed to attract

**110**

*The Eye and Foot in Diabetes*

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the same level of interest by healthcare professionals as other diabetes complications.

The concept of critical limb ischaemia (CLI) implies that there are objective values that inform about the perfusion below which, if we do not increase the blood supply, the limb will be lost. CLI was defined for the first time in 1982 as rest pain with ankle pressure < 40 mmHg or necrosis and ankle pressure < 60 mmHg [2]. In 2017 the European Society of Cardiology and the European Society for Vascular Surgery (ESC/ESVS) guidelines on the diagnosis and treatment of peripheral arterial disease (PAD) have replaced the term critical limb ischaemia with chronic limbthreatening ischaemia (CLTI). The authors gave three arguments for this change: first, not all patients are in a "critical" situation even if they are not revascularized. Second, due to change in the population affected, mostly diabetics with neuroischaemic ulcers, it was recognized that severe ischaemia was not the only underlying cause. And finally, the risk of amputation does not only depend on the extent of ischaemia but also on the presence of wound and infection [3].

According to the World Health Organization (WHO), the diabetic foot may be defined as a group of syndromes in which neuropathy, ischaemia and infection lead to tissue breakdown, resulting in morbidity, possible amputation and mortality [4].

However, data about natural history of the disease are scarce. Elgzyri in 602 patients with diabetic foot ulcer (DFU) who had been considered as CLTI and were

*Contributors to the neuro-ischaemic and ischaemic diabetic foot ulcers (DFUs) outcomes. \*PAD, peripheral*

*Chronic Limb-Threatening Ischemia (CLTI) in Diabetic Patients: Looking at the Big Picture…*

Dr. Joslin, the famous American diabetologist, observed that after the introduction of insulin, "the mortality from diabetic coma had fallen dramatically (from 60 to 5%) yet deaths from diabetic gangrene of the foot and leg had risen significantly". He believed that diabetic gangrene was preventable and his remedy was a team approach involving nurses, surgeons and podiatrists for limb salvage and foot care. He was also the first to advocate for teaching patients to care for their own diabetes and the first who named diabetes as a serious public health issue that was becoming

Dr. Edmonds in 1979 in UK recognized the need for coordinated intensive care

of patients with diabetic foot with input from several disciplines, including diabetology, medicine, orthopedics and vascular surgery as well as podiatrists, orthotists and nurses. This initiative resulted in an immediate 50% reduction in major amputations (1984). Specific emphasis was placed on podiatric debridement,

The diabetic rapid response acute foot team (DRRAFT) guidelines [12], published in 2009, suggest that the vascular surgeon and diabetic podiatrist consti-

The authors defined seven vital skills for such a team to be able to effectively

The Multidisciplinary Diabetic Foot Unit (MDFU) was introduced at our institution in February 2011. The team was working in three levels of care: primary prevention, acute patients' treatment and outpatient postoperative management. Day-to-day care was carried out by a podiatrist and a vascular surgeon, the basic American "toe and flow" approach [13]. An algorithm for urgent referral was introduced in our Unit regarding the ulcer, the leg and the patient (see **Figure 2**).

• 50% healed primarily with wound care or with minor amputation

not revascularized reported that [9]:

*arterial disease; \*\*CO-MORB, comorbidities.*

*DOI: http://dx.doi.org/10.5772/intechopen.91970*

**Figure 1.**

**1.1 Multidisciplinary team approach**

a pandemic [10].

**113**

• 17% healed, but after a major amputation

off-loading, infection control and diabetes care [11].

tute the minimum in the formation of a diabetic foot team.

manage the lower-extremity complications of diabetes (see **Table 1**).

• 33% died with limbs intact but with unhealed wounds

It is admitted that ischaemic and neuro-ischaemic ulcers have similar behaviour to each other compared to the neuropathic ones referred to major amputation and survival [5].

Before the Eurodiale study, published in 2007 [6], it was widely believed that most diabetic ulcers were neuropathic, but this study found that:


The results from the Eurodiale study underlined that not only ulcer healing depends on the wound, the limb and the patient, but also the future of the extremity and patient survival too.

The International Guidelines [7] have published similar results: the neuro-ischaemic and ischaemic diabetic ulcer outcome is connected to:


Apelqvist in 1151 patients with diabetes and CLTI confirmed the three abovementioned factors. Moreover, revascularization is the major driver for ulcer healing. In fact, both percutaneous transluminal angioplasty (PTA) and open vascular surgery increased the probability for primary healing with an odds ratio (OR) of 1.77 and 2.05, respectively [8].

*Chronic Limb-Threatening Ischemia (CLTI) in Diabetic Patients: Looking at the Big Picture… DOI: http://dx.doi.org/10.5772/intechopen.91970*

#### **Figure 1.**

the same level of interest by healthcare professionals as other diabetes

ischaemia but also on the presence of wound and infection [3].

most diabetic ulcers were neuropathic, but this study found that:

The concept of critical limb ischaemia (CLI) implies that there are objective values that inform about the perfusion below which, if we do not increase the blood supply, the limb will be lost. CLI was defined for the first time in 1982 as rest pain with ankle pressure < 40 mmHg or necrosis and ankle pressure < 60 mmHg [2]. In 2017 the European Society of Cardiology and the European Society for Vascular Surgery (ESC/ESVS) guidelines on the diagnosis and treatment of peripheral arterial disease (PAD) have replaced the term critical limb ischaemia with chronic limbthreatening ischaemia (CLTI). The authors gave three arguments for this change: first, not all patients are in a "critical" situation even if they are not revascularized. Second, due to change in the population affected, mostly diabetics with neuroischaemic ulcers, it was recognized that severe ischaemia was not the only underlying cause. And finally, the risk of amputation does not only depend on the extent of

According to the World Health Organization (WHO), the diabetic foot may be defined as a group of syndromes in which neuropathy, ischaemia and infection lead to tissue breakdown, resulting in morbidity, possible amputation and mortality [4]. It is admitted that ischaemic and neuro-ischaemic ulcers have similar behaviour to each other compared to the neuropathic ones referred to major amputation and

Before the Eurodiale study, published in 2007 [6], it was widely believed that

• More than 50% (52%) of the foot ulcers were non-plantar (ischaemic and

• One third of the patients (31%) had signs of both peripheral arterial disease and infection. These patients have a worse prognosis; they take longer to heal and have more amputations and more risk of dying. They have a distinct profile: they are older and have more non-plantar ulcers, greater tissue loss and

The results from the Eurodiale study underlined that not only ulcer healing depends on the wound, the limb and the patient, but also the future of the extremity

The International Guidelines [7] have published similar results: the neuro-ischaemic and ischaemic diabetic ulcer outcome is connected to:

• Limb-related factors (in these cases severity of PAD).

• Patients' comorbidities (see **Figure 1**).

• Factors related to the wound (the most important is the extent of tissue

Apelqvist in 1151 patients with diabetes and CLTI confirmed the three abovementioned factors. Moreover, revascularization is the major driver for ulcer healing. In fact, both percutaneous transluminal angioplasty (PTA) and open vascular surgery increased the probability for primary healing with an odds ratio (OR) of 1.77

• More than 50% (58%) of patients with an ulcer had signs of infection.

complications.

*The Eye and Foot in Diabetes*

survival [5].

neuro-ischaemic).

and patient survival too.

involvement).

and 2.05, respectively [8].

**112**

more serious comorbidities.

*Contributors to the neuro-ischaemic and ischaemic diabetic foot ulcers (DFUs) outcomes. \*PAD, peripheral arterial disease; \*\*CO-MORB, comorbidities.*

However, data about natural history of the disease are scarce. Elgzyri in 602 patients with diabetic foot ulcer (DFU) who had been considered as CLTI and were not revascularized reported that [9]:


#### **1.1 Multidisciplinary team approach**

Dr. Joslin, the famous American diabetologist, observed that after the introduction of insulin, "the mortality from diabetic coma had fallen dramatically (from 60 to 5%) yet deaths from diabetic gangrene of the foot and leg had risen significantly". He believed that diabetic gangrene was preventable and his remedy was a team approach involving nurses, surgeons and podiatrists for limb salvage and foot care. He was also the first to advocate for teaching patients to care for their own diabetes and the first who named diabetes as a serious public health issue that was becoming a pandemic [10].

Dr. Edmonds in 1979 in UK recognized the need for coordinated intensive care of patients with diabetic foot with input from several disciplines, including diabetology, medicine, orthopedics and vascular surgery as well as podiatrists, orthotists and nurses. This initiative resulted in an immediate 50% reduction in major amputations (1984). Specific emphasis was placed on podiatric debridement, off-loading, infection control and diabetes care [11].

The diabetic rapid response acute foot team (DRRAFT) guidelines [12], published in 2009, suggest that the vascular surgeon and diabetic podiatrist constitute the minimum in the formation of a diabetic foot team.

The authors defined seven vital skills for such a team to be able to effectively manage the lower-extremity complications of diabetes (see **Table 1**).

The Multidisciplinary Diabetic Foot Unit (MDFU) was introduced at our institution in February 2011. The team was working in three levels of care: primary prevention, acute patients' treatment and outpatient postoperative management. Day-to-day care was carried out by a podiatrist and a vascular surgeon, the basic American "toe and flow" approach [13]. An algorithm for urgent referral was introduced in our Unit regarding the ulcer, the leg and the patient (see **Figure 2**).

Haemodynamic and anatomic vascular assessment with revascularization, as necessary

Biomechanical and podiatric assessment with surgical and non-surgical intervention as necessary

Peripheral neurological examinations

Wound assessment and staging/grading of infection and ischaemia

Site-specific bedside and intraoperative incisions and debridement, taking samples for culture using an appropriate technique

Initiate and modify culture-specific and patient-appropriate antibiotic therapy

Conduct appropriate postoperative monitoring to reduce risks of re-ulceration

#### **Table 1.**

*Minimum skills for constituting a diabetic foot team from DRRAFT [12].*

**Figure 2.**

*Multidisciplinary diabetic foot unit organization (toe and flow inspired). GP, general practitioner; ER, emergency room; N&E, nurses and endocrinologist; CV, cardio vascular; iv AB, intravenous antibiotics.*

#### **1.2 Understanding diabetic foot ulcer classifications**

Classifications that we use in daily clinical practice are compartmentalized: some refer only to infection, and others only to ischaemia or only treat descriptive aspect of ulcers [14] (see **Table 2**).

(ESRF)); others, limb-related (e.g., PAD and loss of protective sensation) and lastly ulcer-related (area, depth, site, single or multiple and infection). They identified five clinical key situations too and recommended one specific classification for each one: communication among health professionals; predicting the outcome of an individual ulcer; aid to clinical decision-making for an individual case; assessment of a wound, with or without infection, and peripheral artery disease; and audit of outcome in local, regional or national populations [16–18] (see **Tables 3**–**5**).

**Clinical scenario Classification recommended**

**Main points Pros/cons**

*Chronic Limb-Threatening Ischemia (CLTI) in Diabetic Patients: Looking at the Big Picture…*

Well established

Well established

are not fully addressed

the outcome of DFUs

Conversely, infection and ischaemia

Describes infection and ischaemia better than Meggitt-Wagner but informs only about yes or no (is not categorized). May help in predicting

User-friendly (clear definitions, few categories) for practitioners with a lower level of experience with diabetic foot management

Simplified version of the S (AD) SAD classification system. Includes ulcer site as data suggests this might be an important determinant of outcome

presence of gangrene and loss of perfusion using six grades (0–5)

ischaemia using a matrix of four grades combined with four stages

Developed by IWGDF Uses four grades (1–4)

*Pros and cons of some common wound classification systems for DFUs [14].*

Communication among health professionals \*SINBAD Predicting the outcome of an individual ulcer None

Assessment of perfusion and the likely benefit of revascularization WIfI## Audit of outcome in local, regional or national populations SINBAD

*SINBAD, site, ischaemia, neuropathy, bacterial infection, area and depth.*

Assessment of infection \*\*IDSA/IWGDF#

It grades area, depth, infection arteriopathy and neuropathy and site. Uses a scoring system to help predict outcomes and enable comparisons between different settings and countries

In order for a stratification system of a disease to be relevant, it is expected that it will give us a risk scale with respect to natural history and that the classification is detailed enough to compare different treatments. Thus, the scale could be descriptive and predictive at the same time. In January 2014 the Society for Vascular Surgery (SVS) published the new classification system for CLTI based on wound extent, degree of ischaemia and foot infection (WIfI), with scales from 0 to 3, for

each one of these parameters [19].

*\*\*IDSA, Infectious Diseases Society of America.*

*##WIfI, Wound, Ischaemia and foot Infection.*

*IWGDF, International Working Group on Diabetic Foot.*

*IWGDF classification system recommendations [16].*

**Classification system**

PEDIS

SINBAD Site, ischaemia, neuropathy, bacterial infection, area and depth

**Table 2.**

*\**

*#*

**115**

**Table 3.**

Perfusion, extent (size), depth (tissue loss), infection and sensation (neuropathy)

Meggitt-Wagner Assesses ulcer depth plus the

*DOI: http://dx.doi.org/10.5772/intechopen.91970*

Texas University Assesses ulcer depth, infection and

Monteiro-Soares in a meta-analysis published in 2014 identified 25 different classification systems for diabetic foot ulcers. Of those, eight used a descriptive basis, and seven utilized prognostic stratification classification systems, but few studies evaluated their reliability or external validity [15].

The International Working Group on Diabetic Foot (IWGDF) has published in 2019 his updated guidelines on the prevention and management of diabetic foot disease with a new and special chapter focus on the classification of active diabetic foot ulcers. The authors identified eight key factors judged to contribute to the scoring of classifications: some are patient-related (e.g., end-stage renal failure

*Chronic Limb-Threatening Ischemia (CLTI) in Diabetic Patients: Looking at the Big Picture… DOI: http://dx.doi.org/10.5772/intechopen.91970*


#### **Table 2.**

*Pros and cons of some common wound classification systems for DFUs [14].*


*##WIfI, Wound, Ischaemia and foot Infection.*

#### **Table 3.**

**1.2 Understanding diabetic foot ulcer classifications**

studies evaluated their reliability or external validity [15].

of ulcers [14] (see **Table 2**).

Classifications that we use in daily clinical practice are compartmentalized: some refer only to infection, and others only to ischaemia or only treat descriptive aspect

Monteiro-Soares in a meta-analysis published in 2014 identified 25 different classification systems for diabetic foot ulcers. Of those, eight used a descriptive basis, and seven utilized prognostic stratification classification systems, but few

*Multidisciplinary diabetic foot unit organization (toe and flow inspired). GP, general practitioner; ER, emergency room; N&E, nurses and endocrinologist; CV, cardio vascular; iv AB, intravenous antibiotics.*

Haemodynamic and anatomic vascular assessment with revascularization, as necessary

Wound assessment and staging/grading of infection and ischaemia

*Minimum skills for constituting a diabetic foot team from DRRAFT [12].*

Initiate and modify culture-specific and patient-appropriate antibiotic therapy Conduct appropriate postoperative monitoring to reduce risks of re-ulceration

Peripheral neurological examinations

appropriate technique

*The Eye and Foot in Diabetes*

**Table 1.**

**Figure 2.**

**114**

Biomechanical and podiatric assessment with surgical and non-surgical intervention as necessary

Site-specific bedside and intraoperative incisions and debridement, taking samples for culture using an

The International Working Group on Diabetic Foot (IWGDF) has published in 2019 his updated guidelines on the prevention and management of diabetic foot disease with a new and special chapter focus on the classification of active diabetic foot ulcers. The authors identified eight key factors judged to contribute to the scoring of classifications: some are patient-related (e.g., end-stage renal failure

*IWGDF classification system recommendations [16].*

(ESRF)); others, limb-related (e.g., PAD and loss of protective sensation) and lastly ulcer-related (area, depth, site, single or multiple and infection). They identified five clinical key situations too and recommended one specific classification for each one: communication among health professionals; predicting the outcome of an individual ulcer; aid to clinical decision-making for an individual case; assessment of a wound, with or without infection, and peripheral artery disease; and audit of outcome in local, regional or national populations [16–18] (see **Tables 3**–**5**).

In order for a stratification system of a disease to be relevant, it is expected that it will give us a risk scale with respect to natural history and that the classification is detailed enough to compare different treatments. Thus, the scale could be descriptive and predictive at the same time. In January 2014 the Society for Vascular Surgery (SVS) published the new classification system for CLTI based on wound extent, degree of ischaemia and foot infection (WIfI), with scales from 0 to 3, for each one of these parameters [19].


**Wound grade Diabetic foot ulcer (DFU) Gangrene**

(1 or 2 digits)

*DOI: http://dx.doi.org/10.5772/intechopen.91970*

1 Small, shallow ulcer(s) on distal leg or

the distal phalanx

(1 or 2 digits)

3 Extensive, deep ulcer involving the

involvement

loss

**Ankle-brachial index**

**Foot infection grade Clinical manifestations**

0 No symptoms or signs of infection

**Table 6.**

**Table 7.**

**Table 8.**

**117**

*Foot infection from WIfI system [19].*

**Ischemia grade**

*Wound from WIfI system [19].*

*Ischemia from WIfI system [19].*

2 Deeper ulcer with exposed bone, joint

Clinical description: minor tissue loss

*Chronic Limb-Threatening Ischemia (CLTI) in Diabetic Patients: Looking at the Big Picture…*

foot; no exposed bone, unless limited to

Clinical description: minor tissue loss

or tendon; generally, not involving the heel; shallow heel ulcer, without calcaneal involvement

Clinical description: major tissue loss

forefoot and/or midfoot; deep fullthickness heel ulcer calcaneal

Clinical description: extensive tissue

**Ankle systolic pressure (mmHg)**

1 Local infection involving only the skin and the subcutaneous tissue (without

cu/mm or 10% immature (band) forms

neuro-osteoarthropathy, fracture, thrombosis, venous stasis) 2 Local infection (as described above) with erythema >2 cm, or involving structures

3 Local infection (as described above) with the signs of SIRS, as manifested by two or more

 >0.80 >100 >60 0.6–0.79 70–100 40–59 0.4–0.59 50–70 30–39 <0.39 <50 <30

No gangrene

skin coverage

No gangrene

skin coverage

calcaneal involvement

soft tissue defect

Infection present, as defined by the presence of at least 2 of the following items: local swelling or induration; erythema >0.5 to <2 cm around the ulcer; local tenderness or pain; local warmth; purulent discharge: thick, opaque to white or sanguineous secretion

involvement of deeper tissues and without systemic signs as described below). Exclude other causes of an inflammatory response of the skin (e.g. trauma, gout, acute Charcot,

of the following: temperature > 38°C or < 36°C; heart rate > 90 beats/min; respiratory rate > 20 breaths/min or PaCO2 < 32 mmHg; white blood cell count >12,000 or < 4000

deeper than the skin and subcutaneous tissues (e.g. abscess, osteomyelitis, septic arthritis, fasciitis), and no systemic inflammatory response signs (as described below)

Salvageable with simple digital amputation or

Salvageable with simple digital amputation or

Extensive gangrene involving the forefoot and/ or midfoot; full-thickness heel necrosis and

**Toe pressure, trans-cutaneous oxygen pressure (mmHg)**

Gangrenous changes limited to digits Salvageable with multiple (>3) digital amputation or standard trans-metatarsal amputation (TMA) skin coverage

Salvageable only with a complex foot reconstruction or non-traditional TMA (Chopart or Lisfranc) flap coverage or complex wound management needed for large

0 No ulcer

#### **Table 4.**

*SINBAD classification system [17].*


#### **Table 5.**

*IDSA/IWGDF system [18].*

WIfI classification represents a summary of multiple previously published classifications focused on diabetic foot ulcers and pure ischaemia or infection models and is the first one which reports on the risk of amputation and benefit of revascularization at 1 year.

With respect to the wound, WIfI integrates the Texas University classification that is validated and adds the gangrene component. The authors include pain at rest and gangrene of ischaemic cause. Depth takes preference over extension, and there is a measure of what is going to lose (see **Table 6**).

WIfI ischaemia is stratified not only according to ankle-brachial index (ABI) figures but also ankle pressure and digital pressure. They are categorized up to moderate degrees of ischaemia. Alternatives to the ABI are included, and digital pressure is considered mandatory in diabetic patients (see **Table 7**).

WIfI collects the characteristics of the Infectious Diseases Society of America (IDSA) (validated) and the IWGDF (see **Table 8**).

Based on the results obtained in each parameter, a Delphi survey among 12 experts was conducted. A table for estimating the risk of major amputation over the first year and the theoretical benefit of revascularization was elaborated.

*Chronic Limb-Threatening Ischemia (CLTI) in Diabetic Patients: Looking at the Big Picture… DOI: http://dx.doi.org/10.5772/intechopen.91970*


**Table 6.**

*Wound from WIfI system [19].*


#### **Table 7.**

WIfI classification represents a summary of multiple previously published classifications focused on diabetic foot ulcers and pure ischaemia or infection models and is the first one which reports on the risk of amputation and benefit of revascu-

**Category Definition Score**

Ischemia Pedal blood flow intact (at least one palpable pulse)

Depth Ulcer confined to the skin and subcutaneous tissue

**Clinical manifestations Infection**

Presence of >2 manifestations of inflammation (purulence, erythema, tenderness, warmth or induration), but any cellulitis/erythema extends <2 cm around the ulcer, and the infection is limited to the skin or superficial subcutaneous tissues; no other local complications or systemic illness

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)

Wound lacking purulence or any manifestations of inflammation Uninfected 1

Midfoot and hindfoot

Clinical evidence of reduced pedal flow

Protective sensation lost

Present

Ulcer >1 cm2

Ulcer reaching the muscle, tendon or deeper

Total possible score 6

0 1

0 1

0 1

0 1

0 1

0 1

**PEDIS grade**

**severity**

Mild 2

Moderate 3

Severe 4

Site Forefoot

Bacterial infection None

Area Ulcer <1 cm2

Neuropathy Protective sensation intact

With respect to the wound, WIfI integrates the Texas University classification that is validated and adds the gangrene component. The authors include pain at rest and gangrene of ischaemic cause. Depth takes preference over extension, and there

WIfI ischaemia is stratified not only according to ankle-brachial index (ABI) figures but also ankle pressure and digital pressure. They are categorized up to moderate degrees of ischaemia. Alternatives to the ABI are included, and digital

WIfI collects the characteristics of the Infectious Diseases Society of America

Based on the results obtained in each parameter, a Delphi survey among 12 experts was conducted. A table for estimating the risk of major amputation over the

pressure is considered mandatory in diabetic patients (see **Table 7**).

first year and the theoretical benefit of revascularization was elaborated.

larization at 1 year.

*IDSA/IWGDF system [18].*

**Table 5.**

**116**

**Table 4.**

*SINBAD classification system [17].*

*The Eye and Foot in Diabetes*

is a measure of what is going to lose (see **Table 6**).

(IDSA) (validated) and the IWGDF (see **Table 8**).

*Ischemia from WIfI system [19].*



Existing systems of classification of critical ischaemia (e.g., classical Fontaine and Rutherford) do not adequately explain the extent of tissue loss or the presence and severity of infection. In recent years, most classifications have focused on anatomical details extracted from arteriography without paying attention to the physiological state of the limb, for example, the Bollinger, Graziani and Trans-Atlantic Inter-Society Consensus (TASC-I and TASC-II) classifications. Although there are criticisms, the TASC-I and TASC-II classifications are the only ones that carry recommendations for treatment [21] (see **Figure 3**). And we should also use a

*Chronic Limb-Threatening Ischemia (CLTI) in Diabetic Patients: Looking at the Big Picture…*

If we assume that in ulcer healing, factors are related not only to the wound itself but also to the limb and the patients are involved, we need an objective scale that indicates the type of patient we are treating. For this purpose, among other scales (e.g. Prevent III and Finnvasc), we have included the categorization of the chronic

Other scales used in vascular surgery units are Prevent III and Finnvasc. Prevent III was designed to calculate the amputation-free time after revascularization surgery and consists of a scoring system on various pathologies: dialysis 4 points, tissue loss 3 points, age ≥ 75 years 2 points, hematocrit ≤30% 2 points and coronary disease 1 point. A low risk ≤3, medium risk 4–7 or severe risk ≥8 points is attributed according to the score obtained [24]. Finnvasc score seems to behave better also when predicting the immediate postoperative outcome [25]. The accuracy of these scales is acceptable. They are easy to use and very valuable in clinical practice,

Based on this background, as part of a doctoral thesis [26], we collected retrospectively our data. The aim of the study was to evaluate the implementation of the WIfI classification mainly on the risk of major amputation and benefit of revascularization at 1 year in a population diagnosed with CLTI and neuro-ischaemic or pure ischaemic wounds and diabetes. Adding up the TASC-II classification to have more information on the arterial status of the limb and the result of applying the

It is a retrospective and observational study based on episodes of active ulcer in patients with diabetes collected in a prospective database open from the beginning of the care activity related to the creation of the Multidisciplinary Diabetic Foot

From February 2011 to June 2012, we treated 122 consecutive patients (151 episodes) with diabetic foot ulcer. The median age was 70 years (SD 11.35). Men are 73.8%. The median HbA1c was 62.8 mmol/mol (7.9%). Hypertension was present in 82% of our population, coronary artery disease in 53%, chronic kidney disease in 38%

Kaiser Permanente pyramid to better profile the type of patient affected.

especially to help us decide when not to revascularize.

classification that describes the state of the arteries in the foot [22].

*DOI: http://dx.doi.org/10.5772/intechopen.91970*

pluripathological patient adopted by Osakidetza-Servicio Vasco de Salud

[23] (see **Figure 4**).

**2.1 Population in our study**

Unit at Cruces University Hospital.

**119**

(Osakidetza-SVS, Basque Country National Health Service) in 2011 based on the good practice model of Kaiser Permanente. Chronic patients are stratified into three levels of intervention depending on the complexity of the case. At the baseline of the Kaiser Permanente pyramid, the healthy members of the population are located for whom prevention, health promotion and risk factor control interventions are a priority. In the first level, where the majority of chronic patients we find concentrated, the interest is focused on promoting self-care. In the second level are chronic patients with the prominence of a particular disease or organ and who can benefit from the "disease management", and, finally, in the highest level of the pyramid are those patients with very complex cases that need integral management. Although they are not the most numerous, these are the ones that consume the most resources




#### **Table 9.**

```
WIfI prediction tables. Adapted from the original [19].
```
When calculating the benefit of revascularization, they assume that the infection is controlled. Intraclass correlation coefficient for the amputation in the first year was 0.81/0.98 and for the benefit of revascularization 0.76/0.97 (see **Table 9**).

### **2. Looking at the big picture**

In a recent meta-analysis published in 2019 regarding the prognostic value of the WIfI classification in patients with CLTI and where 12 studies comprising 2669 patients were evaluated, the authors conclude that "the likelihood of an amputation after 1 year in patients with CLTI increases with higher WIfI stages". But, "the current evidence is not sufficient for the instrument to be helpful in clinical decision making for patients with CLTI and prospective studies are needed to determine its role in clinical practice" [20]. We are aware that the risk of amputation increases as the WIfI clinical stage progresses from stage 1 to stage 4. However, data regarding those with PAD and their anatomical conditions and patients' comorbidities are lacking in WIfI classification system. By better defining and understanding CLTI spectrum, we need to include arterial lesion classification and patients' comorbidities.

#### *Chronic Limb-Threatening Ischemia (CLTI) in Diabetic Patients: Looking at the Big Picture… DOI: http://dx.doi.org/10.5772/intechopen.91970*

Existing systems of classification of critical ischaemia (e.g., classical Fontaine and Rutherford) do not adequately explain the extent of tissue loss or the presence and severity of infection. In recent years, most classifications have focused on anatomical details extracted from arteriography without paying attention to the physiological state of the limb, for example, the Bollinger, Graziani and Trans-Atlantic Inter-Society Consensus (TASC-I and TASC-II) classifications. Although there are criticisms, the TASC-I and TASC-II classifications are the only ones that carry recommendations for treatment [21] (see **Figure 3**). And we should also use a classification that describes the state of the arteries in the foot [22].

If we assume that in ulcer healing, factors are related not only to the wound itself but also to the limb and the patients are involved, we need an objective scale that indicates the type of patient we are treating. For this purpose, among other scales (e.g. Prevent III and Finnvasc), we have included the categorization of the chronic pluripathological patient adopted by Osakidetza-Servicio Vasco de Salud (Osakidetza-SVS, Basque Country National Health Service) in 2011 based on the good practice model of Kaiser Permanente. Chronic patients are stratified into three levels of intervention depending on the complexity of the case. At the baseline of the Kaiser Permanente pyramid, the healthy members of the population are located for whom prevention, health promotion and risk factor control interventions are a priority. In the first level, where the majority of chronic patients we find concentrated, the interest is focused on promoting self-care. In the second level are chronic patients with the prominence of a particular disease or organ and who can benefit from the "disease management", and, finally, in the highest level of the pyramid are those patients with very complex cases that need integral management. Although they are not the most numerous, these are the ones that consume the most resources [23] (see **Figure 4**).

Other scales used in vascular surgery units are Prevent III and Finnvasc. Prevent III was designed to calculate the amputation-free time after revascularization surgery and consists of a scoring system on various pathologies: dialysis 4 points, tissue loss 3 points, age ≥ 75 years 2 points, hematocrit ≤30% 2 points and coronary disease 1 point. A low risk ≤3, medium risk 4–7 or severe risk ≥8 points is attributed according to the score obtained [24]. Finnvasc score seems to behave better also when predicting the immediate postoperative outcome [25]. The accuracy of these scales is acceptable. They are easy to use and very valuable in clinical practice, especially to help us decide when not to revascularize.

#### **2.1 Population in our study**

Based on this background, as part of a doctoral thesis [26], we collected retrospectively our data. The aim of the study was to evaluate the implementation of the WIfI classification mainly on the risk of major amputation and benefit of revascularization at 1 year in a population diagnosed with CLTI and neuro-ischaemic or pure ischaemic wounds and diabetes. Adding up the TASC-II classification to have more information on the arterial status of the limb and the result of applying the Kaiser Permanente pyramid to better profile the type of patient affected.

It is a retrospective and observational study based on episodes of active ulcer in patients with diabetes collected in a prospective database open from the beginning of the care activity related to the creation of the Multidisciplinary Diabetic Foot Unit at Cruces University Hospital.

From February 2011 to June 2012, we treated 122 consecutive patients (151 episodes) with diabetic foot ulcer. The median age was 70 years (SD 11.35). Men are 73.8%. The median HbA1c was 62.8 mmol/mol (7.9%). Hypertension was present in 82% of our population, coronary artery disease in 53%, chronic kidney disease in 38%

When calculating the benefit of revascularization, they assume that the infection is controlled. Intraclass correlation coefficient for the amputation in the first year was 0.81/0.98 and for the benefit of revascularization 0.76/0.97 (see **Table 9**).

In a recent meta-analysis published in 2019 regarding the prognostic value of the

WIfI classification in patients with CLTI and where 12 studies comprising 2669 patients were evaluated, the authors conclude that "the likelihood of an amputation after 1 year in patients with CLTI increases with higher WIfI stages". But, "the current evidence is not sufficient for the instrument to be helpful in clinical decision making for patients with CLTI and prospective studies are needed to determine its role in clinical practice" [20]. We are aware that the risk of amputation increases as the WIfI clinical stage progresses from stage 1 to stage 4. However, data regarding those with PAD and their anatomical conditions and patients' comorbidities are lacking in WIfI classification system. By better defining and understanding CLTI

spectrum, we need to include arterial lesion classification and patients'

**2. Looking at the big picture**

*The Eye and Foot in Diabetes*

*WIfI prediction tables. Adapted from the original [19].*

comorbidities.

**118**

**Table 9.**

#### **Figure 3.**

*Modified from TASC-II classification system including below the knee (BTK) lesions [21].*

was 0.5 (95% CI = 0.20–1.23). In the negative LR, if a patient was in stage 1, 2 or 3,

*Chronic Limb-Threatening Ischemia (CLTI) in Diabetic Patients: Looking at the Big Picture…*

*DOI: http://dx.doi.org/10.5772/intechopen.91970*

Regarding the benefit of revascularization, we compared patients classified as high benefit versus those of moderate and low benefit. Those of very low benefit were excluded because the intervention would not really be indicated. The positive LR was 2.08 (95% CI = 1.39–3.13) and negative LR 0.00. Thus, the probability that a patient with a high benefit of being revascularized according to the WIfI scale, if

In our study the analysis of the area under the receiver operating characteristic (ROC) curve (AUC) regarding the predictive ability related to amputation risk at

In our population the median time for suffering a major amputation was 4.01 years (95% CI = 3.69–4.31). Patients who had not undergone prior amputation

**WIfI amputation risk at 1 year No Yes Total**

5 100.0

12 100.0

> 30 88.2

59 80.8

106 85.5

0 0.0

0 0.0

4 11.8

14 19.2

18 14.5

5 100.0

12 100.0

34 100.0

73 100.0

124 100.0

he/she had double probability for limb salvage than in stage 4.

this intervention is performed, saves the limb is 73.1%.

1 year was 0.61 (95% CI = 0.47–0.74) (see **Figure 6**).

*Number of major amputations at 1 year according to WIfI [26].*

*2.2.1 Survival function for major amputation*

**Figure 5.**

*Population under study [26].*

Very low, Number

Moderate, Number

Low, Number

High, Number

Total Number

%

%

%

%

%

**Table 10.**

**121**

#### **Figure 4.**

*Adapted from the Kaiser Permanente pyramid model [23].*

and 6.0% on dialysis. We retrospectively collected data on 124 (82.11%) ischaemic and neuro-ischaemic ulcers; 27 pure neuropathic (17.89%) were excluded from the study. Therefore 115 ulcers in 93 patients were the final population (see **Figure 5**).

To verify the influence of the different factors on the time to amputation, the survival of the patients or until healing, we make use of Kaplan–Meier tables. A univariate and multivariate Cox regression has also been carried out using a non-automatic stepping method. A level of statistical significance p < 0.05 has been considered for all tests. The statistical analysis was carried out with the SPSS program vs. 22.0.

#### **2.2 Our results**

In our study 72.6% of patients were revascularized. We follow the "endovascular-first" policy, but whether the intervention was endovascular or open is not specified. We had 18 (14.5%) major amputations at one year. Fourteen of them (78%) were in WIfI stage 4 and 4 (22%) in WIfI stage 3 (see **Table 10**). The positive likelihood ratio (LR) was 1.40 (95% CI = 1.04–1.89); and the negative LR

*Chronic Limb-Threatening Ischemia (CLTI) in Diabetic Patients: Looking at the Big Picture… DOI: http://dx.doi.org/10.5772/intechopen.91970*

was 0.5 (95% CI = 0.20–1.23). In the negative LR, if a patient was in stage 1, 2 or 3, he/she had double probability for limb salvage than in stage 4.

Regarding the benefit of revascularization, we compared patients classified as high benefit versus those of moderate and low benefit. Those of very low benefit were excluded because the intervention would not really be indicated. The positive LR was 2.08 (95% CI = 1.39–3.13) and negative LR 0.00. Thus, the probability that a patient with a high benefit of being revascularized according to the WIfI scale, if this intervention is performed, saves the limb is 73.1%.

In our study the analysis of the area under the receiver operating characteristic (ROC) curve (AUC) regarding the predictive ability related to amputation risk at 1 year was 0.61 (95% CI = 0.47–0.74) (see **Figure 6**).

#### *2.2.1 Survival function for major amputation*

In our population the median time for suffering a major amputation was 4.01 years (95% CI = 3.69–4.31). Patients who had not undergone prior amputation


#### **Table 10.**

*Number of major amputations at 1 year according to WIfI [26].*

and 6.0% on dialysis. We retrospectively collected data on 124 (82.11%) ischaemic and neuro-ischaemic ulcers; 27 pure neuropathic (17.89%) were excluded from the study. Therefore 115 ulcers in 93 patients were the final population (see **Figure 5**). To verify the influence of the different factors on the time to amputation, the survival of the patients or until healing, we make use of Kaplan–Meier tables. A univariate and multivariate Cox regression has also been carried out using a non-automatic stepping method. A level of statistical significance p < 0.05 has been considered for all

tests. The statistical analysis was carried out with the SPSS program vs. 22.0.

*Adapted from the Kaiser Permanente pyramid model [23].*

*Modified from TASC-II classification system including below the knee (BTK) lesions [21].*

In our study 72.6% of patients were revascularized. We follow the

"endovascular-first" policy, but whether the intervention was endovascular or open is not specified. We had 18 (14.5%) major amputations at one year. Fourteen of them (78%) were in WIfI stage 4 and 4 (22%) in WIfI stage 3 (see **Table 10**). The positive likelihood ratio (LR) was 1.40 (95% CI = 1.04–1.89); and the negative LR

**2.2 Our results**

**120**

**Figure 3.**

*The Eye and Foot in Diabetes*

**Figure 4.**

**Figure 6.** *Area under the ROC curve [26].*

and those who had only a minor one take a median of 4.08 years (95% CI = 3.77– 4.40) and (95% CI = 3.47–4.69), respectively. Patients who had suffered a previous major amputation were amputated in a median of 1.76 years (95% CI = 0.76–2.77); the difference was statistically significant p < 0.001 (see **Figure 7**).

**Figure 7.**

**Figure 8.**

**123**

*Survival function for major amputation according to previous one [26].*

*Chronic Limb-Threatening Ischemia (CLTI) in Diabetic Patients: Looking at the Big Picture…*

*DOI: http://dx.doi.org/10.5772/intechopen.91970*

*Survival function for TASC-II major amputation risk at 1 year comparing a, B and C versus D.*

Patients in TASC A, B and C take a median of 4.14 years (95% CI = 3.921–4.367) to suffer a major amputation, whereas patients classified as TASC D took a median of 3.75 years (95% CI = 3.306–4.200). The difference was statistically significant p = 0.009 (see **Figure 8**).

We found statistical differences regarding the amputation rate only when WIfI stages 1, 2 and 3 were compared with stage 4. Patients classified according to the WIfI scale as very low, low and moderate risk of being amputated during the first year underwent such amputation in a median of 3.92 years (95% CI = 3.60–4.23). And those classified as high risk presented it in a median of 3.73 years (95% CI = 3.27–4.18), p = 0.044 (see **Figure 9**).

Patients with small lesions take a median of 3.90 years to be amputated (95% CI = 3.58–4.23); those with a major lesion took 4.01 years (95% CI = 3.58–4.43) compared to those who had extensive wound that took 1.35 years (95% CI = 0.21– 2.48); the difference was statistically significant p < 0.001 (see **Figure 10**).

Cox regression multivariate analysis identified previous major amputation, TASC D arterial lesions and extensive ulcer from WIfI (but no global WIfI) as independent risk factors for major amputation (see **Table 11**).

#### *2.2.2 Survival function for survival*

We must not forget that we are facing elderly and pluripathological patients. The median survival was 3.42 years (95% CI = 3.08–3.76). Patient's survival was 84% at 1 year, 66% at 3 years and 50% at 5 years. Five years after the diagnosis of CLTI, only half of the population survived regardless of whether the limb was saved or amputated (see **Figure 11**).

*Chronic Limb-Threatening Ischemia (CLTI) in Diabetic Patients: Looking at the Big Picture… DOI: http://dx.doi.org/10.5772/intechopen.91970*


#### **Figure 7.**

and those who had only a minor one take a median of 4.08 years (95% CI = 3.77– 4.40) and (95% CI = 3.47–4.69), respectively. Patients who had suffered a previous major amputation were amputated in a median of 1.76 years (95% CI = 0.76–2.77);

Patients in TASC A, B and C take a median of 4.14 years (95% CI = 3.921–4.367) to suffer a major amputation, whereas patients classified as TASC D took a median of 3.75 years (95% CI = 3.306–4.200). The difference was statistically significant

We found statistical differences regarding the amputation rate only when WIfI stages 1, 2 and 3 were compared with stage 4. Patients classified according to the WIfI scale as very low, low and moderate risk of being amputated during the first year underwent such amputation in a median of 3.92 years (95% CI = 3.60–4.23). And those classified as high risk presented it in a median of 3.73 years (95%

Patients with small lesions take a median of 3.90 years to be amputated (95% CI = 3.58–4.23); those with a major lesion took 4.01 years (95% CI = 3.58–4.43) compared to those who had extensive wound that took 1.35 years (95% CI = 0.21– 2.48); the difference was statistically significant p < 0.001 (see **Figure 10**). Cox regression multivariate analysis identified previous major amputation, TASC D arterial lesions and extensive ulcer from WIfI (but no global WIfI) as

We must not forget that we are facing elderly and pluripathological patients. The median survival was 3.42 years (95% CI = 3.08–3.76). Patient's survival was 84% at 1 year, 66% at 3 years and 50% at 5 years. Five years after the diagnosis of CLTI, only half of the population survived regardless of whether the limb was saved

the difference was statistically significant p < 0.001 (see **Figure 7**).

independent risk factors for major amputation (see **Table 11**).

p = 0.009 (see **Figure 8**).

*Area under the ROC curve [26].*

*The Eye and Foot in Diabetes*

**Figure 6.**

CI = 3.27–4.18), p = 0.044 (see **Figure 9**).

*2.2.2 Survival function for survival*

or amputated (see **Figure 11**).

**122**

*Survival function for major amputation according to previous one [26].*


#### **Figure 8.**

*Survival function for TASC-II major amputation risk at 1 year comparing a, B and C versus D.*


In our study, 51% of patients were in the Kaiser Permanente pyramid highest risk zone. Patients who did not reach the top of the pyramid survive a median of 4.25 years (95% CI = 3.88–4.62), and those who accumulate more pathology survive

Yes, minor 0.987 0.987 0.197 4.934 Yes, major <0.001 20.720 6.013 71.406 TASC D (recoded) 0.003 27.952 3.000 260.452

*Chronic Limb-Threatening Ischemia (CLTI) in Diabetic Patients: Looking at the Big Picture…*

Small lesion 0.194 2.248 0.662 7.632 Major lesion 0.004 11.868 2.184 64.490

**HR 95% CI**

**p-value HR Inferior Superior**

The Cox regression multivariate analysis has shown that only the stratification of the pluripathological patient according to the Kaiser Permanente model is an independent risk factor for death. The most pluripathological patients are classified at the top of the pyramid (red color) and have a risk of dying 8.27 times higher (95%

a median of 3.30 years (95% CI = 2.90–3.70), p < 0.001 (see **Figure 12**).

No previous amputation (reference) <0.001

*DOI: http://dx.doi.org/10.5772/intechopen.91970*

WIfI extensive lesion (reference) 0.016

*Cox regression multivariate analysis for major amputation.*

*2.2.3 Survival function for wound healing time (WHT)*

CI = 5.723–9.587) which is equal to 230 days.

The median time for ulcer healing, in our study, was 7.65 months (95%

patients with a major one, 34.5 months (95% CI = 23.50–45.55), p = 0.006.

Previous history of amputation influences wound healing time. Thus, in patients with no past history of amputation, the median WHT was 13.4 months (95% CI = 9.65– 17.20); in those with a minor amputation, 15.7 months (95% CI = 10.34–21.20); and in

CI = 2.48–27.59).

**Figure 11.**

**125**

*Patient's survival function [26].*

**Table 11.**

#### **Figure 9.**

*Survival function for WIfI major amputation risk at 1 year stages 1, 2 and 3 compared with stage 4 [26].*


**Figure 10.**

*Survival function for major amputation according to wound from WIfI.*

*Chronic Limb-Threatening Ischemia (CLTI) in Diabetic Patients: Looking at the Big Picture… DOI: http://dx.doi.org/10.5772/intechopen.91970*


#### **Table 11.**

**Figure 9.**

*The Eye and Foot in Diabetes*

**Figure 10.**

**124**

*Survival function for major amputation according to wound from WIfI.*

*Survival function for WIfI major amputation risk at 1 year stages 1, 2 and 3 compared with stage 4 [26].*

*Cox regression multivariate analysis for major amputation.*

In our study, 51% of patients were in the Kaiser Permanente pyramid highest risk zone. Patients who did not reach the top of the pyramid survive a median of 4.25 years (95% CI = 3.88–4.62), and those who accumulate more pathology survive a median of 3.30 years (95% CI = 2.90–3.70), p < 0.001 (see **Figure 12**).

The Cox regression multivariate analysis has shown that only the stratification of the pluripathological patient according to the Kaiser Permanente model is an independent risk factor for death. The most pluripathological patients are classified at the top of the pyramid (red color) and have a risk of dying 8.27 times higher (95% CI = 2.48–27.59).


#### **Figure 11.**

*Patient's survival function [26].*

#### *2.2.3 Survival function for wound healing time (WHT)*

The median time for ulcer healing, in our study, was 7.65 months (95% CI = 5.723–9.587) which is equal to 230 days.

Previous history of amputation influences wound healing time. Thus, in patients with no past history of amputation, the median WHT was 13.4 months (95% CI = 9.65– 17.20); in those with a minor amputation, 15.7 months (95% CI = 10.34–21.20); and in patients with a major one, 34.5 months (95% CI = 23.50–45.55), p = 0.006.

**2.3 Discussion**

**2.4 Conclusions**

**Table 13.**

**Table 14.**

**127**

*Results of van Reijen meta-analysis [20].*

Reviewing the van Reijen meta-analysis which compares the best methodological 12 scientific papers published until June 2018 focused on the prognostic value of the WIfI classification in patients with CLTI, only one study included exclusively

*Chronic Limb-Threatening Ischemia (CLTI) in Diabetic Patients: Looking at the Big Picture…*

Regarding treatment, six studies included revascularized patients in different

The prognostic value of the WIfI classification was studied retrospectively (as in

The authors recognize that the likelihood of a major amputation after 1 year in patients with CLTI increases with higher clinical WIfI stages, especially in stage 4 in spite of diverging range of patients included (hospitalized/outpatients; requiring hemodialysis or not; invasively or conservative treatment; diabetics/non-diabetics; etc.). This could, partly, explain the statistical heterogeneity that they found. Although the concept of the WIfI classification is well designed, it only considers the status of the affected limb with neither additional information related to vascular anatomy involved nor patients' comorbidities [20] (see **Tables 13** and **14**).

In conclusion, in our study, we identified a previous amputation, TASC-II classification and wound from WIfI (but no global WIfI) as independent risk factors for major amputation and wound healing time. And, among other comorbidities, only

Age (years) 70 +/ 11 58 +/ 16 66 77 +/ 15 71 +/ 12 62.8 70 +/ 11 Males % 62 79 62 61 53 — 74 HbA1c % — — — — —— 7.9 DM % 66 93 76 0 77 72 100 Prevent III at high risk — — 17% 5.2 +/ 2.4 ——— Kaiser high risk level % — — — — —— 51 Hypertension % 93 86 85 — 84 84 82 CAD % 63 55 47 54 49 — 53 CKD % — 41 — 37.5 23 — 38 Dialysis % 14 20 23 15.5 18 — 6

*Population comparison from some studies included on van Reijen meta-analysis and our study.*

WIfI I 0 83 95 WIfI II 8 76 92 WIfI III 11 75 91 WIfI IV 38 55 61

**% Major amputation >1 year % AFS >1 year % Limb salvage >1 year**

**Cull Zhan Causey Beropoulis Darling Ward Vela**

ways, and the other six also included patients with conservative treatment.

our study) in all but one which implies a certain risk of information bias. Five studies performed a multivariate analysis for the WIfI classification on major amputation, but in four of them, clinical stage or reference was not reported.

patients with diabetes, whereas others excluded them.

*DOI: http://dx.doi.org/10.5772/intechopen.91970*


#### **Figure 12.**

*Survival function comparing low and median levels with high level at Kaiser Permanente pyramid [26].*

As the arterial lesions become more complex according to TASC-II and more extensive according to WIfI, wound healing time is longer, p = 0.005 and p < 0.001, respectively. There is more information about WHT in a previous paper published by our group in 2017 [27].

Patients who followed podiatric treatment take a median of 7.5 months in healing (95% CI = 6.14–9.03) and those who did not take a median of 12 months (95% CI = 2.18–22.00), p = 0.012. Unfortunately, this factor was only significative at Cox regression univariate analysis.

Cox regression multivariate analysis identified previous amputation, TASC-II classification and wound from WIfI (but no global WIfI) as independent risk factors for wound healing (see **Table 12**).


#### **Table 12.**

*Cox regression multivariate analysis for wound healing time [26].*

*Chronic Limb-Threatening Ischemia (CLTI) in Diabetic Patients: Looking at the Big Picture… DOI: http://dx.doi.org/10.5772/intechopen.91970*

#### **2.3 Discussion**

Reviewing the van Reijen meta-analysis which compares the best methodological 12 scientific papers published until June 2018 focused on the prognostic value of the WIfI classification in patients with CLTI, only one study included exclusively patients with diabetes, whereas others excluded them.

Regarding treatment, six studies included revascularized patients in different ways, and the other six also included patients with conservative treatment.

The prognostic value of the WIfI classification was studied retrospectively (as in our study) in all but one which implies a certain risk of information bias. Five studies performed a multivariate analysis for the WIfI classification on major amputation, but in four of them, clinical stage or reference was not reported.

The authors recognize that the likelihood of a major amputation after 1 year in patients with CLTI increases with higher clinical WIfI stages, especially in stage 4 in spite of diverging range of patients included (hospitalized/outpatients; requiring hemodialysis or not; invasively or conservative treatment; diabetics/non-diabetics; etc.). This could, partly, explain the statistical heterogeneity that they found. Although the concept of the WIfI classification is well designed, it only considers the status of the affected limb with neither additional information related to vascular anatomy involved nor patients' comorbidities [20] (see **Tables 13** and **14**).

#### **2.4 Conclusions**

As the arterial lesions become more complex according to TASC-II and more

*Survival function comparing low and median levels with high level at Kaiser Permanente pyramid [26].*

Patients who followed podiatric treatment take a median of 7.5 months in healing (95% CI = 6.14–9.03) and those who did not take a median of 12 months (95% CI = 2.18–22.00), p = 0.012. Unfortunately, this factor was only significative

Cox regression multivariate analysis identified previous amputation, TASC-II classification and wound from WIfI (but no global WIfI) as independent risk

TASC A 0.001 6.672 2.206 20.181 TASC B <0.001 5.517 2.208 13.783 TASC C 0.028 1.828 1.068 3.126

Small 0.025 9.959 1.336 74.252 Major 0.057 6.985 0.946 51.580

No amputation 0.010 13.696 1.868 100.391 Minor amputation 0.044 8.099 1.060 61.874

**HR 95% CI**

**p-value HR Inferior Superior**

extensive according to WIfI, wound healing time is longer, p = 0.005 and p < 0.001, respectively. There is more information about WHT in a previous

paper published by our group in 2017 [27].

at Cox regression univariate analysis.

factors for wound healing (see **Table 12**).

TASC D (reference) <0.001

Extensive lesion (reference) 0.040

Previous major amputation (reference) 0.008

*Cox regression multivariate analysis for wound healing time [26].*

**Table 12.**

**126**

**Figure 12.**

*The Eye and Foot in Diabetes*

In conclusion, in our study, we identified a previous amputation, TASC-II classification and wound from WIfI (but no global WIfI) as independent risk factors for major amputation and wound healing time. And, among other comorbidities, only


#### **Table 13.**

*Results of van Reijen meta-analysis [20].*


#### **Table 14.**

*Population comparison from some studies included on van Reijen meta-analysis and our study.*

the stratification of the pluripathological patient according to the Kaiser Permanente model was recognized as an independent risk factor for death.

Of course, our study has certain limitations: it is retrospective but is based on test and images included in our electronic database. The population is small, and we need to recode some items in order to increase statistical significance. Moreover, our patients are in-hospital, with CLTI and diabetes. But our goal was "the better definition of the population, the better accuracy of the results". Infection was no significant because it was controlled on antibiotics.

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*DOI: http://dx.doi.org/10.5772/intechopen.91970*

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[11] Edmonds M, Foster A. Reduction of major amputations in the diabetic ischaemic foot: A strategy to "take control" with conservative care as well as revascularization. VASA 2001;**58**

[12] Fitzgerald RH, Mills JL Joseph W and Armstrong DG. The diabetic rapid response acute foot team (DRRAFT): 7 essential skills for targeted limb salvage.

[13] Rogers LC, Andros G, Caporusso J, Harkless LB, Mills JL, Armstrong DG. Toe and flow: Essential components and structure of the amputation prevention team. Journal of Vascular Surgery. 2010;

[14] Chadwick P, Edmonds M, McCardle J, Armstrong D. International best practice guidelines: Wound Management

in Diabetic Foot Ulcers. Wounds International. 2013:1-24. Available from:

www.woundsinternational.com

[15] Monteiro-Soares M, Martins-Mendes D, Vaz-Carneiro A, Sampaio S

Medicine 1934;**211**:16-20

who had no invasive vascular intervention. European Journal of Vascular and Endovascular Surgery.

[2] PRF B, Charlesworth D, De Palma RG, HHG E, Eklöf B,

[3] Aboyans V, Ricco JB, MEL B, Bjorck M, Brodmann M, Cohnert T, et al. Editor's choice - 2017 ESC guidelines on the diagnosis and

treatment of peripheral arterial diseases, in collaboration with the European society for vascular surgery (ESVS). European Journal of Vascular and Endovascular Surgery. 2018;**55**:305e68

[4] World Health Organization. WHO Study group on Prevention of Diabetes Mellitus. WHO Technical Report Series; 844. Geneva: WHO; 1994. pp. 63-68

[5] Moulik PK, Mtonga R, Gill GV. Amputation and mortality in new onset

[6] Prompers L, Huijberts M, Apelqvist J, Jude E, Piagessi A, Bakker K et al. High prevalence of ischaemia, infection and serious comorbidity in patients with diabetic foot disease in Europe. Baseline results from the Eurodiale study. Diabetologia. 2007;**50**:18-25

[7] International Consensus on the Diabetic Foot 2015. Prevention and management of foot problems in Diabetes. Guidance documents and recommendations. The international working group on the diabetic foot (IWGDF)/Consultative section of the

diabetic foot ulcers stratified by etiology. Diabetes Care 2003;**26**(2):

491-494

**129**

Jamieson CV, et al. The definition of critical ischaemia of a limb. Working party of the international vascular symposium. The British Journal of Surgery. 1982;**69**(Suppl):S2

In line with other publications, our data support that the WIfI classification system correlates well with clinical outcomes regarding risk of amputation at one year and WHT. However, when adding TASC-II and, in our case, Kaiser Permanente pyramid assessment, the outcome is even more accurate not only for limb salvage but also for patients'survival.

Considering all this information, not only more prospective studies if not a new threedimensional score capable to predicting the outcome of an individual ulcer paying attention to the better characterization of the population involved should be implemented.

## **Acknowledgements**

First of all, we thank Tania Iglesias-Soria, podiatrist at Multidisciplinary Diabetic Foot Unit (Cruces University Hospital), and Lorea Martínez-Indart, statistical data manager from Biocruces Bizkaia Institute, for their constant support. Second, we also appreciate the Biocruces Bizkaia Institute and Merck Sharp & Dohme de España, S.A. for their technological and economical assistance.

## **Conflict of interest**

The authors declare no conflict of interest.

## **Author details**

Maria Pilar Vela-Orús<sup>1</sup> \* and María Sonia Gaztambide-Sáenz<sup>2</sup>

1 Biocruces Bizkaia, Bizkaia Health Research Institute, Vascular Surgeon Consultant, Multidisciplinary Diabetic Foot Unit at Cruces University Hospital, Osakidetza-SVS, Barakaldo-Vizcaya, Spain

2 Biocruces Bizkaia, UPV/EHU, CIBERDEM, CIBERER, Endo-ERN (Project Number 739527), Endocrinologist Consultant and Chief of Department, Multidisciplinary Diabetic Foot Unit at Cruces University Hospital, Osakidetza-SVS, Barakaldo-Vizcaya, Spain

\*Address all correspondence to: pilarvelaorus@movistar.es

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Chronic Limb-Threatening Ischemia (CLTI) in Diabetic Patients: Looking at the Big Picture… DOI: http://dx.doi.org/10.5772/intechopen.91970*

## **References**

the stratification of the pluripathological patient according to the Kaiser Permanente model was recognized as an independent risk factor for death.

year and WHT. However, when adding TASC-II and, in our case, Kaiser

España, S.A. for their technological and economical assistance.

The authors declare no conflict of interest.

Osakidetza-SVS, Barakaldo-Vizcaya, Spain

provided the original work is properly cited.

SVS, Barakaldo-Vizcaya, Spain

significant because it was controlled on antibiotics.

limb salvage but also for patients'survival.

**Acknowledgements**

*The Eye and Foot in Diabetes*

**Conflict of interest**

**Author details**

**128**

Maria Pilar Vela-Orús<sup>1</sup>

Of course, our study has certain limitations: it is retrospective but is based on test and images included in our electronic database. The population is small, and we need to recode some items in order to increase statistical significance. Moreover, our patients are in-hospital, with CLTI and diabetes. But our goal was "the better definition of the population, the better accuracy of the results". Infection was no

In line with other publications, our data support that the WIfI classification system correlates well with clinical outcomes regarding risk of amputation at one

Permanente pyramid assessment, the outcome is even more accurate not only for

Considering all this information, not only more prospective studies if not a new threedimensional score capable to predicting the outcome of an individual ulcer paying attention to the better characterization of the population involved should be implemented.

First of all, we thank Tania Iglesias-Soria, podiatrist at Multidisciplinary Diabetic Foot Unit (Cruces University Hospital), and Lorea Martínez-Indart, statistical data manager from Biocruces Bizkaia Institute, for their constant support. Second, we also appreciate the Biocruces Bizkaia Institute and Merck Sharp & Dohme de

\* and María Sonia Gaztambide-Sáenz<sup>2</sup>

1 Biocruces Bizkaia, Bizkaia Health Research Institute, Vascular Surgeon Consultant, Multidisciplinary Diabetic Foot Unit at Cruces University Hospital,

2 Biocruces Bizkaia, UPV/EHU, CIBERDEM, CIBERER, Endo-ERN (Project Number 739527), Endocrinologist Consultant and Chief of Department,

\*Address all correspondence to: pilarvelaorus@movistar.es

Multidisciplinary Diabetic Foot Unit at Cruces University Hospital, Osakidetza-

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

[1] Cavanagh P, Attinger C, Abbas Z, Bal A, Rojas N, Xu ZR. Cost of treating diabetic foot ulcers in five different countries. Diabetes/Metabolism Research and Reviews. 2012;**28** (Suppl. 1):107-111

[2] PRF B, Charlesworth D, De Palma RG, HHG E, Eklöf B, Jamieson CV, et al. The definition of critical ischaemia of a limb. Working party of the international vascular symposium. The British Journal of Surgery. 1982;**69**(Suppl):S2

[3] Aboyans V, Ricco JB, MEL B, Bjorck M, Brodmann M, Cohnert T, et al. Editor's choice - 2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European society for vascular surgery (ESVS). European Journal of Vascular and Endovascular Surgery. 2018;**55**:305e68

[4] World Health Organization. WHO Study group on Prevention of Diabetes Mellitus. WHO Technical Report Series; 844. Geneva: WHO; 1994. pp. 63-68

[5] Moulik PK, Mtonga R, Gill GV. Amputation and mortality in new onset diabetic foot ulcers stratified by etiology. Diabetes Care 2003;**26**(2): 491-494

[6] Prompers L, Huijberts M, Apelqvist J, Jude E, Piagessi A, Bakker K et al. High prevalence of ischaemia, infection and serious comorbidity in patients with diabetic foot disease in Europe. Baseline results from the Eurodiale study. Diabetologia. 2007;**50**:18-25

[7] International Consensus on the Diabetic Foot 2015. Prevention and management of foot problems in Diabetes. Guidance documents and recommendations. The international working group on the diabetic foot (IWGDF)/Consultative section of the International Diabetes Federation (IDF) 2007. Actualized in 2011 & 2015

[8] Apelqvist J, Elgzyri T, Larsson J, Löndahl M, Nyberg P, Thöme J. Factors related to outcome of neuroischaemic/ ischaemic foot ulcer in diabetic patients. Journal of Vascular Surgery. 2011;**53**(6): 1582-1588.e2

[9] Elgzyri T, Larsson J, Thörne J, Eriksson KF, Apelqvist J. Outcome of ischaemic foot ulcer in diabetic patients who had no invasive vascular intervention. European Journal of Vascular and Endovascular Surgery. 2013;**46**:110-117

[10] Joslin EP. Menace of diabetic gangrene. The New England Journal of Medicine 1934;**211**:16-20

[11] Edmonds M, Foster A. Reduction of major amputations in the diabetic ischaemic foot: A strategy to "take control" with conservative care as well as revascularization. VASA 2001;**58** (Suppl):6-14

[12] Fitzgerald RH, Mills JL Joseph W and Armstrong DG. The diabetic rapid response acute foot team (DRRAFT): 7 essential skills for targeted limb salvage. Eplasty. 2009;**9**:e15

[13] Rogers LC, Andros G, Caporusso J, Harkless LB, Mills JL, Armstrong DG. Toe and flow: Essential components and structure of the amputation prevention team. Journal of Vascular Surgery. 2010; **52**:23S-27S

[14] Chadwick P, Edmonds M, McCardle J, Armstrong D. International best practice guidelines: Wound Management in Diabetic Foot Ulcers. Wounds International. 2013:1-24. Available from: www.woundsinternational.com

[15] Monteiro-Soares M, Martins-Mendes D, Vaz-Carneiro A, Sampaio S and Dinis-Ribeiro M. Classification systems for lower extremity amputation prediction in subjects with active diabetic foot ulcer: A systematic review and meta-analysis. Diabetes/Metabolism Research and Reviews. 2014;**30**(7): 610-622

[16] Monteiro-Soares M, Russell D, Boyko EJ, Jeffcoate W, Mills JL, Morbach S et al on behalf of the International Working Group on Diabetic Foot (IWGDF). IWGDF Guideline on the Classification of Diabetic Foot Ulcers. Part of the 2019 IWGDF Guidelines on the Preventionand Management of Diabetic Foot Disease. Diabetes/Metabolism Research and Reviews. 2020;**36**(S1): e3273

[17] Ince P, Zulfiqarali GA, Lutale JK, Basit A, Ali SM, Farooq Ch et al. Use of the SINBAD classification system and score in comparing outcome of foot ulcer management on three continents. Diabetes Care. 2008;**31**:964-967

[18] Lipsky B, Berendt A, Cornia PB. Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. IDSA guidelines. Clinical Infectious Diseases. 2012;**54**(12): 132-173

[19] Mills JL, Conte MS, Armstrong DG, Pomposelli FB, Schanzer A, Sidawy AN et al. The Society for Vascular Surgery Lower Extremity Threatened Limb Classification System: Risk stratification based on wound, ischaemia and foot infection (WIfI). Journal of Vascular Surgery. 2014;**59**:220.e2-234.e2

[20] Van Reijen NS, Ponchant K, Ubbink DT and Koelemay MJW. Editor's choice: The prognostic value of the WIfI classification in patients with chronic limb threatening Ischaemia: A systematic review and meta-analysis. European Journal of Vascular and Endovascular Surgery. 2019;**58**:362-371

[21] Jaff MR, White ChJ, Hiatt WR, Fowkes GR, Dormandy J, Razavi M et al. An update on methods for revascularization and expansion of the TASC lesion classification to include below-the-knee arteries: A supplement to the inter-society consensus for the management of peripheral arterial disease (TASC II) Journal of Endovascular Therapy. 2015;**22**:663-667

Universidad del Pais Vasco EHU/UPV;

*DOI: http://dx.doi.org/10.5772/intechopen.91970*

*Chronic Limb-Threatening Ischemia (CLTI) in Diabetic Patients: Looking at the Big Picture…*

[27] Vela-Orús MP, Iglesias-Soria T, Martínez-Indart L, Arana-Arri E and Gaztambide-Sáenz S. Evaluation of the WIfI classification system in older patients with diabetes. Wounds International. 2017;**8**(4):23-27

2016

**131**

[22] Hae Won J, Young-Guk K, Sung-Jin H, Chul-Min A, Jung-Sun K, Byeong-Keuk K et al. Editor's choice-impact of endovascular pedal artery revascularization on wound healing in patients with critical limb ischaemia. European Journal of Vascular and Endovascular Surgery. 2019;**58**: 854-863

[23] Feachem RGA, Sekhri NK, White KL. Getting more for their dollar: A comparison of the NHS with California's Kaiser Permanente. BMJ Clinical Research. 2003;**324**(7330):135-141

[24] Schanzer A, Goodney PP, Li Y, Eslami M, Cronenwett J, Messina L et al. Validation of the PIII CLI score for the prediction of amputation-free survival in patients undergoing infrainguinal autogenous vein bypass for critical limb ischaemia. Journal of Vascular Surgery. 2009;**50**(4):769-775

[25] Arvela E, Söderström M, Korhonen M, Halmesmäki K, Albäck A, Lepäntalo M et al. Finnvasc score and modified prevent III score predict longterm outcome after infrainguinal surgical and endovascular revascularization for critical limb ischaemia. Journal of Vascular Surgery. November 2010;**52**(5):1218-1225

[26] Vela-Orús MP [Directed by Gaztambide-Sáenz MS]. Isquemia crítica en pacientes con diabetes. ¿Es válida la nueva clasificación WIfI? [Doctoral Thesis]. Bilbao-Vizcaya. Spain: Euskal Herriko Unibertsitatea/ *Chronic Limb-Threatening Ischemia (CLTI) in Diabetic Patients: Looking at the Big Picture… DOI: http://dx.doi.org/10.5772/intechopen.91970*

Universidad del Pais Vasco EHU/UPV; 2016

and Dinis-Ribeiro M. Classification systems for lower extremity amputation prediction in subjects with active diabetic foot ulcer: A systematic review and meta-analysis. Diabetes/Metabolism Research and Reviews. 2014;**30**(7):

*The Eye and Foot in Diabetes*

[21] Jaff MR, White ChJ, Hiatt WR, Fowkes GR, Dormandy J, Razavi M et al.

revascularization and expansion of the TASC lesion classification to include below-the-knee arteries: A supplement to the inter-society consensus for the management of peripheral arterial disease (TASC II) Journal of

Endovascular Therapy. 2015;**22**:663-667

[22] Hae Won J, Young-Guk K, Sung-Jin H, Chul-Min A, Jung-Sun K, Byeong-Keuk K et al. Editor's choice-impact of

revascularization on wound healing in patients with critical limb ischaemia. European Journal of Vascular and Endovascular Surgery. 2019;**58**:

[23] Feachem RGA, Sekhri NK, White KL. Getting more for their dollar: A comparison of the NHS with California's

Kaiser Permanente. BMJ Clinical Research. 2003;**324**(7330):135-141

[24] Schanzer A, Goodney PP, Li Y, Eslami M, Cronenwett J, Messina L et al. Validation of the PIII CLI score for the prediction of amputation-free survival in patients undergoing infrainguinal autogenous vein bypass for critical limb ischaemia. Journal of Vascular Surgery.

2009;**50**(4):769-775

[25] Arvela E, Söderström M,

revascularization for critical limb ischaemia. Journal of Vascular Surgery. November 2010;**52**(5):1218-1225

[26] Vela-Orús MP [Directed by Gaztambide-Sáenz MS]. Isquemia crítica en pacientes con diabetes. ¿Es válida la nueva clasificación WIfI? [Doctoral Thesis]. Bilbao-Vizcaya. Spain: Euskal Herriko Unibertsitatea/

Korhonen M, Halmesmäki K, Albäck A, Lepäntalo M et al. Finnvasc score and modified prevent III score predict longterm outcome after infrainguinal surgical and endovascular

An update on methods for

endovascular pedal artery

854-863

[16] Monteiro-Soares M, Russell D, Boyko EJ, Jeffcoate W, Mills JL, Morbach S et al on behalf of the International Working Group on Diabetic Foot (IWGDF). IWGDF Guideline on the Classification of Diabetic Foot Ulcers. Part of the 2019

Preventionand Management of Diabetic Foot Disease. Diabetes/Metabolism Research and Reviews. 2020;**36**(S1):

[17] Ince P, Zulfiqarali GA, Lutale JK, Basit A, Ali SM, Farooq Ch et al. Use of the SINBAD classification system and score in comparing outcome of foot ulcer management on three continents.

Diabetes Care. 2008;**31**:964-967

[18] Lipsky B, Berendt A, Cornia PB. Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. IDSA guidelines. Clinical Infectious Diseases. 2012;**54**(12):

[19] Mills JL, Conte MS, Armstrong DG, Pomposelli FB, Schanzer A, Sidawy AN et al. The Society for Vascular Surgery Lower Extremity Threatened Limb Classification System: Risk stratification based on wound, ischaemia and foot infection (WIfI). Journal of Vascular Surgery. 2014;**59**:220.e2-234.e2

[20] Van Reijen NS, Ponchant K, Ubbink DT and Koelemay MJW. Editor's choice: The prognostic value of the WIfI classification in patients with chronic limb threatening Ischaemia: A systematic review and meta-analysis. European Journal of Vascular and Endovascular Surgery. 2019;**58**:362-371

IWGDF Guidelines on the

610-622

e3273

132-173

**130**

[27] Vela-Orús MP, Iglesias-Soria T, Martínez-Indart L, Arana-Arri E and Gaztambide-Sáenz S. Evaluation of the WIfI classification system in older patients with diabetes. Wounds International. 2017;**8**(4):23-27

**133**

**Chapter 9**

**Abstract**

revascularization

**1. Introduction**

large vessel atherosclerosis.

the diabetes, and control of diabetes.

Diabetic Foot Ulcer: An Easy and

Foot problems are commonly involved in diabetes, and the most common presentation of diabetes is an ulcer. Diabetic foot ulcer is a complex problem caused by reduced blood supply, nerve damage, or infection. But unfortunately in most of cases, these three factors have played a role for impairment of diabetic feet. Sometimes nerve damage or neuropathy is an initial insult, and multiple times ischemia is the leading factor for ulcer formation. After certain period, infection finally supervenes and makes a sterile ulcer to infected leads to loss of limb or foot. This becomes more complicated because of less pronounced ischemic symptoms in diabetic than non-diabetics. Furthermore, the healing of a neuroischemic ulcer is slowed down by microvascular dysfunction. Therefore, some ulcers can get better by revascularization, but pure ischemic ulcers rarely respond to revascularization. Many guidelines have largely ignored these specific demands related to ulcerated neuroischemic diabetic feet. Any diabetic foot ulcer should always be considered to have vascular impairment unless otherwise proven. This chapter highlights the best way to diagnose and treat these patients with diabetic foot ulcer. Most of the studies dealing with neuroischemic diabetic feet are not comparable in terms of patient populations, interventions, or outcomes. Therefore, there is an urgent need for a paradigm shift in diabetic foot care, that is, a new approach and classification of

diabetics with foot ulcer in regard to clinical practice and research.

**Keywords:** diabetic, ulcer, Hyderabad, diabetic foot, diabetic foot ulcer,

Diabetic foot ulcer is a late and disfiguring complication, which leads to higher risk of amputation of any part of the foot or leg. Therefore diabetic foot disease has major medical, economic, and social consequences. It is very important to treat it with proper protocol to save patients from fatal and disabling complications.

The complexity is to understand the main insult which can be diabetic peripheral arterial disease, neuropathy, or infection. The healing process is also halted due to impaired collagen synthesis. Vascular disease varies from arteritis, occlusion, and

The diabetic foot ulcer is a cave of infection, severe vessel ischemia, and multiple painless traumas. Factors that exacerbate the problem are advanced age, duration of

Comprehensive Approach

*Imran Ali Shaikh, Naila Masood Sddiqui* 

*and Javeria Hameed Shaikh*

## **Chapter 9**

## Diabetic Foot Ulcer: An Easy and Comprehensive Approach

*Imran Ali Shaikh, Naila Masood Sddiqui and Javeria Hameed Shaikh*

## **Abstract**

Foot problems are commonly involved in diabetes, and the most common presentation of diabetes is an ulcer. Diabetic foot ulcer is a complex problem caused by reduced blood supply, nerve damage, or infection. But unfortunately in most of cases, these three factors have played a role for impairment of diabetic feet. Sometimes nerve damage or neuropathy is an initial insult, and multiple times ischemia is the leading factor for ulcer formation. After certain period, infection finally supervenes and makes a sterile ulcer to infected leads to loss of limb or foot. This becomes more complicated because of less pronounced ischemic symptoms in diabetic than non-diabetics. Furthermore, the healing of a neuroischemic ulcer is slowed down by microvascular dysfunction. Therefore, some ulcers can get better by revascularization, but pure ischemic ulcers rarely respond to revascularization. Many guidelines have largely ignored these specific demands related to ulcerated neuroischemic diabetic feet. Any diabetic foot ulcer should always be considered to have vascular impairment unless otherwise proven. This chapter highlights the best way to diagnose and treat these patients with diabetic foot ulcer. Most of the studies dealing with neuroischemic diabetic feet are not comparable in terms of patient populations, interventions, or outcomes. Therefore, there is an urgent need for a paradigm shift in diabetic foot care, that is, a new approach and classification of diabetics with foot ulcer in regard to clinical practice and research.

**Keywords:** diabetic, ulcer, Hyderabad, diabetic foot, diabetic foot ulcer, revascularization

### **1. Introduction**

Diabetic foot ulcer is a late and disfiguring complication, which leads to higher risk of amputation of any part of the foot or leg. Therefore diabetic foot disease has major medical, economic, and social consequences. It is very important to treat it with proper protocol to save patients from fatal and disabling complications.

The complexity is to understand the main insult which can be diabetic peripheral arterial disease, neuropathy, or infection. The healing process is also halted due to impaired collagen synthesis. Vascular disease varies from arteritis, occlusion, and large vessel atherosclerosis.

The diabetic foot ulcer is a cave of infection, severe vessel ischemia, and multiple painless traumas. Factors that exacerbate the problem are advanced age, duration of the diabetes, and control of diabetes.

#### *The Eye and Foot in Diabetes*

Diabetic foot ulcers are classified in many ways, but many systems of classification are complex to interpret. Hence, particular attention to feet care should be a central focus in educating and managing patients with diabetes to ensure that ulcer is either prevented or noticed early enough.

## **2. Classification and epidemiology of diabetes and foot ulcer**

Persistent elevation of blood sugar is associated with major metabolic abnormalities in diabetic patients and damages to various organs and systems, leading to life-threatening complications, which can be overt like major cardiovascular events and cerebrovascular accidents or covert such as retinopathy or nephropathy.

Diabetes mellitus is broadly classified into four types by etiology and clinical presentation, type 1 diabetes, type 2 diabetes, gestational diabetes (GDM), and other less common types of diabetes, which include monogenic diabetes and secondary diabetes.

1.Type 1 diabetes, which involves autoimmune beta-cell destruction, leads to absolute insulin deficiency.

In the past decade, there was a 21% increase in the number of type 1 diabetes in the USA [1], and the prevalence is increasing at a rate of 3% per year globally [2]. Another study reported that the annual increase was 2% in type 1 diabetes and 5% for type 2 diabetes [3].

There is no gender variation in type 1 diabetes [4], and type 1 diabetes reduce life expectancy by 13 years as per data reported [5]. Approximately 15% of adults to diagnosed with type 2 diabetes have actually latent autoimmune diabetes of adults, which are a variant of type 1 diabetes [6].

	- maturity-onset diabetes of the young [MODY] or neonatal diabetes;
	- diseases of the pancreas, for example, cystic fibrosis and chronic pancreatitis; and
	- drug- or chemical-induced diabetes.

Nearly 463 million adults (20–79 years of age) are living with diabetes; by 2045, this will rise to 700 million. The proportion of people with type 2 diabetes is increasing in most countries, and 79% of adults with diabetes are living in lowand middle-income countries. The greatest number of people with diabetes is between 40 and 59 years of age.

In past year, subcontinents were affected enormously. It was estimated that nearly 20 million adults in Pakistan were diabetics, putting them at risk for major or minor complications, and approximately 8 million are still undiagnosed [7].

There are many contributing risk factors for type 2 diabetes: poor socioeconomic status, reduced literacy in 41%, low occupation in 31%, and less income in 40% [8].

**135**

bacterial entry.

*Diabetic Foot Ulcer: An Easy and Comprehensive Approach*

More than 15% of diabetic people during their lives experience foot ulcers [6]. These ulcers account for more than 80% of nontraumatic lower limb amputations [9]. The burden of foot ulcer in diabetes varies from 3% in Oceania to 13% in

The annual incidence of diabetic foot ulcer or necrosis in diabetic patients is

**Males** are affected more than females, and it is more common in **the elderly** above 60 years of age. Several studies have reported **racial predisposition**. One author has evaluated that the increased risk of amputation in African blacks was

The diabetic foot ulcer is seen in **lower socioeconomic** class (78.2%) [13].

It has been observed that 47% of patients who had previous ulceration **walked barefooted** within the house and 17% walked barefooted outside [14]. **Neuropathy** was involved in more than half of diabetic foot ulcers [15], while **peripheral vascular disease** accounts for about 15% alone and 35% in conjunction with neuropathy. The **unequilibrated distribution of pressure** in the foot during walking exposes pressure bearing points to ulceration [16]. The **previous foot ulcers** have tendency

**Previous amputation** is undoubtedly a big risk factor in 50% of the diabetic foot ulcers. **Inappropriate footwears** produce foot ulcer frequently in diabetes. **Poor vision** contributes due to diabetic retinopathy with the patient unable to properly identify injurious objects. **Minor or major trauma to foot** could be an origin of

It is a worst combination of neuropathy and ischemia. It becomes more complicated by infection. This process leads to impaired wound healing, decreased cell growth factor response, reduced tissue perfusion, and decreased local angiogenesis. The precise pattern of diabetic neuropathy is not yet completely understood. More evidence has identified the polyol pathway as a major factor in diabetic neuropathy, which leads to oxidative injury. It becomes more complicated when combined with osmotic cell-induced nerve damage, which triggers nerve cell edema.

Multiple neuropathies are involved in diabetic foot ulcer, which cause impaired pain sensation and impaired temperature sensation. Sensory diabetic neuropathy increases incidence of ulcer at foot approximately sevenfold, compared to diabetic

Finally ulcer appeared which may become chronic and combined to atrophy of foot muscles, flexion extension imbalance and also impaired equilibrium. Progressively, repeated pressure at focal points within the foot leads to ulceration. Furthermore, there is reduced sweating and dryness of the skin predisposing to cracks, which become potential sites for frequent ulceration and portals for

Peripheral arterial disease is a macrovascular complication and an essential contributor to diabetic foot. The endothelial dysregulation that occurs in diabetes

**Smoking** aggravates macrovascular complications including peripheral

North America, Canada (14.8%), Asia 5.5%, and Europe 5.1% [10].

known to be about 2–5%, and the lifetime risk ranges from 15 to 20% [11].

*DOI: http://dx.doi.org/10.5772/intechopen.92585*

**3. Risk factors for diabetic foot ulcer**

2- to 3-fold higher than that in whites [12].

to develop recurrent diabetic foot ulcers.

**4. Pathogenesis of diabetic foot ulcer**

patients without sensory neuropathy [18].

More than half of foot ulcers were caused by neuropathy [17].

a chronic ulcer or wound.

arterial disease.

*The Eye and Foot in Diabetes*

secondary diabetes.

absolute insulin deficiency.

and 5% for type 2 diabetes [3].

third trimester of pregnancy).

pancreatitis; and

between 40 and 59 years of age.

4.Specific types of diabetes due to other causes:

• drug- or chemical-induced diabetes.

is either prevented or noticed early enough.

Diabetic foot ulcers are classified in many ways, but many systems of classification are complex to interpret. Hence, particular attention to feet care should be a central focus in educating and managing patients with diabetes to ensure that ulcer

Persistent elevation of blood sugar is associated with major metabolic abnormalities in diabetic patients and damages to various organs and systems, leading to life-threatening complications, which can be overt like major cardiovascular events

1.Type 1 diabetes, which involves autoimmune beta-cell destruction, leads to

In the past decade, there was a 21% increase in the number of type 1 diabetes in the USA [1], and the prevalence is increasing at a rate of 3% per year globally [2]. Another study reported that the annual increase was 2% in type 1 diabetes

There is no gender variation in type 1 diabetes [4], and type 1 diabetes reduce life expectancy by 13 years as per data reported [5]. Approximately 15% of adults to diagnosed with type 2 diabetes have actually latent autoimmune dia-

2.Type 2 diabetes (steady loss of beta-cell insulin secretion or insulin resistance).

3.Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or

• maturity-onset diabetes of the young [MODY] or neonatal diabetes;

Nearly 463 million adults (20–79 years of age) are living with diabetes; by 2045, this will rise to 700 million. The proportion of people with type 2 diabetes is increasing in most countries, and 79% of adults with diabetes are living in lowand middle-income countries. The greatest number of people with diabetes is

In past year, subcontinents were affected enormously. It was estimated that nearly 20 million adults in Pakistan were diabetics, putting them at risk for major or

minor complications, and approximately 8 million are still undiagnosed [7]. There are many contributing risk factors for type 2 diabetes: poor socioeconomic status, reduced literacy in 41%, low occupation in 31%, and less income in

• diseases of the pancreas, for example, cystic fibrosis and chronic

betes of adults, which are a variant of type 1 diabetes [6].

and cerebrovascular accidents or covert such as retinopathy or nephropathy. Diabetes mellitus is broadly classified into four types by etiology and clinical presentation, type 1 diabetes, type 2 diabetes, gestational diabetes (GDM), and other less common types of diabetes, which include monogenic diabetes and

**2. Classification and epidemiology of diabetes and foot ulcer**

**134**

40% [8].

More than 15% of diabetic people during their lives experience foot ulcers [6]. These ulcers account for more than 80% of nontraumatic lower limb amputations [9]. The burden of foot ulcer in diabetes varies from 3% in Oceania to 13% in North America, Canada (14.8%), Asia 5.5%, and Europe 5.1% [10].

The annual incidence of diabetic foot ulcer or necrosis in diabetic patients is known to be about 2–5%, and the lifetime risk ranges from 15 to 20% [11].

## **3. Risk factors for diabetic foot ulcer**

**Males** are affected more than females, and it is more common in **the elderly** above 60 years of age. Several studies have reported **racial predisposition**. One author has evaluated that the increased risk of amputation in African blacks was 2- to 3-fold higher than that in whites [12].

The diabetic foot ulcer is seen in **lower socioeconomic** class (78.2%) [13]. **Smoking** aggravates macrovascular complications including peripheral arterial disease.

It has been observed that 47% of patients who had previous ulceration **walked barefooted** within the house and 17% walked barefooted outside [14]. **Neuropathy** was involved in more than half of diabetic foot ulcers [15], while **peripheral vascular disease** accounts for about 15% alone and 35% in conjunction with neuropathy. The **unequilibrated distribution of pressure** in the foot during walking exposes pressure bearing points to ulceration [16]. The **previous foot ulcers** have tendency to develop recurrent diabetic foot ulcers.

**Previous amputation** is undoubtedly a big risk factor in 50% of the diabetic foot ulcers. **Inappropriate footwears** produce foot ulcer frequently in diabetes. **Poor vision** contributes due to diabetic retinopathy with the patient unable to properly identify injurious objects. **Minor or major trauma to foot** could be an origin of a chronic ulcer or wound.

## **4. Pathogenesis of diabetic foot ulcer**

It is a worst combination of neuropathy and ischemia. It becomes more complicated by infection. This process leads to impaired wound healing, decreased cell growth factor response, reduced tissue perfusion, and decreased local angiogenesis.

The precise pattern of diabetic neuropathy is not yet completely understood. More evidence has identified the polyol pathway as a major factor in diabetic neuropathy, which leads to oxidative injury. It becomes more complicated when combined with osmotic cell-induced nerve damage, which triggers nerve cell edema. More than half of foot ulcers were caused by neuropathy [17].

Multiple neuropathies are involved in diabetic foot ulcer, which cause impaired pain sensation and impaired temperature sensation. Sensory diabetic neuropathy increases incidence of ulcer at foot approximately sevenfold, compared to diabetic patients without sensory neuropathy [18].

Finally ulcer appeared which may become chronic and combined to atrophy of foot muscles, flexion extension imbalance and also impaired equilibrium. Progressively, repeated pressure at focal points within the foot leads to ulceration. Furthermore, there is reduced sweating and dryness of the skin predisposing to cracks, which become potential sites for frequent ulceration and portals for bacterial entry.

Peripheral arterial disease is a macrovascular complication and an essential contributor to diabetic foot. The endothelial dysregulation that occurs in diabetes leads to reduced production of nitrous oxide (NO), which is a dependable vasodilator and regulates smooth muscle proliferation and leucocyte adhesion, resulting in atherosclerosis and vascular narrowing and ischemia.

The limb or foot ischemia can happen even in the presence of palpable pedal pulses [19].

Also, hyperglycemia promotes increased levels of fibrinogen and plasminogen activator inhibitor which impairs fibrinolysis [20]. These and other abnormalities promote platelet adhesion and thrombosis. In addition, the formation of advanced glycation end products which are compounds formed by the nonenzymatic reaction between sugars and proteins leads to cross linking of molecules in the extracellular matrix of the basement membrane. This alters the structure of the vessels and promotes stiffness [21]. There is also an increased expression of growth factors and adhesion molecules, e.g., intracellular adhesion molecule 1 and vascular endothelial growth factor [22]. Dyslipidemia also contributes to atherosclerosis. In fact, a 1% increase in HbA1C is related to 25–28% of relative risk of peripheral arterial disease [23–26].

Wound healing is defective in diabetes partly due to deficient angiogenesis. It has been noticed that abnormal excessive and inadequate angiogenesis occurs with diabetic complications, delayed closure time, and impaired tissue remodeling [27]. The inadequate mobilization of bone marrow-derived endothelial progenitor cells (EPCs) to the site of injury is another possible mechanism of impaired healing. These cells respond to ischemia and populate the injury site where they form new vessels [28].

About 60% of diabetic foot ulcers have been infected which could be superficial, deep, or more complex such as osteomyelitis [29]. Although typical signs and symptoms could be absent, severe infection could present with systemic symptoms, e.g., fever, chills, and tachycardia. The Infectious Diseases Society of America (IDSA) criteria for severe diabetic foot infection are temperature of >100°F, tachycardia, tachypnea or respiratory alkalosis, leukocytosis, or leucopenia [30]. The commonly isolated organisms are *Staphylococcus aureus*, *S. epidermidis*, and *Streptococcus* species. Methicillin-resistant *S. aureus* (MRSA) complicates 32% of infections, and it is associated with treatment failure. Among anaerobes, *Peptostreptococcus magnus* and *Bacteroides fragilis* have been isolated. The majority of cases are polymicrobial. *S. aureus*, Group B *Streptococcus*, and gram-negative *Bacilli* are associated with limbthreatening infections [31].

## **5. Classification of diabetic foot ulcer**

**Wagner classification system**: This system focused on physical characteristics of ulcer, depth, and the presence of osteomyelitis or gangrene (0–5) [32].

**SINBAD** ƒ assesses site, ischemia, neuropathy, bacterial infection, and depth and uses a scoring system 0–6. It has been focused on clinical and gross pathological changes of ulcer.

**PEDIS classification**: This system was designed by the International Working Group on the Diabetic Foot and uses the same five components of S(AD) SAD: perfusion, extent, depth, infection, and sensation. It does not include ulcer location [33].

**DEPA classification**: This system looks at four aspects of ulcers: depth, extent of bacterial colonization, phase of healing, and associated etiology. Each category is scored from 1 to 3 according to severity.

**University of Texas** ƒ has been proven effective at predicting lower extremity amputation when combined with Wagner classification, and it comprises four grades, A to D, and four stages, 1–4 [34].

**137**

*Diabetic Foot Ulcer: An Easy and Comprehensive Approach*

for selecting population for prospective research [36].

determines severity, with the score ranging from 0 to 4.

surrounded by callus

the foot, such as metatarsal heads, the heel, and over the dorsum of clawed toes

Prevalence 35% 15% 50%

**Diabetic Ulcer Severity Score (DUSS)**

**6. Approach to diabetic foot ulcer**

Wound bed Pink and granulating,

Typical location Weight-bearing areas of

Loss of plantar sensation

**7. Assessment of risk**

Foot temperature and pulses

**8. Investigations**

• CRP and ESR

• Renal function tests

• CBC

**Risk category 0 [37]**

Norma plantar sensation

**Kobe's Classification** focused on neuropathy, infection and vasculopathy: Type 1, mainly peripheral neuropathy (PN); type 2, mainly peripheral arterial disease (PAD); type 3, mainly infection; and type 4: all three combined, neuropathy, peripheral arte-

**SAD** stands for sepsis, arteriopathy, and denervation system. The major drawback of this classification is that it is potentially complex and is primarily intended

The Diabetic Ulcer Severity Score (DUSS) is based on the categorization of wounds into specific severity subgroups for a comparison of outcomes. Assessment using the DUSS system includes the presence of pedal pulses, the ability to probe to the bone within the ulcer, and ulcer quantity and location. The sum of points

**Feature Neuropathic Ischemic Neuroischemic** Sensation Sensory loss Pain Degree of sensory loss Callus/necrosis Callus present Necrosis common Minimal callus; prone

Warm with bounding Cool with absent

Other Dry skin and fissuring Delayed healing Risk of infection

Pale and sloughy with poor granulation

Nail edges and between the toes and lateral borders of the foot

pulses

**Risk category 1 Risk category 2 Risk category 3**

Loss of plantar sensation or poor circulation or foot deformity or

onychomycosis

Low risk Moderate risk High risk Very high risk

to necrosis

Poor granulation

Cool with absent pulses

Margins of the foot

History of ulceration, neuropathic fracture, or

amputation

and toes

*DOI: http://dx.doi.org/10.5772/intechopen.92585*

rial disease with infection [35].

*Diabetic Foot Ulcer: An Easy and Comprehensive Approach DOI: http://dx.doi.org/10.5772/intechopen.92585*

*The Eye and Foot in Diabetes*

arterial disease [23–26].

new vessels [28].

threatening infections [31].

changes of ulcer.

**5. Classification of diabetic foot ulcer**

scored from 1 to 3 according to severity.

grades, A to D, and four stages, 1–4 [34].

pulses [19].

leads to reduced production of nitrous oxide (NO), which is a dependable vasodilator and regulates smooth muscle proliferation and leucocyte adhesion, resulting in

The limb or foot ischemia can happen even in the presence of palpable pedal

Also, hyperglycemia promotes increased levels of fibrinogen and plasminogen activator inhibitor which impairs fibrinolysis [20]. These and other abnormalities promote platelet adhesion and thrombosis. In addition, the formation of advanced glycation end products which are compounds formed by the nonenzymatic reaction between sugars and proteins leads to cross linking of molecules in the extracellular matrix of the basement membrane. This alters the structure of the vessels and promotes stiffness [21]. There is also an increased expression of growth factors and adhesion molecules, e.g., intracellular adhesion molecule 1 and vascular endothelial growth factor [22]. Dyslipidemia also contributes to atherosclerosis. In fact, a 1% increase in HbA1C is related to 25–28% of relative risk of peripheral

Wound healing is defective in diabetes partly due to deficient angiogenesis. It has been noticed that abnormal excessive and inadequate angiogenesis occurs with diabetic complications, delayed closure time, and impaired tissue remodeling [27]. The inadequate mobilization of bone marrow-derived endothelial progenitor cells (EPCs) to the site of injury is another possible mechanism of impaired healing. These cells respond to ischemia and populate the injury site where they form

About 60% of diabetic foot ulcers have been infected which could be superficial, deep, or more complex such as osteomyelitis [29]. Although typical signs and symptoms could be absent, severe infection could present with systemic symptoms, e.g., fever, chills, and tachycardia. The Infectious Diseases Society of America (IDSA) criteria for severe diabetic foot infection are temperature of >100°F, tachycardia, tachypnea or respiratory alkalosis, leukocytosis, or leucopenia [30]. The commonly isolated organisms are *Staphylococcus aureus*, *S. epidermidis*, and *Streptococcus* species. Methicillin-resistant *S. aureus* (MRSA) complicates 32% of infections, and it is associated with treatment failure. Among anaerobes, *Peptostreptococcus magnus* and *Bacteroides fragilis* have been isolated. The majority of cases are polymicrobial. *S. aureus*, Group B *Streptococcus*, and gram-negative *Bacilli* are associated with limb-

**Wagner classification system**: This system focused on physical characteristics

**SINBAD** ƒ assesses site, ischemia, neuropathy, bacterial infection, and depth and uses a scoring system 0–6. It has been focused on clinical and gross pathological

**PEDIS classification**: This system was designed by the International Working Group on the Diabetic Foot and uses the same five components of S(AD) SAD: perfusion, extent, depth, infection, and sensation. It does not include ulcer location [33]. **DEPA classification**: This system looks at four aspects of ulcers: depth, extent of bacterial colonization, phase of healing, and associated etiology. Each category is

**University of Texas** ƒ has been proven effective at predicting lower extremity amputation when combined with Wagner classification, and it comprises four

of ulcer, depth, and the presence of osteomyelitis or gangrene (0–5) [32].

atherosclerosis and vascular narrowing and ischemia.

**136**

**Kobe's Classification** focused on neuropathy, infection and vasculopathy: Type 1, mainly peripheral neuropathy (PN); type 2, mainly peripheral arterial disease (PAD); type 3, mainly infection; and type 4: all three combined, neuropathy, peripheral arterial disease with infection [35].

**SAD** stands for sepsis, arteriopathy, and denervation system. The major drawback of this classification is that it is potentially complex and is primarily intended for selecting population for prospective research [36].

## **Diabetic Ulcer Severity Score (DUSS)**

The Diabetic Ulcer Severity Score (DUSS) is based on the categorization of wounds into specific severity subgroups for a comparison of outcomes. Assessment using the DUSS system includes the presence of pedal pulses, the ability to probe to the bone within the ulcer, and ulcer quantity and location. The sum of points determines severity, with the score ranging from 0 to 4.


## **6. Approach to diabetic foot ulcer**

## **7. Assessment of risk**


## **8. Investigations**


Ankle brachial index: in normal subjects, the ankle systolic pressure is higher than the brachial systolic pressure. The normal ABI > 1; in the presence of ischemia, it is <0.9. Absent or feeble pulses, with ABI < 0.9, confirm ischemia [40].

Transcutaneous oxygen tension method TcPO2 less than 20 mmHg has been associated with early wound healing failure [41].



## **9. Diabetic foot examination**

## **10. Treatment**

Treating diabetic foot ulcer is an art and involves multiple specialties. The essential team members are physicians, chiropodist, orthopedics, radiologist, and

**139**

*Diabetic Foot Ulcer: An Easy and Comprehensive Approach*

vascular surgeon. The focus would be ensuring targeted HbA1c, revascularization, wound healing with or without debridement, shading of excessive load over foot or limb, and limiting infection by antibiotics and assessment of complications. Focus on the patient's education and nutrition is very important in reducing recurrence of

It means reduction, redistribution, or sharing pressures over the ulcer area. It is a well-known fact that offloading is one of the cornerstones of successful diabetic foot ulceration management and prevention. The aim is to reduce the plantar pressure by redistributing it to a larger area, to avoid shear and friction, and to accom-

For diabetic foot ulcer, a proper cast is necessary; for example, nonremovable cast devices are the most clinically effective for neuropathic forefoot and mid-foot ulceration. The aim is to immobilize the foot and ankle within the cast, which

The total contact cast is a below-knee cast that encroaches the lower limb, encasing the whole foot. It is the main cast for mid- and forefoot lesions and for neuropathic noninfected plantar ulcers. Healing was reported in almost 100% cases of ulcers within 5–8 weeks. For non-cast offloading devices, half shoes are designed to offload either the fore or rear foot. We can decide by giving examples below about casting devices:

Crutches with or without a below-knee cast and a half shoe.

shaped to cover the sole of the foot with a cavity at the ulcer site.

Leg trough, pressure-relieving mattress and flexible heel cast or pillows.

Total contact cast, below-knee cast, or fiberglass boot. Felt padding can be

Half shoe; leg- or boot-type cast is the most effective method for offloading; sandals with a foam-filled sink in the sole unit located over the ulcer site may also

Cut a hole in the part of the shoe overlying the ulcer site to remove the whole toe

A recent systematic review has found nonremovable offloading devices like total contact cast to be more effective for ulcer healing than removable offloading

While most DFIs are relatively superficial at presentation, microorganisms can spread contiguously to subcutaneous tissues, including fascia, tendons, muscle,

First-generation cephalosporin, clindamycin, fluoroquinolone, linezolid.

Ticarcillin/clavulanate, piperacillin/tazobactam; second- or third-generation

Moderate infection without systemic involvement.

*DOI: http://dx.doi.org/10.5772/intechopen.92585*

diabetic foot ulcer.

modate the deformities [43].

significantly reduces shear force.

**10.1 Offloading**

**Rear foot**

**Mid-foot**

**Forefoot**

be useful. **Toe**

from shoe.

devices [44].

cephalosporin.

For weight-bearing:

For non-weight-bearing:

**11. Control of foot infection**

joints, and bones [45, 46].

vascular surgeon. The focus would be ensuring targeted HbA1c, revascularization, wound healing with or without debridement, shading of excessive load over foot or limb, and limiting infection by antibiotics and assessment of complications. Focus on the patient's education and nutrition is very important in reducing recurrence of diabetic foot ulcer.

## **10.1 Offloading**

*The Eye and Foot in Diabetes*

• Blood sugar levels

• Blood culture and sensitivity

• PET scan in osteomyelitis [39]

associated with early wound healing failure [41].

• Ultrasound Doppler vascular studies

Ankle brachial index: in normal subjects, the ankle systolic pressure is higher than the brachial systolic pressure. The normal ABI > 1; in the presence of ischemia,

Transcutaneous oxygen tension method TcPO2 less than 20 mmHg has been

**Vascular examination Deformity Ulcer examination**

bone spurs, plantarflexed metatarsals, pes cavus

foot type

Achilles/ gastro equinus, overpronation

Rocker bottom appearance

Dry skin and fissuring Gait evaluation Depth; probe test

Foot drop, atrophy, necrobiosis lipoidica diabeticorum

Bunions, hammertoes,

Area, toe, metatarsal forefoot, lateral, medial

Ischemic or neuropathic

Small <10 cm, moderate 11–40 cm, severe >40 cm

Healing or nonhealing (inflammatory granulating epithelialization)

or mixed

Prior amputation Cool with absent pulses

Treating diabetic foot ulcer is an art and involves multiple specialties. The essential team members are physicians, chiropodist, orthopedics, radiologist, and

it is <0.9. Absent or feeble pulses, with ABI < 0.9, confirm ischemia [40].

Pedal pulses: dorsalis pedis, posterior tibial, perforating peroneal

Achilles reflex Erythema or cyanosis Hallux limitus,

Intermittent claudication score

Temperature comparison between

ultrasonography

feet

Pain sensation Vascular Doppler

• X-ray of the foot [38]

• MRI of the foot

• CT angiogram

Vibratory perception: 128 Hz tuning fork or electronic tuning

Monofilament test 10 point touch [42]

Vibration perception threshold (VPT)

**Sensory exanimation**

fork

**9. Diabetic foot examination**

• HbA1C

**138**

**10. Treatment**

Temperature sensation

It means reduction, redistribution, or sharing pressures over the ulcer area. It is a well-known fact that offloading is one of the cornerstones of successful diabetic foot ulceration management and prevention. The aim is to reduce the plantar pressure by redistributing it to a larger area, to avoid shear and friction, and to accommodate the deformities [43].

For diabetic foot ulcer, a proper cast is necessary; for example, nonremovable cast devices are the most clinically effective for neuropathic forefoot and mid-foot ulceration. The aim is to immobilize the foot and ankle within the cast, which significantly reduces shear force.

The total contact cast is a below-knee cast that encroaches the lower limb, encasing the whole foot. It is the main cast for mid- and forefoot lesions and for neuropathic noninfected plantar ulcers. Healing was reported in almost 100% cases of ulcers within 5–8 weeks. For non-cast offloading devices, half shoes are designed to offload either the fore or rear foot. We can decide by giving examples below about casting devices:

## **Rear foot**

For weight-bearing: Crutches with or without a below-knee cast and a half shoe. For non-weight-bearing:

Leg trough, pressure-relieving mattress and flexible heel cast or pillows.

## **Mid-foot**

Total contact cast, below-knee cast, or fiberglass boot. Felt padding can be shaped to cover the sole of the foot with a cavity at the ulcer site.

## **Forefoot**

Half shoe; leg- or boot-type cast is the most effective method for offloading; sandals with a foam-filled sink in the sole unit located over the ulcer site may also be useful.

## **Toe**

Cut a hole in the part of the shoe overlying the ulcer site to remove the whole toe from shoe.

A recent systematic review has found nonremovable offloading devices like total contact cast to be more effective for ulcer healing than removable offloading devices [44].

## **11. Control of foot infection**

While most DFIs are relatively superficial at presentation, microorganisms can spread contiguously to subcutaneous tissues, including fascia, tendons, muscle, joints, and bones [45, 46].

First-generation cephalosporin, clindamycin, fluoroquinolone, linezolid. Moderate infection without systemic involvement.

Ticarcillin/clavulanate, piperacillin/tazobactam; second- or third-generation cephalosporin.

Third-generation cephalosporin, impinemen.

Ugly ulcer with systemic signs.

Ticarcillin/clavulanate, piperacillin/tazobactam;+ceftazidime, flucloxacillin+cipro, carbapenem.

Ischemic limb/necrosis/gas forming.

Ticarcillin/clavulanate, piperacillin/tazobactam or carbapenem; second−/thirdgeneration cephalosporin + clindamycin or metronidazole.

## **12. Control of ischemia**

Revascularization surgery: Patients with peripheral ischemia who have significant functional disability should undergo surgical revascularization if medical management fails. This may decrease the amputation risk in patients with ischemic DFUs.

The procedures include open (bypass grafting or endarterectomy) or endovascular techniques (angioplasty with or without stent) [47].

Extracorporeal shock wave therapy acts by increasing angiogenesis and blood supply and cellular proliferation and thus hastening wound healing.

Low-energy lasers have also been used as an adjunctive therapy for DFUs [48].

### **13. Wound debridement**

Ulcers heal more quickly if the surface is clean; physicians must debride impediments to healing, such as necrotic tissue and bacteria. The popular strategy is to do sharp debridement. So removal of necrotic tissue often extends beyond the ulcer bed, and some authorities have recommended to debride deeper tissues also.

Other strategy is to convert bad ulcer to fresh ulcer by excise the already an ulcer, underlying bony prominences. Good results have been reported with this approach [49].

Many other strategies of debridement include physical debridement using wet-to-dry dressing, enzymatic debridement using enzymes like collagenase and papain as ointment preparations, autolytic debridement with the use of moistureretaining dressings, and biological debridement with the use of larvae of common green bottle fly [50].

#### **14. Wound dressings**

Dressings can provide a warm, moist environment required for healing after debridement. Common problems associated with some of these dressings have been dehydration of the ulcer bed, saturation with exudate, and/or the failure to properly apply antibiotics and growth factors needed to promote angiogenesis and granulation tissue. Non-medicated dressings include paraffin gauze, while medicated include Xeroform [51].

Dressing materials include saline-moistened gauze dressings (wet-to-dry), moisture-retaining and antiseptic dressings, silver dressings, and cadexomer.

Chemically treated honey can be used alone or in combination with sterile dressings [52].

In terms of ulcer healing, a meta-analysis of trials in which people with neuropathic foot ulcers received good wound care reported that 24% of ulcers attained complete healing by 12 weeks and 31% by 20 weeks.

**141**

*Diabetic Foot Ulcer: An Easy and Comprehensive Approach*

reduce the need for frequent dressing changes.

**15. Nutrition and diabetic foot ulcer**

thropathy is approximately 13% with diabetes [54].

ing pulses. The X-ray of foot is less helpful.

to permanent deformities.

chronic stages [56].

**16. Charcot arthropathy**

In highly exuding ulcers, dressing is essential in managing the high volume of exudate, achieving moisture balance and preventing peri-wound soft tissue damage. The frequency of wound dressing change is important in achieving these goals. Superabsorbent dressings are designed to absorb high volumes of wound exudate and to hold and lock the fluid into the structure of the dressing, which may

In a wound with low exudate levels, which contains slough, dressings should be selected with the aim of increasing wound moisture to aid autolysis and achieve moisture balance. In the case of black, dry, and necrotic toes due to ischemia, the primary goal is to keep the toe dry, prevent infection, and protect adjoining or adjacent issues.

As the other factors are important for proper care of diabetic foot ulcer, nutrition has a pivotal role in healing, prevention of recurrence, and fair outcome. Unfortunately, it is a least considered part of diabetic foot ulcer management. Imran et al. have shown that BMI was significantly associated with severity of ulcer; BMI of 29 was associated with grade 1 ulcer and low BMI of 23 with grade 5 foot ulcer. Over Mini nutritional assessment scale, a score less than 23.5 was associated with advanced foot ulcers, score < 17 was associated with significant p value <0.03, and score in between 17 and 23.5 was associated with p value of 0.05 [53].

Charcot neuroarthropathy, or Charcot foot, is a complication of diabetes mellitus where there is progressive degeneration of the joints. It commonly affects the middle of the foot, hindfoot joints, the ankle, and forefoot joints, and it is believed to result from inflammation in the tissues. The prevalence of Charcot neuroar-

Charcot neuroarthropathy could result in ulceration and infection which can lead to amputation of the limb. Early recognition and intervention is imperative to avoid the rapid progression toward permanent foot deformity, ulceration, and the possibility of limb loss. Once it has started, ongoing inflammation leads to bone deformities. The acute Charcot arthropathy results in bony reabsorption and multiple spon-

**0 (prodromal):** Elevated temperature, with or without foot edema and bound-

**1 Developmental, acute:** An acute destructive period that is induced by minor trauma resulting in fragmentation of bone and joint dislocation and subluxation. This stage should be verified by a physician early; otherwise, misdiagnosis will lead

**2 Subacute:** The patient presents with decreased edema and healing of fractures.

The acute phase is often misdiagnosed and can lead to permanent foot deformity

There are three types of Charcot foot classification: clinical, anatomical, and radiological. In clinical practice, Charcot foot can be classified into the acute and

The best way to deal with this stage is offloading of the foot, avoid weight-bearing, prevention of aim of chronic deformities. The pain must be reduced managed and assessment of disease activity by physical signs, X-rays or C reactive protein.

**3 Chronic:** Healing, deformity and remodeling of bones seen on xary.

and ulceration, thus increasing the risk of lower extremity amputation [55].

taneous fractures. Charcot joint changes can be classified into stages.

*DOI: http://dx.doi.org/10.5772/intechopen.92585*

*The Eye and Foot in Diabetes*

lin+cipro, carbapenem.

**12. Control of ischemia**

with ischemic DFUs.

**13. Wound debridement**

approach [49].

green bottle fly [50].

**14. Wound dressings**

include Xeroform [51].

dressings [52].

Third-generation cephalosporin, impinemen.

generation cephalosporin + clindamycin or metronidazole.

cular techniques (angioplasty with or without stent) [47].

supply and cellular proliferation and thus hastening wound healing.

Ticarcillin/clavulanate, piperacillin/tazobactam;+ceftazidime, flucloxacil-

Revascularization surgery: Patients with peripheral ischemia who have significant functional disability should undergo surgical revascularization if medical management fails. This may decrease the amputation risk in patients

The procedures include open (bypass grafting or endarterectomy) or endovas-

Extracorporeal shock wave therapy acts by increasing angiogenesis and blood

Low-energy lasers have also been used as an adjunctive therapy for DFUs [48].

Ulcers heal more quickly if the surface is clean; physicians must debride impediments to healing, such as necrotic tissue and bacteria. The popular strategy is to do sharp debridement. So removal of necrotic tissue often extends beyond the ulcer bed, and some authorities have recommended to debride deeper tissues also. Other strategy is to convert bad ulcer to fresh ulcer by excise the already an ulcer, underlying bony prominences. Good results have been reported with this

Many other strategies of debridement include physical debridement using wet-to-dry dressing, enzymatic debridement using enzymes like collagenase and papain as ointment preparations, autolytic debridement with the use of moistureretaining dressings, and biological debridement with the use of larvae of common

Dressings can provide a warm, moist environment required for healing after debridement. Common problems associated with some of these dressings have been dehydration of the ulcer bed, saturation with exudate, and/or the failure to properly apply antibiotics and growth factors needed to promote angiogenesis and granulation tissue. Non-medicated dressings include paraffin gauze, while medicated

Dressing materials include saline-moistened gauze dressings (wet-to-dry), moisture-retaining and antiseptic dressings, silver dressings, and cadexomer. Chemically treated honey can be used alone or in combination with sterile

In terms of ulcer healing, a meta-analysis of trials in which people with neuropathic foot ulcers received good wound care reported that 24% of ulcers attained

complete healing by 12 weeks and 31% by 20 weeks.

Ticarcillin/clavulanate, piperacillin/tazobactam or carbapenem; second−/third-

Ugly ulcer with systemic signs.

Ischemic limb/necrosis/gas forming.

**140**

In highly exuding ulcers, dressing is essential in managing the high volume of exudate, achieving moisture balance and preventing peri-wound soft tissue damage. The frequency of wound dressing change is important in achieving these goals.

Superabsorbent dressings are designed to absorb high volumes of wound exudate and to hold and lock the fluid into the structure of the dressing, which may reduce the need for frequent dressing changes.

In a wound with low exudate levels, which contains slough, dressings should be selected with the aim of increasing wound moisture to aid autolysis and achieve moisture balance. In the case of black, dry, and necrotic toes due to ischemia, the primary goal is to keep the toe dry, prevent infection, and protect adjoining or adjacent issues.

## **15. Nutrition and diabetic foot ulcer**

As the other factors are important for proper care of diabetic foot ulcer, nutrition has a pivotal role in healing, prevention of recurrence, and fair outcome. Unfortunately, it is a least considered part of diabetic foot ulcer management.

Imran et al. have shown that BMI was significantly associated with severity of ulcer; BMI of 29 was associated with grade 1 ulcer and low BMI of 23 with grade 5 foot ulcer. Over Mini nutritional assessment scale, a score less than 23.5 was associated with advanced foot ulcers, score < 17 was associated with significant p value <0.03, and score in between 17 and 23.5 was associated with p value of 0.05 [53].

## **16. Charcot arthropathy**

Charcot neuroarthropathy, or Charcot foot, is a complication of diabetes mellitus where there is progressive degeneration of the joints. It commonly affects the middle of the foot, hindfoot joints, the ankle, and forefoot joints, and it is believed to result from inflammation in the tissues. The prevalence of Charcot neuroarthropathy is approximately 13% with diabetes [54].

Charcot neuroarthropathy could result in ulceration and infection which can lead to amputation of the limb. Early recognition and intervention is imperative to avoid the rapid progression toward permanent foot deformity, ulceration, and the possibility of limb loss. Once it has started, ongoing inflammation leads to bone deformities.

The acute Charcot arthropathy results in bony reabsorption and multiple spontaneous fractures. Charcot joint changes can be classified into stages.

**0 (prodromal):** Elevated temperature, with or without foot edema and bounding pulses. The X-ray of foot is less helpful.

**1 Developmental, acute:** An acute destructive period that is induced by minor trauma resulting in fragmentation of bone and joint dislocation and subluxation. This stage should be verified by a physician early; otherwise, misdiagnosis will lead to permanent deformities.

**2 Subacute:** The patient presents with decreased edema and healing of fractures. **3 Chronic:** Healing, deformity and remodeling of bones seen on xary.

The acute phase is often misdiagnosed and can lead to permanent foot deformity and ulceration, thus increasing the risk of lower extremity amputation [55].

There are three types of Charcot foot classification: clinical, anatomical, and radiological. In clinical practice, Charcot foot can be classified into the acute and chronic stages [56].

The best way to deal with this stage is offloading of the foot, avoid weight-bearing, prevention of aim of chronic deformities. The pain must be reduced managed and assessment of disease activity by physical signs, X-rays or C reactive protein.

The surgery is indicated for correction of deformities. One researcher has been followed up 100 patients for a median of 3.8 years after conservative treatment for Charcot foot [27] and noted amputations in 2.7% and ulcer recurrence in 49%, but some of them have been prevented by earlier surgical intervention [57].

## **17. Conclusion**

Diabetic foot ulcer contributes to be a major cause for morbidity in patients despite of multiple, advanced, and suitable interventions at different levels. This problem could be addressed and managed by encouraging the patient's education, especially to foot care.

Patients should be motivated to care better for themselves by getting involved in learning programs, which highlight the risk factors and consequences of diabetic foot. These patients should be taught in the simple way to examine an ulcer and assess modified risk factors. The synthesis of national and local guidelines on diabetic foot care should be a priority, and the adherence to such guidelines has to be monitored by concerned organizations.

## **Author details**

Imran Ali Shaikh1 \*, Naila Masood Sddiqui1 and Javeria Hameed Shaikh<sup>2</sup>

1 Department of Medicine, Liaquat University of Medical and Health Sciences, Jamshoro Sindh, Pakistan

2 Department of Physiology, Liaquat University of Medical and Health Sciences, Jamshoro Sindh, Pakistan

\*Address all correspondence to: imran2naila@yahoo.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**143**

2017;**49**:106-116

*Diabetic Foot Ulcer: An Easy and Comprehensive Approach*

[11] Khanolkar MP, Bain SC,

[12] Leggetter S, Fuller JH, et al. Ethnicity and risk of diabetes-related lower extremity amputation. Archives of Internal Medicine. 2002;**162**(1):73-78

2008;**101**(9):685-695

Stephens JW. The diabetic foot. QJM.

[13] Adeleye JO. Diabetic foot disease: The perspective of a Nigerian tertiary health care center. Practical Diabetes International. 2005;**22**(6):211-214

[14] Gulliford MC, Mahabir D. Diabetic foot disease and foot care in a Caribbean community. Diabetes Research and Clinical Practice. 2002;**56**(1):35-40

[15] Dyck PJ, Davies JL, Wilson DM, Service FJ, et al. Risk factors for severity of diabetic polyneuropathy: Intensive longitudinal assessment of the Rochester Diabetic Neuropathy Study Cohort. Diabetes Care.

[16] Kruse I, Endelman S. Evaluation and treatment of diabetic foot ulcers. Clinical Diabetes. 2006;**24**:91-93

[17] Clayton W, Elcasy TA. A review of the pathophysiology, classification, and treatment of foot ulcers in diabetic patients. Clinical Diabetes. 2009;**27**:52-58

[18] Wild S, Roglic G, Green A,

2004;**27**:1047-1053

Sicree R, King H. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care.

[19] Armstrong DA. Lavery LADiabetic foot ulcers: Prevention, diagnosis and classification. American Family Physician. 1998;**57**:1325-1332

[20] Vinik AI, Erbas T, et al. Platelet dysfunction in type 2 diabetes. Diabetes

Care. 2001;**24**(8):1476-1485

1999;**22**:1479-1486

*DOI: http://dx.doi.org/10.5772/intechopen.92585*

[1] Dabelea D, Mayer-Davis EJ, Saydah S, et al. Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. JAMA.

[2] Cho NH, Whiting D, Forouhi N, et al. IDF Diabetes Atlas. Diabetes in

[3] Mayer-Davis E, Lawrence JM, Dabelea D, et al. Incidence trends of Type 1 and Type 2 diabetes among youths. NEJM. 2017;**376**:1419-1429

[4] Maahs DM, West NA, Lawrence JM, et al. Epidemiology of type 1 diabetes. Endocrinology and Metabolism Clinics of North America. 2010;**39**:481-497

[5] Livingstone SJ, Levin D, Looker HC, et al. Estimated life expectancy in a Scottish cohort with type 1 diabetes, 2008-2010. JAMA. 2015;**313**:37-44

Bakhtadze E, et al. Latent autoimmune

[7] Cho NH. Estimates of diabetes for projections to 2030 and 2045. IDF Diabetes Atlas. 2019:9-10. Available from: http://doi.org/10.1016/j.

[8] Allebeck P, Hallqvist J, Moradi T, et al. Type 2 diabetes incidence and socioeconomic position: A systematic review and meta-analysis. International Journal of Epidemiology. 2011;**40**:804-818

[9] Trautner C, Haastert B, et al. Incidence of lower limb amputations and diabetes. Diabetes Care. 1996;**9**:1006-1009

[10] Zhang P, Lu J, Jing Y, Tang S, Zhu D, et al. Global epidemiology of diabetic foot ulceration: A systematic review and meta-analysis. Annals of Medicine.

[6] Stenström G, Gottsäter A,

diabetes in adults: Definition, prevalence, β-cell function, and treatment. Diabetes. 2005;**54**:S68

diabetes.2019.107843

**References**

2014;**311**:1778-1786

Children. 2015;**7**:14-16

*Diabetic Foot Ulcer: An Easy and Comprehensive Approach DOI: http://dx.doi.org/10.5772/intechopen.92585*

## **References**

*The Eye and Foot in Diabetes*

**17. Conclusion**

especially to foot care.

be monitored by concerned organizations.

**142**

**Author details**

Imran Ali Shaikh1

Jamshoro Sindh, Pakistan

Jamshoro Sindh, Pakistan

\*, Naila Masood Sddiqui1

\*Address all correspondence to: imran2naila@yahoo.com

provided the original work is properly cited.

1 Department of Medicine, Liaquat University of Medical and Health Sciences,

The surgery is indicated for correction of deformities. One researcher has been followed up 100 patients for a median of 3.8 years after conservative treatment for Charcot foot [27] and noted amputations in 2.7% and ulcer recurrence in 49%, but

Diabetic foot ulcer contributes to be a major cause for morbidity in patients despite of multiple, advanced, and suitable interventions at different levels. This problem could be addressed and managed by encouraging the patient's education,

Patients should be motivated to care better for themselves by getting involved in learning programs, which highlight the risk factors and consequences of diabetic foot. These patients should be taught in the simple way to examine an ulcer and assess modified risk factors. The synthesis of national and local guidelines on diabetic foot care should be a priority, and the adherence to such guidelines has to

some of them have been prevented by earlier surgical intervention [57].

2 Department of Physiology, Liaquat University of Medical and Health Sciences,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

and Javeria Hameed Shaikh<sup>2</sup>

[1] Dabelea D, Mayer-Davis EJ, Saydah S, et al. Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. JAMA. 2014;**311**:1778-1786

[2] Cho NH, Whiting D, Forouhi N, et al. IDF Diabetes Atlas. Diabetes in Children. 2015;**7**:14-16

[3] Mayer-Davis E, Lawrence JM, Dabelea D, et al. Incidence trends of Type 1 and Type 2 diabetes among youths. NEJM. 2017;**376**:1419-1429

[4] Maahs DM, West NA, Lawrence JM, et al. Epidemiology of type 1 diabetes. Endocrinology and Metabolism Clinics of North America. 2010;**39**:481-497

[5] Livingstone SJ, Levin D, Looker HC, et al. Estimated life expectancy in a Scottish cohort with type 1 diabetes, 2008-2010. JAMA. 2015;**313**:37-44

[6] Stenström G, Gottsäter A, Bakhtadze E, et al. Latent autoimmune diabetes in adults: Definition, prevalence, β-cell function, and treatment. Diabetes. 2005;**54**:S68

[7] Cho NH. Estimates of diabetes for projections to 2030 and 2045. IDF Diabetes Atlas. 2019:9-10. Available from: http://doi.org/10.1016/j. diabetes.2019.107843

[8] Allebeck P, Hallqvist J, Moradi T, et al. Type 2 diabetes incidence and socioeconomic position: A systematic review and meta-analysis. International Journal of Epidemiology. 2011;**40**:804-818

[9] Trautner C, Haastert B, et al. Incidence of lower limb amputations and diabetes. Diabetes Care. 1996;**9**:1006-1009

[10] Zhang P, Lu J, Jing Y, Tang S, Zhu D, et al. Global epidemiology of diabetic foot ulceration: A systematic review and meta-analysis. Annals of Medicine. 2017;**49**:106-116

[11] Khanolkar MP, Bain SC, Stephens JW. The diabetic foot. QJM. 2008;**101**(9):685-695

[12] Leggetter S, Fuller JH, et al. Ethnicity and risk of diabetes-related lower extremity amputation. Archives of Internal Medicine. 2002;**162**(1):73-78

[13] Adeleye JO. Diabetic foot disease: The perspective of a Nigerian tertiary health care center. Practical Diabetes International. 2005;**22**(6):211-214

[14] Gulliford MC, Mahabir D. Diabetic foot disease and foot care in a Caribbean community. Diabetes Research and Clinical Practice. 2002;**56**(1):35-40

[15] Dyck PJ, Davies JL, Wilson DM, Service FJ, et al. Risk factors for severity of diabetic polyneuropathy: Intensive longitudinal assessment of the Rochester Diabetic Neuropathy Study Cohort. Diabetes Care. 1999;**22**:1479-1486

[16] Kruse I, Endelman S. Evaluation and treatment of diabetic foot ulcers. Clinical Diabetes. 2006;**24**:91-93

[17] Clayton W, Elcasy TA. A review of the pathophysiology, classification, and treatment of foot ulcers in diabetic patients. Clinical Diabetes. 2009;**27**:52-58

[18] Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;**27**:1047-1053

[19] Armstrong DA. Lavery LADiabetic foot ulcers: Prevention, diagnosis and classification. American Family Physician. 1998;**57**:1325-1332

[20] Vinik AI, Erbas T, et al. Platelet dysfunction in type 2 diabetes. Diabetes Care. 2001;**24**(8):1476-1485

[21] Cooper ME, Bonnet F, Oldfield M, et al. Mechanism of diabetic vasculopathy: An overview. American Journal of Hypertension. 2001;**14**:475-486

[22] Basta G, Lazzerini G, et al. Advanced glycation end-product activate endothelium signaltransduction receptor RAGE. A mechanism for amplification of inflammatory responses. Circulation. 2002;**105**:816-822

[23] Bucala R, Makita Z, Vega G, et al. Modification of low density lipoprotein by advanced glycation end-products contribute to the dyslipidemia of diabetes and renal insufficiency. Protocol for the National Academy of Sciences USA. Medical Science. 1994;**91**:9441-9445

[24] Okonkwo UA, Di Pietro LA. Diabetes and wound angiogenesis. International Journal of Molecular Sciences. 2017;**18**(7):1419

[25] Dinh T, Veves A. Microcirculation of the diabetic foot. Current Pharmaceutical Design. 2005;**11**(18):2301-2309

[26] Selvin E, Marinopoulos S, Berkenblit G, Rami T, et al. Metaanalysis: Glycosylated hemoglobin and CVD disease in diabetes mellitus. Annals of Internal Medicine. 2004;**21**: 421-431

[27] Ayuk SM, Abrahamse H, et al. The role of matrix metalloproteinases in diabetic wound healing in relation to photo bio modulation. Journal of Diabetes Research. 2016;**2016**:9. Article ID 289756. Available from: http//dx.doi. org/10.1155/2016/2897656

[28] Brem H, Tomic-Canic M. Cellular and molecular basis of wound healing in diabetes. Journal of Clinical Investigation. 2007;**117**(5):1219-1222

[29] Prompers L, Huijberts M, Apelqvist J, et al. High prevalence of ischemia, infection and serious comorbidity in patients with diabetic foot disease in Europe. Baseline results from the Eurodiale study. Diabetologia. 2007;**50**(1):18-25

[30] Lipsky BA, Anthony R, et al. Infectious Diseases Society of America clinical practice guidelines for the diagnosis and treatment of diabetic foot infections. Clinical Infectious Diseases. 2012;**54**(12):132-173

[31] Gadepalli R, Dhawan B, Sreenivas V, et al. A clinico-microbiological study of diabetic foot ulcers in an Indian tertiary care hospital. Diabetes Care. 2006;**29**:1727-1732

[32] Wagner FW. The dysvascular foot: A system of diagnosis and treatment. Foot & Ankle. 1981;**2**:64-122

[33] Chuan F et al. Reliability and validity of the perfusion, extent, depth, infection and sensation (PEDIS) classification system and score in patients with diabetic foot ulcer. PLoS One. 2015;**10**(4):e0124739

[34] Armstrong D, 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**(5):855-859

[35] Terashi H, Kitano I, Tsuji Y. Total management of diabetic foot ulcerations: Kobe classification as a new classification of diabetic foot wounds. The Keio Journal of Medicine. 2011;**60**:17-21

[36] Macfarlane RM, Jeffcoate WJ. Classification of diabetic foot ulcers: SAD system. The Diabetic Foot. 1999;**2**(4):123-130

[37] Game F. Classification of diabetic foot ulcers. Diabetes/ Metabolism Research and Reviews. 2015;**32**(1):186-194

**145**

*Diabetic Foot Ulcer: An Easy and Comprehensive Approach*

[46] LoGerfo FW, Gibbons GW, Pomposelli FB Jr, Campbell DR, Miller A, et al. Trends in the care of the diabetic foot. Expanded role of arterial reconstruction. Archives of Surgery. 1992;**127**(5):617-621. DOI: 10.1001/ archsurg.1992.01420050145019

[47] Albayati MA, Shearman CP. Peripheral arterial disease and bypass surgery in the diabetic lower limb. The Medical Clinics of North America.

[48] Schindl A, Schindl M, Schön H, Knobler R, Havelec L, et al. Low intensity laser irradiation improves skin circulation in patients with diabetic microangiopathy. Diabetes Care.

[49] Pai DR, Madan SS. Techniques in chronic wound management: Review of the literature and recent concepts. Journal of Novel Physiotherapies.

[50] Wong MW, Leung PC, Wong WC. Limb salvage in extensive diabetic foot ulceration—A preliminary clinical study using simple debridement and herbal drinks. Hong Kong Medical Journal.

[51] Wu L, Norman G, Dumville JC, et al. Dressings for treating foot ulcers in people with diabetes: An overview of systematic reviews. Cochrane Database of Systematic Reviews.

2013;**97**:821-834

1998;**21**:580-584

2013;**3**:22-27

2001;**7**:403-407

2015;**14**(7):CD101471

[52] Shukrimi A, Sulaiman AR,

of Malaysia. 2008;**63**:44-46

Journal. 2017;**24**(5):707-712

Halim AY, Azril A. A comparative study between honey and povidone iodine as dressing solution for Wagner type II diabetic foot ulcers. The Medical Journal

[53] Shaikh IA, Masood N, Shaikh FA, Shaikh MA. Diabetic foot ulcers; correlation of nutritional status of type 2 diabetic patients of Hyderabad Sindh, Pakistan. The Professional Medical

*DOI: http://dx.doi.org/10.5772/intechopen.92585*

neuroarthropathy in diabetes mellitus. Diabetologia. 2002;**45**:1085-1096

neuroarthropathy of the foot and ankle. Orthopaedic Surgery. 2013;**5**(2):86-93

[40] Doobay AV, Anand SS. Sensitivity and specificity of the ankle-brachial index to predict future cardiovascular outcomes: A systematic review. Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;**25**:1463-1469

Boyko EJ, Stensel VL. Chronology and determinants of tissue repair in diabetic lower-extremity ulcers. Diabetes.

[42] Boyko EJ, Ahroni JH, Cohen V, Nelson KM, Heagerty PJ. Prediction of diabetic foot ulcer occurrence using commonly available clinical information: The Seattle Diabetic Foot Study. Diabetes Care.

[43] Verity S, Sochocki M, Embil JM, Trepman E. Treatment of Charcot foot and ankle with a prefabricated removable walker brace and custom insole. Foot and Ankle Surgery.

Comparison of the clinical effectiveness of different off-loading devices for the treatment of neuropathic foot ulcers in patients with diabetes: A systematic review and metaanalysis. Diabetes/ Metabolism Research and Reviews.

[45] Lipsky BA, Aragón-Sánchez J, Diggle M. IWGDF guidance on the diagnosis and management of foot infections in persons with diabetes. Diabetes/Metabolism Research and

Reviews. 2016;**32**(1):45-74

[44] Morona JK, Buckley ES, Jones S, Reddin EA, Merlin TL.

[38] Rajbhandari SM, Jenkins RC, Davies C, Tesfaye S. Charcot

[39] Madan SS, Pai DR. Charcot

[41] Pecoraro RE, Ahroni JH,

1991;**40**(10):1305-1313

2006;**29**:1202-1207

2008;**14**:26-31

2013;**29**:183-193

*Diabetic Foot Ulcer: An Easy and Comprehensive Approach DOI: http://dx.doi.org/10.5772/intechopen.92585*

[38] Rajbhandari SM, Jenkins RC, Davies C, Tesfaye S. Charcot neuroarthropathy in diabetes mellitus. Diabetologia. 2002;**45**:1085-1096

*The Eye and Foot in Diabetes*

[21] Cooper ME, Bonnet F,

[22] Basta G, Lazzerini G, et al. Advanced glycation end-product activate endothelium signaltransduction receptor RAGE. A mechanism for amplification of inflammatory responses. Circulation.

2002;**105**:816-822

1994;**91**:9441-9445

Oldfield M, et al. Mechanism of diabetic vasculopathy: An overview. American Journal of Hypertension. 2001;**14**:475-486 of ischemia, infection and serious comorbidity in patients with diabetic foot disease in Europe. Baseline results from the Eurodiale study. Diabetologia.

[30] Lipsky BA, Anthony R, et al. Infectious Diseases Society of America clinical practice guidelines for the diagnosis and treatment of diabetic foot infections. Clinical Infectious Diseases.

[31] Gadepalli R, Dhawan B, Sreenivas V, et al. A clinico-microbiological study of diabetic foot ulcers in an Indian tertiary care hospital. Diabetes Care.

[32] Wagner FW. The dysvascular foot: A system of diagnosis and treatment.

Foot & Ankle. 1981;**2**:64-122

One. 2015;**10**(4):e0124739

Care. 1998;**21**(5):855-859

2011;**60**:17-21

1999;**2**(4):123-130

2015;**32**(1):186-194

[35] Terashi H, Kitano I, Tsuji Y. Total management of diabetic foot ulcerations: Kobe classification as a new classification of diabetic foot wounds. The Keio Journal of Medicine.

[36] Macfarlane RM, Jeffcoate WJ. Classification of diabetic foot ulcers: SAD system. The Diabetic Foot.

[37] Game F. Classification of diabetic foot ulcers. Diabetes/ Metabolism Research and Reviews.

[34] Armstrong D, Lavery LA, Harkless LB. Validation of a diabetic wound classification system: The contribution of depth, infection and ischemia to risk of amputation. Diabetes

[33] Chuan F et al. Reliability and validity of the perfusion, extent, depth, infection and sensation (PEDIS) classification system and score in patients with diabetic foot ulcer. PLoS

2007;**50**(1):18-25

2012;**54**(12):132-173

2006;**29**:1727-1732

[23] Bucala R, Makita Z, Vega G, et al. Modification of low density lipoprotein by advanced glycation end-products contribute to the dyslipidemia of diabetes and renal insufficiency. Protocol for the National Academy of Sciences USA. Medical Science.

[24] Okonkwo UA, Di Pietro LA. Diabetes and wound angiogenesis. International Journal of Molecular

[25] Dinh T, Veves A. Microcirculation of the diabetic foot. Current Pharmaceutical

Sciences. 2017;**18**(7):1419

Design. 2005;**11**(18):2301-2309

[26] Selvin E, Marinopoulos S, Berkenblit G, Rami T, et al. Metaanalysis: Glycosylated hemoglobin and CVD disease in diabetes mellitus. Annals of Internal Medicine. 2004;**21**:

[27] Ayuk SM, Abrahamse H, et al. The role of matrix metalloproteinases in diabetic wound healing in relation to photo bio modulation. Journal of Diabetes Research. 2016;**2016**:9. Article ID 289756. Available from: http//dx.doi.

[28] Brem H, Tomic-Canic M. Cellular and molecular basis of wound healing

org/10.1155/2016/2897656

in diabetes. Journal of Clinical Investigation. 2007;**117**(5):1219-1222

[29] Prompers L, Huijberts M, Apelqvist J, et al. High prevalence

**144**

421-431

[39] Madan SS, Pai DR. Charcot neuroarthropathy of the foot and ankle. Orthopaedic Surgery. 2013;**5**(2):86-93

[40] Doobay AV, Anand SS. Sensitivity and specificity of the ankle-brachial index to predict future cardiovascular outcomes: A systematic review. Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;**25**:1463-1469

[41] Pecoraro RE, Ahroni JH, Boyko EJ, Stensel VL. Chronology and determinants of tissue repair in diabetic lower-extremity ulcers. Diabetes. 1991;**40**(10):1305-1313

[42] Boyko EJ, Ahroni JH, Cohen V, Nelson KM, Heagerty PJ. Prediction of diabetic foot ulcer occurrence using commonly available clinical information: The Seattle Diabetic Foot Study. Diabetes Care. 2006;**29**:1202-1207

[43] Verity S, Sochocki M, Embil JM, Trepman E. Treatment of Charcot foot and ankle with a prefabricated removable walker brace and custom insole. Foot and Ankle Surgery. 2008;**14**:26-31

[44] Morona JK, Buckley ES, Jones S, Reddin EA, Merlin TL. Comparison of the clinical effectiveness of different off-loading devices for the treatment of neuropathic foot ulcers in patients with diabetes: A systematic review and metaanalysis. Diabetes/ Metabolism Research and Reviews. 2013;**29**:183-193

[45] Lipsky BA, Aragón-Sánchez J, Diggle M. IWGDF guidance on the diagnosis and management of foot infections in persons with diabetes. Diabetes/Metabolism Research and Reviews. 2016;**32**(1):45-74

[46] LoGerfo FW, Gibbons GW, Pomposelli FB Jr, Campbell DR, Miller A, et al. Trends in the care of the diabetic foot. Expanded role of arterial reconstruction. Archives of Surgery. 1992;**127**(5):617-621. DOI: 10.1001/ archsurg.1992.01420050145019

[47] Albayati MA, Shearman CP. Peripheral arterial disease and bypass surgery in the diabetic lower limb. The Medical Clinics of North America. 2013;**97**:821-834

[48] Schindl A, Schindl M, Schön H, Knobler R, Havelec L, et al. Low intensity laser irradiation improves skin circulation in patients with diabetic microangiopathy. Diabetes Care. 1998;**21**:580-584

[49] Pai DR, Madan SS. Techniques in chronic wound management: Review of the literature and recent concepts. Journal of Novel Physiotherapies. 2013;**3**:22-27

[50] Wong MW, Leung PC, Wong WC. Limb salvage in extensive diabetic foot ulceration—A preliminary clinical study using simple debridement and herbal drinks. Hong Kong Medical Journal. 2001;**7**:403-407

[51] Wu L, Norman G, Dumville JC, et al. Dressings for treating foot ulcers in people with diabetes: An overview of systematic reviews. Cochrane Database of Systematic Reviews. 2015;**14**(7):CD101471

[52] Shukrimi A, Sulaiman AR, Halim AY, Azril A. A comparative study between honey and povidone iodine as dressing solution for Wagner type II diabetic foot ulcers. The Medical Journal of Malaysia. 2008;**63**:44-46

[53] Shaikh IA, Masood N, Shaikh FA, Shaikh MA. Diabetic foot ulcers; correlation of nutritional status of type 2 diabetic patients of Hyderabad Sindh, Pakistan. The Professional Medical Journal. 2017;**24**(5):707-712

#### *The Eye and Foot in Diabetes*

[54] Younis BB, Shahid A, Arshad R, Khurshid S, Masood J. Charcot osteoarthropathy in type 2 diabetes persons presenting to specialist diabetes clinic at a tertiary care hospital. BMC Endocrine Disorders. 2015;**15**:28

[55] Wukich D, Sung W, Wipf S, Armstrong DG. The consequences of complacency: Managing the effects of unrecognized Charcot feet. Diabetic Medicine. 2011;**28**(2):195-198

[56] Rogers LC, Frykberg RG. The charcot foot. Medical Clinics of North America. 2013;**97**(5):847-856

[57] Saltzman CL, Hagy ML, Zimmerman B, et al. How effective is intensive nonoperative initial treatment of patients with diabetes and Charcot arthropathy of the feet? Clinical Orthopaedics and Related Research. 2005;**435**:185-190

**147**

**Chapter 10**

**Abstract**

Diabetic Foot

prevention of diabetic foot.

**1. Introduction**

*Fanna Liu and Lianghong Yin*

Diagnosis, Treatment,

Multidisciplinary Collaborative

Diabetic foot (DF) is one of the most common complications of diabetes. Diabetic foot is one of the main causes of disability and death of diabetic patients, and it is also a major public health problem that causes a heavy burden on society. Diabetic foot involves a variety of factors including peripheral nerve tissue lesions, ischemic lesions, and reduced body immunity. With the development of medical standards, clinical knowledge and treatment of diabetic foot are constantly improving. Early diagnosis and intervention is the key to reducing the incidence of diabetic foot and improving the cure rate. This chapter will briefly introduce the diagnosis, the treatment, the multidisciplinary collaborative therapy and

**Keywords:** diabetic foot, multidisciplinary collaborative therapy, prevention

also a major public health problem that causes a heavy burden on society.

diabetes in the United States is used for diabetic foot patients [7].

in the world [2]. According to the statistics of the World Health Organization, about 50% of all non-traumatic amputations are due to diabetic foot amputation [3]. The annual mortality rate of patients with diabetic foot is as high as 11%, and the mortality rate of amputated patients is as high as 22% [4]; many studies have shown that diabetic foot costs are huge, accounting for about one-third of the entire diabetes medical cost. In 2017, the global medical cost of diabetes was as high as 727 billion US dollars, of which China was 110 billion US dollars [5]. In developed countries, diabetic foot occupies 12–15% of diabetes medical and health resources, while in developing countries, up to 40% [6]. One third of the medical cost of

Diabetes Mellitus is a chronic non-communicable epidemic that has become the most important in the world. Diabetic foot (DF) is one of the most common complications of diabetes. The global prevalence of diabetic foot is 6.3%, male are higher than female, and type 2 diabetes is higher than type 1 diabetes. The prevalence of diabetic foot varies greatly from country to country, varying from 1.5 to 16.6% [1]. DF is one of the primary causes of disability and death of diabetic patients, and it is

It is estimated that there is one amputation of diabetic patients every 20 seconds

Therapy and Prevention of

## **Chapter 10**

*The Eye and Foot in Diabetes*

[54] Younis BB, Shahid A, Arshad R, Khurshid S, Masood J. Charcot osteoarthropathy in type 2 diabetes persons presenting to specialist diabetes clinic at a tertiary care hospital. BMC Endocrine Disorders. 2015;**15**:28

[55] Wukich D, Sung W, Wipf S, Armstrong DG. The consequences of complacency: Managing the effects of unrecognized Charcot feet. Diabetic Medicine. 2011;**28**(2):195-198

[56] Rogers LC, Frykberg RG. The charcot foot. Medical Clinics of North

Zimmerman B, et al. How effective is intensive nonoperative initial treatment of patients with diabetes and Charcot arthropathy of the feet? Clinical Orthopaedics and Related Research.

America. 2013;**97**(5):847-856

[57] Saltzman CL, Hagy ML,

2005;**435**:185-190

**146**
