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I.

INTRODUCTION

Diabetes affects approximately 170 million people worldwide, including 20.8


million in the USA, and by 2030 these numbers are projected to double.1
Currently, it is the seventh-leading cause of death in the US, totaling 4.6 million
deaths in 2011 (with healthcare expenditures reaching more than $471 billion).2 A
condition that increases ones risk for heart disease and stroke, diabetes is also the
leading cause of kidney failure, new cases of blindness among adults, and non-
traumatic lower-limb amputations. Diabetic foot is one of the most significant and
devastating complications of diabetes, and is defined as a foot affected by
ulceration that is associated with neuropathy and/or peripheral arterial disease of
the lower limb in a patient with diabetes. The prevalence of diabetic foot
ulceration in the diabetic population is 410%; the condition is more frequent in
older patients. It is estimated that about 5% of all patients with diabetes present
with a history of foot ulceration, while the lifetime risk of diabetic patients
developing this complication is 15%.3

The majority (6080%) of foot ulcers will heal, while 1015% of them will
remain active, and 524% of them will finally lead to limb amputation within a
period of 618 months after the first evaluation. Neuropathic wounds are more
likely to heal over a period of 20 weeks, while neuroischemic ulcers take longer
and will more often lead to limb amputation. It has been found that 4070% of all
nontraumatic amputations of the lower limbs occur in patients with diabetes.
Furthermore, many studies have reported that foot ulcers precede approximately
85% of all amputations performed in diabetic patients. The risk of foot ulceration
and limb amputation increases with age and the duration of diabetes. The
prevention of diabetic foot is crucial, considering the negative impact on a
patients quality of life and the associated economic burden on the healthcare
system.4-6 The factors that delay wound healing in diabetes are multiple and relate
both to the impaired glucose metabolism and to the effect of neurovascular
complications. Diabetic foot ulcers readily become chronic; all too often these
wounds do not heal primarily. Treatment of chronic wounds should be essentially
directed against the main etiologic factors responsible for the wound.
Management is based on the simple principles of eliminating infection, the use of
dressings to maintain a moist wound bed and to absorb exsudate, offloading high
pressure from the wound bed, and debridement to accelerate endogenous healing
and facilitate the effectiveness of topically applied substances.7 Diabetic foot
ulceration is a major health problem and its management involves a
multidisciplinary approach. This review aims to provide a synopsis of the current
management strategies of diabetic foot ulcers, from prevention to the options for
treatment.
II. LITERATURE REVIEW

2.1 Diabetic Wounds

Diabetic wound / Diabetic foot ulcers (DFUs), a leading cause of amputations,


affect 15% of people with diabetes. Individuals suffering from diabetes and
neuropathy with no other confounders will develop an ulcer in 710% of the
cases annually, whereas the rate for patients with additional risk factors, such
as peripheral arterial disease (PAD), foot deformity, previous ulcers or
previous amputation is 2530%. Major amputation will be needed within 1
year in 5-8% of patients with diabetic ulcers.Of all amputations on diabetic
patients, 85% are preceded by a foot ulcer which subsequently deteriorates to
a severe infection or gangrene. Diabetes increases the risk of amputation 8-
fold in patients aged >45 years,8 12-fold in patients aged >65 years and 23-
fold in those aged 6574 years.8

A series of multiple mechanisms, including decreased cell and growth factor


response, lead to diminished peripheral blood flow and decreased local
angiogenesis, all of which can contribute to lack of healing in persons with
DFUs. DFUs are complex, chronic wounds, which have a major long-term
impact on the morbidity, mortality and quality of patients lives. Individuals
who develop a DFU are at greater risk of premature death, myocardial
infarction and fatal stroke than those without a history of DFU. Unlike other
chronic wounds, the development and progression of a DFU is often
complicated by wide-ranging diabetic changes, such as neuropathy and
vascular disease. These, along with the altered neutrophil function, diminished
tissue perfusion and defective protein synthesis that frequently accompany
diabetes, present practitioners with specific and unique management
challenges.9
Globally, DFUs have a major economic impact. A US study in 1999 estimated
the average outpatient cost of treating one DFU episode as $28,000 USD over
a twoyear period9. Average inpatient costs for lower limb complications in
1997 were reported as $16,580 USD for DFUs, $25,241 USD for toe or toe
plus other distal amputations and $31,436 USD for major amputations.9,10 The
EURODIALE study examined total direct and indirect costs for one year
across several European countries. Average total costs based on 821 patients
were approximately 10,000 euros, with hospitalization representing the
highest direct cost. Based on prevalence data for Europe, they estimated that
costs associated with treatment of DFUs may be as high as 10 billion euros per
year.11 In England, foot complications account for 20% of the total National
Health Service spend on diabetes care, which equates to around 650 million
per year (or 1 in every 150)5. Of course, these figures do not take account
of the indirect costs to patients, such as the effect on physical, psychological
and social wellbeing and the fact that many patients are unable to work long
term as a result of their wounds.11

A DFU is a pivotal event in the life of a person with diabetes and a marker of
serious disease and comorbidities. Without early and optimal intervention, the
wound can rapidly deteriorate, leading to amputation of the affected limb. It
has been estimated that every 20 seconds a lower limb is amputated due to
complications of diabetes. In Europe, the annual amputation rate for people
with diabetes has been cited as 0.5-0.8%, and in the US it has been reported
that around 85% of lower-extremity amputations due to diabetes begin with
foot ulceration.12 Mortality following amputation increases with level of
amputation and ranges from 5068% at five years, which is comparable or
worse than for most malignancies.13

It has been suggested that up to 85% of amputations can be avoided when an


effective care plan is adopted. Unfortunately, insufficient training, suboptimal
assessment and treatment methods, failure to refer patients appropriately and
poor access to specialist footcare teams hinder the prospects of achieving
optimal outcomes. Successful diagnosis and treatment of patients with DFUs
involves a holistic approach that includes:

Optimal diabetes control


Effective local wound care
Infection control
Pressure relieving strategies
Restoring pulsatile blood flow.

Many studies have shown that planned intervention aimed at healing of DFUs
is most effective in the context of a multidisciplinary team with the patient at
the centre of this care. One of the key tenets underpinning this document is
that infection is a major threat to DFUs, much more so than to wounds of
other etiologies not subject to diabetic changes. A European-wide study found
that 58% of patients attending a foot clinic with a new ulcer had a clinically
infected wound. Similarly a single-centre US study found that about 56% of
DFUs were clinically infected. This study also showed the risk of
hospitalization and lower-extremity amputation to be 56155 times greater for
diabetes patients with a foot infection than those without. Recognizing the
importance of starting treatment early may allow practitioners to prevent
progression to severe and limb threatening infection and potentially halt the
inevitable pathway to amputation.14-16
2.2 Etiology and Pathogenesis of Diabetic Wound

The most significant risk factors for foot ulceration are diabetic neuropathy,
peripheral arterial disease, and consequent traumas of the foot. In most
patients, peripheral neuropathy and peripheral arterial disease (PAD) (or
both) play a central role and DFUs are therefore commonly classified as 17:

Neuropathic
Ischaemic
Neuroischaemic

Diabetic neuropathy is the common factor in almost 90% of diabetic foot


ulcers. Nerve damage in diabetes affects the motor, sensory, and autonomic
fibers. Motor neuropathy causes muscle weakness, atrophy, and paresis.
Sensory neuropathy leads to loss of the protective sensation of pain, pressure,
and heat. Autonomic dysfunction causes vasodilation and decreased sweating,
resulting in a loss of skin integrity, providing a site vulnerable to microbial
infection. Peripheral neuropathy may predispose the foot to ulceration through
its effects on the sensory, motor and autonomic nerves:

The loss of protective sensation experienced by patients with sensory


neuropathy renders them vulnerable to physical, chemical and thermal
trauma. In patients with peripheral diabetic neuropathy, loss of sensation
in the feet leads to repetitive minor injuries from internal (calluses, nails,
foot deformities) or external causes (shoes, burns, foreign bodies) that are
undetected at the time and may consequently lead to foot ulceration. This
may be followed by infection of the ulcer, which may ultimately lead to
foot amputation, especially in patients with peripheral arterial disease.
Motor neuropathy can cause foot deformities (such as hammer toes and
claw foot), which may result in abnormal pressures over bony
prominences. Structural foot deformities and abnormalities, such as
flatfoot, hallux valgus, claw toes, Charcot neuroarthropathy, and hammer
foot, play an important role in the pathway of diabetic foot ulcers since
they contribute to abnormal plantar pressures and therefore predispose to
ulceration.
Autonomic neuropathy is typically associated with dry skin, which can
result in fissures, cracking and callus. Another feature is bounding pulses,
which is often misinterpreted as indicating a good circulation28.

Loss of protective sensation is a major component of nearly all DFUs. It is


associated with a sevenfold increase in risk of ulceration6. Patients with a
loss of sensation will have decreased awareness of pain and other symptoms
of ulceration and infection.17

Peripheral arterial disease is 28 times more common in patients with


diabetes, starting at an earlier age, progressing more rapidly, and usually being
more severe than in the general population. PAD in diabetics is often
multisegmental, typically infrapopliteal and poorly collateralised. It has been
proven to be an independent risk factor for cardiovascular disease as well as a
predictor of the outcome of foot ulceration. Almost all diabetic patient have
micro & or macroangiopathy causing decrease oxygenation of tissue. Ischemia
causes tissue to become inflamed and cells to release factors that attract
neutrophils. While they fight pathogens, neutrophils also release inflammatory
cytokines and enzymes that damage cells. They also produce ROS (Reactive
oxygen species) to kill bacteria, for which they use an enzyme called
myeloperoxidase. The enzymes and ROS produced by neutrophils and other
leukocytes damage cells and prevent cell proliferation and wound closure by
damaging DNA,lipids, proteins,the ECM, and cytokines (who speed healing).
Neutrophils remain in chronic wounds for longer than they do in acute
wounds, and contribute to the fact that chronic wounds have higher levels of
inflammatory cytokines and ROS.18

The majority of foot ulcers are of mixed etiology (neuroischemic), particularly


in older patients. Neuroischaemia is the combined effect of diabetic
neuropathy and ischaemia, whereby macrovascular disease and, in some
instances, microvascular dysfunction impair perfusion in a diabetic foot.
Neuroischaemia is the combined effect of diabetic neuropathy and ischaemia,
impairing the oxygen delivery to meet metabolic tissue demands in a
synergetic way. Macrovascular disease and microvascular dysfunction both
impair perfusion in a diabetic foot. Peripheral autonomic neuropathy, or auto-
sympathectomy, causes deficient sweating and altered blood flow regulation
with an opening of arteriovenous shunts and precapillary sphincter
malfunction, which decreases nutritive blood flow and manifests as warm, dry
skin, increasing the likelihood of skin breakdown. The microvascular
dysfunction is further characterised by the subsequent capillary leakage and
venous pooling as well as hormonal activity in the vessel and inflammation in
the wall, all indicating that decreased perfusion in the diabetic foot is more
complex and not only related to PAD. Yet PAD is the most important cause of
vascular impairment of diabetic foot.18

Other risk factors for foot ulceration include a previous history of foot
ulceration or amputation, visual impairment, diabetic nephropathy, poor
glycemic control, and cigarette smoking. Some studies have shown that foot
ulceration is more common in men with diabetes than in women. Social
factors, such as low socioeconomic status, poor access to healthcare services,
and poor education are also proven to be related to more frequent foot
ulceration. DFUs usually result from two or more risk factors occurring
together. Intrinsic elements such as neuropathy, PAD and foot deformity
(resulting, for example, from neuropathic structural changes), accompanied by
an external trauma such as poorly fitting footwear or an injury to the foot can,
over time, lead to a DFU.18
Fig. 1. Pathway to diabetic ulcer. Modified from the International Working Group
on the Diabetic Foot, International Consensus on the Diabetic Foot

2.3 Physiological Process of Wound Healing

Research regarding acute wounds in animal models demonstrates that wounds


heal in 4 phases. It is believed that chronic wounds also undergo 4 basic
phases of healing (although some authors combine the first 2 phases). These
are19,20 :

a. Hemostasis
Once the source of damage to a house has been removed and before work
can start, utility workers must cap damaged gas or water lines. So, too, in
wound healing must damaged blood vessels be sealed. In wound healing,
the platelets are the cells that act as utility workers sealing off the damaged
blood vessels. The blood vessels themselves constrict in response to
injury, but this spasm ultimately relaxes. The platelets secrete
vasoconstrictive substances to aid this process, but their prime role is to
form a stable clot sealing the damaged vessel. Under the influence of ADP
(adenosine diphosphate) leaking from damaged tissues, the platelets
adhere to the exposed type 1 collagen. They become activated and secrete
adhesive glycoproteins, leading to platelet aggregation. They also secrete
factors that interact with and stimulate the intrinsic clotting cascade
through the production of thrombin, which in turn initiates the formation
of fibrin from fibrinogen. The fibrin mesh strengthens the platelet
aggregate into a stable hemostatic plug. Finally, platelets also secrete
growth factors such as platelet-derived growth factor, which is recognized
as one of the first factors in initiating the subsequent healing steps. These
growth factors recruit neutrophils and monocytes (initiating the next phase
of wound healing), stimulate epithelial cells and recruit fibroblasts.
Hemostasis occurs within minutes of the initial injury unless the patient
has underlying clotting disorders.

b. Inflammation
Clinically, inflammation (the second stage of wound healing) presents as
erythema, swelling and warmth often associated with pain, the classic
rubor et tumor cum calore et dolore. This stage usually lasts up to 4 days
post injury. In the damaged house analogy, once the utilities are capped
the second job is to clean up the debris. This is a job for unskilled
labourers. In a wound, these unskilled labourers are the neutrophils
(polymorphonucleocytes). The inflammatory response causes the blood
vessels to become leaky, releasing asma and neutrophils into the
surrounding tissue. The neutrophils phagocytose debris and
microorganisms and provide the first line of defence against infection. As
they digest bacteria and debris, neutrophils die and release intracellular
enzymes into the surrounding matrix, which further digest tissue. As fibrin
is broken down as part of this clean-up, the degradation products attract
the next cells involved such as fibroblasts and epithelial cells. They are
aided by local mast cells. The task of repairing a house is complex and
requires someone, such as a contractor, to direct this activity. Similarly,
wound repair requires coordinated cell activity and good cell-to-cell
communication. Cells communicate through soluble proteins call
cytokines and growth factors. These cytokines and growth factors are
released by 1 cell and bind to a receptor on a target cell. Once a cytokine
binds to a target cell it stimulates the cell to move. Growth factors, on the
other hand, stimulate the target cell to either divide and produce more cells
or synthesize and release substances such as collagen, which is required to
form the extracellular matrix. The extracellular matrix also plays an active
role in wound healing by interacting with the cells through receptors called
integrins, leading to platelet activation, epithelial migration and fibroblast
movement. In wound healing, cells known as macrophages act as the
contractors. Circulating monocytes differentiate into macrophages after
they exit the blood vessels and come in contact with the extracellular
matrix. Macrophages are able to phagocytose bacteria and provide a
second line of defence. Macrophages also secrete extracellular enzymes to
degrade necrotic tissue at the wound site. These enzymes belong to a
family of substances called matrix metalloproteases (MMPs). MMPs
require calcium to form a functional shape and zinc for the active site.

About 20 different types of MMPs are secreted by many different cells


including neutrophils, macrophages, epithelial cells and fibroblasts under
the influence of inflammatory cytokines such as tumour necrosis factor-
alpha and interleukin-1 and -6. MMPs act on all components of the
extracellular matrix and are responsible for removing devitalized tissue,
repairing lost or damaged tissue and remodelling. MMPs are balanced by
tissue inhibitors of metalloproteases (TIMPs), which are released locally
by cells and inactivate MMPs by reversibly binding to them. Uncontrolled
MMPs can degrade newly formed tissue or destroy growth factors.
Macrophages secrete a variety of cytokines and growth factors, such as
fibroblast growth factor, epidermal growth factor, transforming growth
factor-beta and interleukin-1, which appear to direct the next stage.

c. Proliferation
The proliferation phase starts approximately 4 days after wounding and
usually lasts until day 21 in acute wounds, depending on the size of the
wound and the health of the patient. It is characterized by angiogenesis,
collagen deposition, granulation tissue formation, wound contraction and
epithelialization. Clinically, proliferation is observed by the presence of
pebbled red tissue or collagen in the wound base and involves replacement
of dermal tissues and sometimes subdermal tissues in deeper wounds, as
well as contraction of the wound. In the house analogy, once the site has
been cleared of debris under the direction of the contractor, framers move
in to build the framework of the new house. Subcontractors can now
install new plumbing and wiring on the framework and siders and roofers
can finish the exterior of the house. The framer cells are fibroblasts,
which secrete the collagen framework on which further dermal
regeneration occurs. Specialized fibroblasts are responsible for wound
contraction. The plumber cells are the pericytes, which regenerate the
outer layers of capillaries, and the endothelial cells, which produce the
lining. This process is called angiogenesis. The roofer and sider cells
are the keratinocytes, which are responsible for epithelialization. In the
final stage of epithelialization, contracture occurs as the keratinocytes
differentiate to form the protective outer layer or stratum corneum. In a
healing wound, the cells under the influence of growth factors divide to
produce new cells, which migrate to where they are needed under the
influence of cytokines. There is a balance between the MMPs and TIMPs
so that there is a net production of new tissue. In chronic wounds, in
contrast, in which healing is stalled, cell division and migration are
suppressed, there are high levels of inflammatory cytokines and MMPs,
and low levels of TIMPs and growth factors. Cells are often senescent and
unresponsive to the growth factors. This lack of response is characteristic
of a chronic inflammatory state. It may be caused by an increased bacterial
burden, the presence of devitalized tissue, chronic ischemia or repetitive
trauma.

d. Remodelling
Once the basic structure of the house is completed, interior finishing may
begin. Similarly, in wound repair, the healing process involves
remodelling and realignment of the collagen tissue to produce greater
tensile strength. In addition, cell and capillary density decrease. The main
cells involved in this process are the fibroblasts. Remodelling can take up
to 2 years after wounding. This explains why closed wounds can quickly
breakdown if attention is not paid to the initial causative factors.

2.4 Patophysiology of Wound Healing in Diabetes

Diabetes mellitus affects soft tissue healing via metabolic, vascular, and
neuropathic pathways. Wound healing in diabetes is impaired by factors that
are both extrinsic and intrinsic to the wound and its biology. Extrinsic factors
include repeated trauma or mechanical stress applied to a foot that has been
rendered insensitive due to neuropathy as well as ischemia as a result of macro
or microvascular disease. Thickening of the basement membrane of the
capillaries and arterioles frequently occurs in individuals with diabetes,
resulting in an impaired wound healing and persistent ulcer formation. Factors
that affect the microcirculation in diabetes include stiffened red blood cells
and increased blood viscosity; susceptibility of the tibial and peroneal arteries
to atherosclerosis; high venous back-pressure in the lower extremities that
increases transudation and edema; affinity of glycosylated hemoglobin for
oxygen contributing to low oxygen delivery at the capillary; and impaired
phagocytosis and bacterial killing, which along with neuropathy and ischemia
make the patient vulnerable to infection. Moreover, this population is prone to
develop chronic non-healing diabetic foot ulcers (DFUs). The impaired
healing of both DFUs and acute cutaneous wounds in persons with diabetes
involves multiple complex pathophysiological mechanisms.21

DFUs, like venous stasis disease and pressure-related chronic non-healing


wounds, are always accompanied by hypoxia. A situation of prolonged
hypoxia, which may be derived from both insufficient perfusion and
insufficient angiogenesis, is detrimental for wound healing. Hypoxia can
amplify the early inflammatory response, thereby prolonging injury by
increasing the levels of oxygen radicals. As mentioned above, hypoxia
contributes to the compromised healing of DFUs, and diabetic wounds exhibit
inadequate angiogenesis. Several studies that have investigated the
mechanisms behind the decreased restoration of vasculature in diabetic
wounds have implied that EPC mobilization and homing are impaired, and
that the level of VEGF, the primary pro-angiogenic factor in wounds, is
decreased in the diabetic state. Stem-cell-based therapies aimed at inducing
EPCs or BM-MSCs have shown a promising outcome in diabetic non-healing
wounds, both in animals and in clinical trials. In animal studies, therapeutic
restoration of VEGF has been shown to improve repair outcomes
significantly.21

An important role has been attributed to factors intrinsic to the biology of the
chronic wound in diabetes. It has been postulated that hyperglycaemia itself
has a deleterious effect on wound healing through the formation of advanced
glycation end-products (AGEs)which induce the production of inflammatory
molecules (TNF-, IL-1) and interfere with collagen synthesis. Furthermore,
Spravchikov et al. showed that exposure to high glucose is associated with
changes in cellular morphology, decreased proliferation, and abnormal
differentiation of keratinocytes, thus revealing another mechanism by which
hyperglycaemia may affect wound healing in diabetes. Interestingly, the
healing times of leg and foot ulcers are decreased in diabetic patients with
lower HbA1c, thereby emphasizing the clinical correlation between
hyperglycaemia and impaired wound healing. Hyperglycemia can also add to
the oxidative stress when the production of ROS exceeds the anti-oxidant
capacity. The formation of advanced glycation end-products (AGEs) under
hyperglycemia and the interaction with their receptors (RAGE) are associated
with impaired wound healing in diabetic mice as well.22

Several dysregulated cellular functions are involved in diabetic wounds, such


as defective T-cell immunity, defects in leukocyte chemotaxis, phagocytosis,
and bactericidal capacity, and dysfunctions of fibroblasts and epidermal cells.
These defects are responsible for inadequate bacterial clearance and delayed
or impaired repair in individuals with diabetes. Decreased chemotaxis,
phagocytosis, bacterial killing, and reduced heat shock protein expression
have been implicated in the early phase of wound healing in diabetes. Altered
leukocyte infiltration and wound fluid IL-6 characterize the late inflammatory
phases of wound healing in diabetes. It therefore seems that an altered pattern
of cytokine appearance in the wound milieu may contribute to delayed wound
healing in diabetes. This is substantiated by the fact that altered bioavailability
of cytokines and growth factors have been implicated in the pathogenesis of
chronic wounds. These signalling molecules are secreted by various cell types
to control cellular proliferation, differentiation, migration, and metabolism.
Abnormal expression of growth factors has been observed in diabetic foot
ulcers. It has been postulated that trapping of growth factors and cytokines by
certain macromolecules such as albumin, fibrinogen, and 2-macroglobulin
may disrupt the healing process. Furthermore, increased degradation of
growth factors in wound fluid of diabetic subjects has been discussed as a
factor contributing to an impaired wound healing process. For example,
Duckworth et al. have reported an increased activity of insulin degrading
enzyme (IDE) activity in wound fluid from patients with diabetic foot ulcers.
Interestingly, insulin degrading activity in the wound fluid was found to be
positively correlated with HbA1c levels, thereby supporting the fact that
glucose control is an essential prerequisite for wound healing.23
In addition, normal wound healing requires a balance between the
accumulation of collagenous and noncollagenous extracellular matrix
components. Their remodelling is determined by matrix metalloproteinases
(MMPs) and the tissue inhibitors of metalloproteinases (TIMPs). MMPs play
essential roles in initialwound debridement as well as in angiogenesis,
epithelialization, and remodelling of scar tissue. High levels of
metalloproteases are a feature of diabetic foot ulcers, and the MMP levels in
chronic wound fluid are almost 60 times higher than those in acute wounds.
This increased protease activity supports tissue destruction and inhibits normal
repair processes.

The neuropathy that occurs in diabetic individuals probably also contributes to


impaired wound healing. Neuropeptides such as nerve growth factor,
substance P, and calcitonin gene-related peptide are relevant to wound
healing, because they promote cell chemotaxis, induce growth factor
production, and stimulate the proliferation of cells. A decrease in
neuropeptides has been associated with DFU formation. In addition, sensory
nerves play a role in modulating immune defense mechanisms, with
denervated skin exhibiting reduced leukocyte infiltration. In summary, the
impaired healing that occurs in individuals with diabetes involves hypoxia,
dysfunction in fibroblasts and epidermal cells, impaired angiogenesis and
neovascularization, high levels of metalloproteases, damage from ROS and
AGEs, decreased host immune resistance, and neuropathy.
Fig 2. Mechanisms of wound healing in healthy people versus people with
diabetes

2.5 Assesment of Diabetic Foot Ulcer

For the non-specialist practitioner, the key skill required is knowing when and
how to refer a patient with a DFU to the multidisciplinary footcare team
(MDFT). Patients with a DFU should be assessed by the team within one
working day of presentation, or sooner in the presence of severe infection. In
many places, however, MDFTs do not exist and practitioners instead work as
individuals. In these situations, the patients prognosis often depends on a
particular practitioners knowledge and interest in the diabetic foot. Patients
with a DFU need to be assessed holistically to identify intrinsic and extrinsic
factors. This should encompass a full patient history including medication,
comorbidities and diabetes status. It should also take into consideration the
history of the wound, previous DFUs or amputations and any symptoms
suggestive of neuropathy or PAD. Physical examination of the diabetic foot is
based on assessment of the skin and of the vascular, neurological, and
musculoskeletal systems.24 Below are the details of assessment of diabetic
foot ulcer from International Best Practice Guidelines. 25

a. Examination of Ulcers
The dermatological examination includes a visual inspection of the skin of
the legs and feet, particularly the dorsal, plantar, medial, lateral, and
posterior surfaces, as well as a close examination of each toenail. Other
observations to be noted include the presence of peeling skin and
maceration or fissuring of the interdigital skin. The visual inspection may
discover signs of autonomic neuropathy and sudomotor dysfunction. A
physical examination should determine:

Is the wound predominantly neuropathic, ischaemic or


neuroischaemic?
If ischaemic, is there critical limb ischaemia?
Are there any musculoskeletal deformities?
What is the size/depth/location of the wound?
What is the colour/status of the wound bed?
Is there any exposed bone?
Is there any necrosis or gangrene?
Is the wound infected? If so, are there systemic signs and symptoms of
infection (such as fevers, chills, rigors, metabolic instability and
confusion)?
Is there any malodour?
Is there local pain?
Is there any exudate? What is the level of production (high, moderate,
low, none), colour and consistency of exudate, and is it purulent?
What is the status of the wound edge (callus, maceration, erythema,
oedema, undermining )?
b. Documenting ulcer characteristics
Recording the size, depth, appearance and location of the DFU will help to
establish a baseline for treatment, develop a treatment plan and monitor
any response to interventions. It is important also to assess the area around
the wound: erythema and maceration indicate additional complications
that may hinder wound healing. Digitally photographing DFUs at the first
consultation and periodically thereafter to document progress is helpful.
This is particularly useful for ensuring consistency of care among
healthcare practitioners, facilitating telehealth in remote areas and
illustrating improvement to the patient.
.
c. Testing for loss sensation
The physical examination of the foot assesses the perception of superficial
pain (pinprick), temperature sensation (using a two-metal rod), light
sensation (using the edge of a cotton-wool twist), and pressure (using the
SemmesWeinstein 5.07 monofilament). Additionally, the physician
should examine the vibration perception using a tuning fork and/or a
biothesiometer. The examination of position sense (proprioception) and
deep tendon reflexes (Achilles tendon, patellar) is also essential.

The 10g monofilament is the most frequently used screening tool to


determine the presence of neuropathy in patients with diabetes. It should
be applied at various sites along the plantar aspect of the foot. Guidelines
vary in the number of sites advocated, but the international consensus is to
test at three sites (see Figure 3). A positive result is the inability to feel the
monofilament when it is pressed against the foot with enough force to
bend it. Neuropathy is also demonstrated by an inability to sense vibration
from a standard tuning fork. Other tests are available, such as the
biothesiometer and neurothesiometer, which are more complex handheld
devices for assessing the perception of vibration. Do not test for
neuropathy in areas of callus as this can mask feeling from any of the
neuropathy testing devices and may give a false-positive result. Be aware
that patients with small nerve fibre damage and intact sensory nerves may
have a painful neuropathy. They may describe sharp, stabbing, burning,
shooting or electric shock type pain, which may be worse at night and can
disrupt sleep. The absence of coldwarm discrimination may help to
identify patients with small nerve fibre damage.

Fig 3. Monofilament test, IWGDF recommendation

The presence of diabetic neuropathy can be established from an


abbreviated medical history and physical examination. Symptoms such as
a burning sensation; pins and needles; shooting, sharp, or stabbing pains;
and muscle cramps, which are distributed symmetrically in both limbs
(stocking and glove distribution), and often worse at night, are usually
present in peripheral neuropathy. Diabetic peripheral neuropathy may also
be evaluated using the Neuropathy Symptom Score (NSS), which is a
validated symptom score with a high predictive value to screen for
peripheral neuropathy in diabetes
Neuropathic deficits in the feet can be determined using the Neuropathy
Disability Score (NDS), which is derived from the inability to detect
pinprick sensation (using a neurological examination pin), vibration (using
a 128-Hz tuning fork), or differences in temperature sensation (using
warm and cool rods), and loss or reduction of the Achilles reflex (using a
tendon hammer). According to the American Diabetes Association, a foot
that has lost its protective sensation is considered to be a foot at risk for
ulceration. The diagnosis of a foot at risk is confirmed by a positive
5.07/10-g monofilament test, plus one of the following tests: vibration test
(using 128-Hz tuning fork or a biothesiometer), pinprick sensation, or
ankle reflexes. The above tests have been reported to have a positive
predictive value of 46% and a negative predictive value of 87% for the
risk of incident neuropathy.

d. Testing for Vascular Status


Palpation of peripheral pulses should be a routine component of the
physical examination and include assessment of the femoral, popliteal and
pedal (dorsalis pedis and posterior tibial) pulses. Assessment of pulses is a
learned skill and has a high degree of inter-observer variability, with high
falsepositive and false-negative rates. The dorsalis pedis pulse is reported
to be absent in 8.1% of healthy individuals, and the posterior tibial pulse is
absent in 2.0%. Nevertheless, the absence of both pedal pulses, when
assessed by an experienced clinician, strongly suggeststhe presence of
pedal vascular disease. If there is any doubt regarding diagnosis of PAD, it
is important to refer to a specialist for a full vascular assessment. Where
available, Doppler ultrasound, anklebrachial pressure index (ABPI) and
Doppler waveform may be used as adjuncts to the clinical findings when
carried out by a competent practitioner. Toe pressures, and in some
instances, transcutaneous oxygen measurement (where equipment is
available), may be useful for measuring local tissue perfusion. An
ischaemic foot may appear pink and relatively warm even with impaired
perfusion due to arteriovenous shunting. Delayed discolouration (rubor) or
venous refilling greater than five seconds on dependency may indicate
poor arterial perfusion. Other signs suggestive of ischaemia include:

Claudication: pain in the leg muscles and usually exercise-induced


(although this is often absent in people with diabetes)
A temperature difference between the feet. If you suspect severe
ischaemia in a patient with a DFU you should refer as quickly as
possible to a MDFT with access to a vascular surgeon. If the patient
has critical limb ischaemia this should be done urgently. A patient with
acute limb ischaemia characterized by the six Ps (pulselessness, pain,
pallor [mottled colouration], perishing cold, paraesthesia and paralysis)
poses a clinical emergency and may be at great risk if not managed in a
timely and effective way

Inadequate perfusion of a limb, due to peripheral vascular disease, may


crucially affect the progress of the healing of an ulcer, often resulting in
chronic unhealed ulcers that are susceptible to infection. A relatively
simple method to confirm the clinical suspicion of arterial occlusive
disease is to measure the resting systolic blood pressure in the ankles and
arms. This is performed by measuring the systolic blood pressure (using a
Doppler probe) in the brachial, posterior tibial, and dorsalis pedis arteries.
The highest of the four measurements in the ankles and feet is divided by
the higher of the two brachial measurements. This ratio is referred to as the
anklebrachial index (ABI). Normal ABI values range from 1.0 to 1.3,
since the pressure is higher in the ankle than in the arm. Values over 1.3
suggest a noncompressible calcified vessel. An ABI of less than 0.9 is
indicative of peripheral vascular disease and is associated with 50% or
more stenosis in one or more major vessels. An ABI of 0.40.9 suggests a
degree of arterial obstruction associated with claudication. An ABI of less
than 0.4 or an ankle systolic pressure of less than 50 mmHg represents
advanced ischemia. The ABI correlates with clinical measures of lower
extremity function, such as walking distance, velocity, balance, and
overall physical activity. In addition, a low ABI has been associated with a
higher risk of coronary heart disease, stroke, transient ischemic attack,
progressive renal insufficiency, and all-cause mortality. A potential
limitation of the ABI is that calcified vessels may not compress normally,
possibly resulting in falsely elevated Doppler signals. Thus, an ABI of
over 1.3 is suggestive of calcified vessels. In such patients, an accurate
pressure may be obtained by measuring the blood pressure in the toe and
calculating the toebrachial index. If ABIs are normal at rest but
symptoms strongly suggest claudication, ABIs and segmental pressures
should be obtained before and after exercise on a treadmill. This may
unmask a hemodynamically significant stenosis that is subclinical at rest
but significant on exertion.

Diabetic foot ulcers are defined as: neuropathic in the presence of


peripheral diabetic neuropathy and absence of ischemia; ischemic if the
patient presents peripheral artery disease but no diabetic peripheral
neuropathy; and neuroischemic if neuropathy and ischemia coexist. Apart
from this rather crude classification, many efforts have been made to
categorize foot ulcers according to extent, size and depth, location,
presence of infection, and ischemia. The MeggittWagner classification is
one of the most popular validated classifications for the foot ulcers
(Table 1). Other classification systems for diabetic foot ulcers have also
been proposed and validated.

Grade Description of the ulcer


0 Pre- or postulcerative lesion completely epithelialized
1 Superficial, full-thickness ulcer limited to the dermis, not
extending to the subcutis
2 Ulcer of the skin extending through the subcutis with exposed
tendon or bone and without osteomyelitis or abscess formation
3 Deep ulcers with osteomyelitis or abscess formation
4 Localized gangrene of the toes or the forefoot
5 Foot with extensive gangrene
Table 1 MeggittWagner classification of foot ulcers
Whatever method is used for the diabetic foot ulcer evaluation, all
classification systems should aim at facilitating the correct choice of
treatment and reliable monitoring of the healing progress of the ulcer,
while at the same time serving as a communication tool across specialties.

e. Identifying Infection
Recognising infection in patients with DFUs can be challenging, but it is
one of the most important steps in the assessment. It is at this crucial early
stage that practitioners have the potential to curb what is often progression
from simple (mild) infection to a more severe problem, with necrosis,
gangrene and often amputation. Around 56% of DFUs become infected
and overall about 20% of patients with an infected foot wound will
undergo a lower extremity amputation.

Risk factors for infection


Practitioners should be aware of the factors that increase the likelihood of
infection:
A positive probe-to-bone test
DFU present for more than 30 days
A history of recurrent DFUs
A traumatic foot wound
The presence of PAD in the affected limb
A previous lower extremity amputation
Loss of protective sensation
The presence of renal insufficiency
A history of walking barefoot.

The frequent occurrence of arterial insufficiency, an immunocompromised


state and loss of pain sensation means that up to half of patients may not
present with the classic signs of infection and inflammation, such as
redness, heat and swelling. Practitioners should therefore seek the
presence of more subtle 'secondary' signs suggestive of infection,
including friable granulation tissue, wound undermining, malodour or
wound exudate.

Clinical diagnosis and cultures


A diagnosis of diabetic foot infection must be made using clinical signs
and symptoms, not just microbiological results. All open wounds will be
colonised with organisms, making the positive culture difficult to interpret.
The IWGDF and the Infectious Disease Society of America (IDSA) have
developed validated clinical criteria for recognising and classifying
diabetic foot infection. If infection is suspected, practitioners should take
appropriate cultures, preferably soft tissue (or bone when osteomyelitis is
suspected), or aspirations of purulent secretions. Some advocate using a
deep swabbing technique after the wound has been cleansed and debrided.
Superficial swabbing has been shown to be inaccurate as swab cultures are
likely to grow surface contaminants and often miss the true pathogen(s)
causing the infection.

Most acute infections in patients who have not recently been treated with
antimicrobials are caused by aerobic Gram-positive cocci, especially
staphylococci. More chronic infections, or those occurring after antibiotic
treatment are often polymicrobial, with aerobic Gram-negative bacilli
joining the aerobic Gram-positive cocci. Obligate anaerobes may be
isolated with proper techniques, usually as co-pathogens with aerobes, in
ischaemic or necrotic wounds. Tissue specimens or deep swabs should
therefore be cultured for both aerobic and anaerobic organisms. Cultures
should not be taken from clinically non-infected wounds as all ulcers will
be contaminated; microbiological sampling cannot discriminate
colonisation from infection.

Extensive inflammation, crepitus, bullae, necrosis or gangrene are signs


suggestive of severe foot infections. Refer patients immediately to an
MDFT if you suspect a deep or limbthreatening infection. Where there is
no MDFT, the referral should be to the most appropriate practitioner,
notably the person(s) championing the cause of the diabetic foot, for
example an experienced foot surgeon. Refer patients urgently to a member
of the specialist foot care team for urgent surgical treatment and prompt
revascularisation if there is acute spreading infection (Box 1), critical limb
ischaemia, wet gangrene or an unexplained hot, red, swollen foot with or
without the presence of pain. These clinical signs and symptoms are
potentially limb- and even life-threatening.

Where necrosis occurs on the distal part of the limb due to ischaemia and
in the absence of infection (dry gangrene), mummification of the toes and
auto-amputation may occur. In most of these situations, surgery is not
recommended. However, if the necrosis is more superficial then the toe
can be removed with a scalpel.

Assessing bone involvement


Osteomyelitis may frequently be present in patients with moderate to
severe diabetic foot infection. If any underlying osteomyelitis is not
identified and treated appropriately, the woundis unlikely to heal.
Osteomyelitis can be difficult to diagnose in the early stages. Wounds that
are chronic, large, deep or overlie a bony prominence are at high risk for
underlying bone infection, while the presence of a 'sausage toe' or visible
bone is suggestive of osteomyelitis. A simple clinical test for bone
infection is detecting bone by its hard, gritty feel when gently inserting a
sterile blunt metal probe into the ulcer. This canhelp to diagnose bone
infection (when the likelihood is high) or exclude (when the likelihood is
low).

Plain x-rays can help to confirm the diagnosis, but they have a relatively
low sensitivity (early in the infection) and specificity (late in the course of
infection) for osteomyelitis. The National Institute for Health and Care
Excellence (NICE) in the UK and IDSA recommend that if initial x-rays
do not confirm the presence of osteomyelitis and suspicion remains high,
the next advanced imaging test to consider is magnetic resonance imaging
(MRI). If MRI is contraindicated or unavailable, white blood cell scanning
combined with a radionuclide bone scan may be performed instead. The
most definitive way to diagnose osteomyelitis is by the combined findings
of culture and histology from a bone specimen. Bone may be obtained
during deep debridement or by biopsy.

f. Inspecting for Foot Deformities


Excessive or abnormal plantar pressure, resulting from limited joint
mobility, often combined with foot deformities, is a common underlying
cause of DFUs in individuals with neuropathy. These patients may also
develop atypical walking patterns (Figure 7). The resulting altered
biomechanical loading of the foot can result in callus, which increases the
abnormal pressure and can cause subcutaneous haemorrhage. Because
there is commonly loss of sensation, the patient continues to walk on the
foot, increasing the risk of further problems. Typical presentations
resulting in high plantar pressure areas in patients with motor neuropathy
are:
A high-arch foot
Clawed lesser toes
Visible muscle wasting in the plantar arch and on the dorsum between
the metatarsal shafts (a hollowed-out appearance)
Gait changes, such as the foot slapping on the ground
Hallux valgus, hallux rigidus and fatty pad depletion.

In people with diabetes, even minor trauma can precipitate a chronic ulcer.
This might be caused by wearing poorly fitting footwear or walking
barefoot, or from an acute injury. In some cultures the frequent adoption of
the prayer position and/or sitting cross-legged will cause ulcerations on the
lateral malleoli, and to a lesser extent the dorsum of the foot, in the mid-
tarsal area. The dorsal, plantar and posterior surfaces of both feet and
between the toes should be checked thoroughly for breaks in the skin or
newly established DFUs. that occurs most often in the foot and in people
with diabetes. Nerve damage from diabetes causes decreased sensation,
muscle atrophy and subsequent joint instability, which is made worse by
walking on an insensitive joint. In the acute stage there is inflammation
and bone reabsorption, which weakens the bone. In later stages, the arch
falls and the foot may develop a rocker bottom appearance (Figure 8).
Early treatment, particularly offloading pressure, can help stop bone
destruction and promote healing. Corrective foot surgery to offload
pressure areas may be considered where structural deformities cannot be
accommodated by therapeutic footwear

2.6 Diabetic Ulcer Management and Therapy

The principle aim of DFU management is wound closure. More specifically,


the intention should be to treat the DFU at an early stage to allow prompt
healing. The essential components of management are26:

Treating underlying disease processes


Ensuring adequate blood supply
Local wound care, including infection control
Pressure offloading.

Effective foot care should be a partnership between patients, carers and


healthcare professionals. This means providing appropriate information to
enable patients and carers to participate in decision making and understand the
rationale behind some of the clinical decisions as well as supporting good self-
care. Other methods have also been suggested to be beneficial as add-on
therapies, such as hyperbaric oxygen therapy, use of advanced wound care
products, and negative-pressure wound therapy (NPWT). However, data so far
have not provided adequate evidence of the efficacy and cost-effectiveness of
these add-on treatment methods. Practitioners should identify the underlying
cause of the DFU during the patient assessment and, where possible, correct or
eliminate it. Below are the details of the latest management of Diabetic
ulcers.27-30

a. Basic Principles Of Diabetic Ulcers Management

Achieving optimal diabetic control. This should involve tight glycaemic


control and managing risk factors such as high blood pressure,
hyperlipidaemia and smoking. Nutritional deficiencies should also be
managed. Metabolic control also plays an important role in comprehensive
treatment. Blood glucose control may be difficult because of infection. If the
patient is on oral antidiabetic drugs, a temporary switch to insulin may be
necessary. On the other hand, high blood glucose worsens infection and is
associated with poorer operative results, morbidity and mortality. The
recommended target level of HbA1c should be <7.07.5% but higher if
hypoglycaemic episodes are a problem, and the LDL level should be <1.8
mmol/L and blood pressure <130/80 mmHg, while less stringent goals
should be accepted for elderly and multimorbid patients.

Treating any severe ischaemia is critical to wound healing, regardless of


other interventions. It is recommended that all patients with critical limb
ischaemia, including rest pain, ulceration and tissue loss, should be referred
for consideration of arterial reconstruction. A patient with acute limb
ischaemia is a clinical emergency and may be at great risk if not managed in
a timely and effective way. It is important to appreciate that, aside from
critical limb ischaemia, decreased perfusionor impaired circulation may be
an indicator for revascularisation in order to achieve and maintain healing
and to avoid or delay a future amputation.

Addressing the physical cause of the trauma. As well as examining the foot,
practitioners should examine the patient's footwear for proper fit, wear and
tear and the presence of any foreign bodies (such as small stones, glass
fragments, drawing pins, pet hairs) that may traumatise the foot. When
possible and appropriate, practitioners should check other footwear worn at
home and at work (eg slippers and work boots).

b. Optimising Local Wound Care

The European Wound Management Association (EWMA) states that the


emphasis in wound care for DFUs should be on radical and repeated
debridement, frequent inspection and bacterial control and careful
moisture balance to prevent maceration. Its position document on wound
bed preparation suggests the following TIME framework for managing
DFUs :
Tissue debridement
Inflammation and infection control
Moisture balance (optimal dressing selection)
Epithelial edge advancement.

1. Tissue debridement
There are many methods of debridement used in the management of DFUs
including surgical/sharp, larval, autolytic and, more recently, hydrosurgery
and ultrasonic. Debridement may be a one-off procedure or it may need to be
ongoing for maintenance of the wound bed. The requirement for further
debridement should be determined at each dressing change. If the wound is
not progressing, practitioners should review the current treatment plan and
look for an underlying cause of delayed healing (suchas ischaemia, infection
or inflammation) and consider patient concordance with recommended
treatment regimens (such as not wearing offloading devices or not taking
antidiabetic medication). Debridement should be carried out in all chronic
wounds to remove surface debris and necrotic tissues. It improves healing by
promoting the production of granulation tissue and can be achieved surgically,
enzymatically, biologically, and through autolysis.
Sharp debridement
Surgical debridement, known also as the sharp method, is performed by
scalpels, and is rapid and effective in removing hyperkeratosis and dead
tissue. Particular care should be taken to protect healthy tissue, which has a
red or deep pink (granulation tissue) appearance. Using a scalpel blade with
the tip pointed at a 45 angle, all nonviable tissue must be removed until a
healthy bleeding ulcer bed is produced with saucerization of the wound edges.
If severe ischemia is suspected, aggressive debridement should be postponed
until a vascular examination has been carried out and, if necessary, a
revascularization procedure performed. No one debridement method has been
shown to be more effective in achieving complete ulcer healing. However,
inpractice, the gold standard technique for tissue management in DFUs is
regular, local, sharp debridement using a scalpel, scissors and/or forceps. The
benefits of debridement include:
Removes necrotic/sloughy tissue and callus
Reduces pressure
Allows full inspection of the underlying tissues
Helps drainage of secretions or pus
Helps optimise the effectiveness of topical preparations
Stimulates healing.

Sharp debridement is an invasive procedure and can be quite radical.


Practitioners must explain fully to patients the risks and benefits of
debridement in order to gain their informed consent. One small study piloting
an information leaflet showed that many patients did not understand the
procedure despite having undergone debridement on several previous
occasions. Vascular status must always be determined prior to sharp
debridement. Patients needing revascularisation should not undergo extensive
sharp debridement because of the risk of trauma to vascularly compromised
tissues. However, the toothpick approach may be suitable for wounds
requiring removal of loose callus. Seek advice from a specialist if in doubt
about a patients suitability.

Other debridement methods


While sharp debridement is the gold standard technique, other methods may
be appropriate in certain situations:
As an interim measure (eg by practitioners without the necessary skill
sets to carry out sharp debridement; methods include the use of a
monofilament pad or larval therapy)
For patients for whom sharp debridement is contraindicated or
unacceptably painful
When the clinical decision is that another debridement technique may be
more beneficial for the patient
For patients who have expressed another

Enzymatic debridement
It can be achieved using a variety of enzymatic agents, including crab-derived
collagenase, collagen from krill, papain, a combination of streptokinase and
streptodornase, and dextrans. These are able to remove necrotic tissue without
damaging the healthy tissue. Although expensive, enzymatic debridement is
indicated for ischemic ulcers because surgical debridement is extremely
painful in these cases. Enzymatic debridement is based on the application of
topical agents on the ulcer. These agents are usually applied once daily. Their
action is based on the necrotic tissue degradation using proteolytic digestive
enzymes such as streptokinases, trypsin, papain, fibrinolysin-DNase,
collagenase, papain-urea and streptodornase. Data from clinical studies have
shown conflicting results about the efficacy of these topical agents, thus, their
additional benefits to standard wound care remains unclear. Putting into
consideration the need of long time application, as well as, the high cost, their
use is usually limited to slowly soften large eschars or debridement of some
decubitus ulcerations in sensate limbs. In order to improve efficacy of these
agents, a scalpel blade is applied to crosshatch eschars
Biological debridement
It has been applied recently using sterile maggots. Maggots have the ability to
digest surface debris, bacteria, and necrotic tissues only, leaving healthy tissue
intact. Recent reports suggest that this method is also effective in the
elimination of drug-resistant pathogens, such as methicillin-resistant
Staphylococcus aureus, from wound surfaces. Fly can achieve relatively rapid,
atraumatic removal of moist, slimy slough, and can ingest pathogenic
organisms present in the wound. The decision to use larval debridement must
be taken by an appropriate specialist practitioner, but the technique itself may
then be carried out by generalist or specialist practitioners with minimal
training. Larval therapy has been shown to be safe and effective in the
treatment of DFUs. However, it is not recommended as the sole method of
debridement for neuropathic DFUs as the larvae cannot remove callus. A
recent review of debridement methods found some evidence to suggest that
larval therapy may improve outcomes when compared to autolytic
debridement with a hydrogel.

Hydrosurgical debridement
This is an alternative method of wound debridement, which forces water or
saline into a nozzle to create a high-energy cutting beam. This enables precise
visualisation and removal of devitalized tissue in the wound bed.

Autolytic debridement
This is a natural process that uses a moist wound dressing to soften and
remove devitalised tissue. Care must be taken not to use a moisturedonating
dressing as this can predispose to maceration. In addition, the application of
moisture-retentive dressings in the presence of ischaemia and/or dry gangrene
is not recommended. Autolytic debridement involves the use of dressings that
create a moist wound environment so that host defense mechanisms
(neutrophils, macrophages) can clear devitalized tissue using the bodys
enzymes. Autolysis is enhanced by the use of proper dressings, such as
hydrocolloids, hydrogels, and films. Autolysis is highly selective, avoiding
damage to the surrounding skin.

2. Inflammation and infection control


The presence of infection is a common finding in diabetic foot ulcers which
act as an entry route for pathogens. Infections must be diagnosed and treated
promptly and adequately as they may rapidly progress to a limb-threatening
condition. Also high levels of bacteria can delay or event prevent wound
healing and impede surgical closure of diabetic ulcers. Diagnosis of infection
is based initially on clinical signs such as redness, temperature, pain,
tenderness, edema and the presence of suspected discharge. On clinical
suspicion of infection, properly taken cultures from the wound area may be
helpful in proper antibiotic treatment selection. It is important to point out that
uninfected ulcers is not necessary to be cultured as the results will only
indicate the colonizing flora. The most common pathogens in diabetic foot
ulcers are aerobic gram positive cocci and gram negative bacteria. Anaerobic
organisms are frequently isolated too. Staphylococcus and streptococci are the
most frequently causative agents for non-threatening limb infections while
limb-threatening infections are mostly polymicrobial in nature. The use of
antibiotics in infected diabetic foot ulcer should be carefully applied, in order
to be assured that the patient will receive the appropriate antibiotic therapy,
for an adequate period of time, along with wound debridement and drainage.
The high morbidity and mortality associated with infection in DFUs means
that early and aggressive treatment in the presence of even subtle signs of
infection is more appropriate than for wounds of other aetiologies (with the
exception of immunocompromised patients). In one study, nearly half of
patients admitted to a specialised foot clinic in France with a diabetic foot
infection went on to have a lower-limb amputation.
3. Off-loading

Off-loading of the ulcer area is extremely important for the healing of plantar
ulcers. Retrospective and prospective studies have shown that elevated plantar
pressures significantly contribute to the development of plantar ulcers in
diabetic patients. In addition, any existing foot deformities may increase the
possibility of ulceration, especially in the presence of diabetic peripheral
neuropathy and inadequate off-loading. Furthermore, inadequate off-loading
of the ulcer has been proven to be a significant reason for the delay of ulcer
healing even in an adequately perfused limb. The value of ulcer off-loading is
increasing, as it has been reported that the risk of recurrence of a healed foot
ulcer is high if the foot is not properly off-loaded (in the high-pressure areas),
even after closure of the ulcer. The most effective method of off-loading,
which is also considered to be the gold standard, is the nonremovable total-
contact cast (TCC). It is made of plaster or fast-setting fiberglass cast
materials, has relatively low costs, and permits restricted activity.
Nonremovable TCCs are indicated for the effective off-loading of ulcers
located at the forefoot or midfoot. Severe foot ischemia, a deep abscess,
osteomyelitis, and poor skin quality are absolute contraindications to the use
of a nonremovable TCC. Nonremovable TCCs work by distributing the
plantar pressures from the forefoot and midfoot to the heel. They allow
complete rest of the foot whilst also permitting restricted activity.
Nonremovable TCCs also reduce edema, and compliance with treatment is
necessarily high. There are a number of removable cast walkers (RCW),
which usually have a lightweight, semirigid shell that helps support the limb
whilst also providing full-cell protection. The sole is of a rocker type, offering
off-loading of the forefoot during standing and walking. The foot base is wide
and there is enough room for dressings. In some RCWs, overlapping air cells
provide intermittent pneumatic compression for edema reduction. In other
RCWs, there are additional layers of foam or other soft material, offering total
contact.
A modification of RCWs is an instant total-contact cast (ITCC), where there is
a wrapping layer of cohesive tape or plaster bandage around the RCW. The
aim of the ITCC is to combine the efficacy of a TCC with the easy application
of a RCW. Half shoes are another solution for patients who cannot tolerate
other methods of off-loading, although they provide less pressure relief than a
cast boot and are difficult to walk in. Therapeutic shoes, custom insoles, and
the use of felted foam are alternative methods to off-load wounds located on
the forefoot, and can reduce pressure at the site of ulceration by 450%.

4. Dressings

Ulcers heal more quickly and are often less complicated by infection when in
a moist environment. The only exception is dry gangrene, where the necrotic
area should be kept dry in order to avoid infection and conversion to wet
gangrene. A wounds exudate is rich in cytokines, platelets, white blood cells,
growth factors, matrix metalloproteinases (MMPs), and other enzymes. Most
of these factors promote healing via fibroblast and keratinocyte proliferation
and angiogenesis, while others, such as leukocytes and toxins produced by
bacteria, inhibit the healing process. Moreover, it has been reported that local
concentrations of growth factors [platelet-derived growth factor-beta (PDGF-
beta), transforming growth factor-beta] are low in patients with chronic ulcers.
The ideal dressing should be free from contaminants, be able to remove excess
exudates and toxic components, maintain a moist environment at the wound-
dressing interface, be impermeable to microorganisms, allow gaseous
exchange, and, finally, should be easily removed and cost-effective. Various
dressings are available that are intended to prevent infection and enhance
wound healing, and several studies support their effectiveness for this purpose.
However, most of these studies were performed in wounds and not in diabetic
ulcers/ Available data on their use in diabetes are scarce, and therefore further
randomized clinical trials are needed to support the existing evidence for their
benefit in diabetic ulcers.
Most dressings are designed to create a moist wound environment and support
progression towards wound healing. They are not a substitute for sharp
debridement, managing systemic infection, offloading devices and diabetic
control. Moist wound healing has the potential to address multiple factors that
affect wound healing. It involves maintaining a balanced wound environment
that is not too moist or too dry. Dressings that can help to manage wound
exudate optimally and promote a balanced environment are key to improving
outcome. However, a dressing that may be ideal for wounds of other
aetiologies may be entirely inappropriate for certain DFUs. The dressing
selected may have a considerable effect on outcome and, due to the varying
complexities of DFUs, there is no single dressing to suit all scenarios. Many
practitioners are confused by the great range of dressings available.
Impressive claims are rarely supported by scientific studies and there is often a
lack of highquality evidence to support decision making. One inherent
problem is whether the characteristics of each wound randomised to a specific
dressing in a trial correspond to the characteristics that the dressing was
designed to manage. Many dressings are designed for non-foot areas of the
body and may be difficult to apply between or over the toes or plantar surface.
In addition, most practitioners have historically had little specific, practical
guidance on selecting dressings.

In the absence of strong evidence of clinical or cost effectiveness, healthcare


professionals should use wound dressings that best match the clinical
appearance and site of the wound, as well as patient preferences. Dressing
choice must begin with a thorough patient and wound assessment. Factors to
consider include:

Location of the wound


Extent (size/depth) of the wound
Amount and type of exudate
The predominant tissue type on the wound surface
Condition of the periwound skin
Compatibility with other therapies (eg contact casts)
Wound bioburden and risk of infection
Avoidance of pain and trauma at dressing changes
Quality of life and patient wellbeing.

The status of the diabetic foot can change very quickly, especially if infection has
not been appropriately addressed. The need for regular inspection and assessment
means that dressings designed to be left in situ for more than five days are not
usually appropriate for DFU management.

Practitioners should also consider the following questions. Does the dressing:
Stay intact and remain in place throughout wear time?
Prevent leakage between dressing changes?
Cause maceration/allergy or sensitivity?
Reduce pain?
Reduce odour?
Retain fluid?
Trap exudate components?

Is the dressing:
Comfortable, conformable, flexible and of a bulk/weight that can be
accommodated in an offloading device/footwear?
Suitable for leaving in place for the required duration?
Easy to remove (does not traumatise the surrounding skin or wound bed)?
Easy to apply?
Cost effective?
Likely to cause iatrogenic lesions?

Regularly reviewing a patient's wound and dressing is vital. For infected or


highly exuding wounds, a healthcare professional should inspect the wound
and change the dressing daily, and then every two or three days once the
infection is stable. A different type of dressing may be needed as the status of
the wound changes. Some patients, especially those with mobility issues or
work commitments may prefer to change their dressings themselves, or have a
relative or carer to do it. These patients should be advised about using aseptic
technique and the wound should continue to be reviewed at regular intervals
by the MDFT or other healthcare team members. Patients should be
encouraged to look out for signs of deterioration, such as increased pain,
swelling, odour, purulence or septic symptoms. In some cases (eg in the first
few days of antibiotic therapy) it is a good idea to mark the extent of any
cellulitis with an indelible marker and tell the patient to contact the footcare
team immediately if the redness moves substantially beyond the line.

c. Another Options for Diabetic Ulcers Management

1. Autologous Skin Transplantation in Diabet ic Foot Ulcers


Flaps and grafts are the two principal surgical procedures for skin tissue
replacement. A flap is a full-thickness portion of skin sectioned and isolated
peripherally and in depth from the surrounding skin, except along one side,
called the peduncle. A graft is a section of skin of variable thicknesses and
sizes completely detached from its original site and used to cover the zone to
be repaired. Particular attention should be paid to mesh grafts which are
obtained by passing a whole dermoepidermal explant through a special
surgical tool (mesher), thereby increasing the initial surface area of the
explanted skin. Skin grafts are traditionally used in the treatment of severe
burns. However, a number of studies have recently reported successful
managing of large tissue defects in patients with diabetic foot ulcers with
microsurgical grafts. The process of graft adoption is defined as the adhesion
of the graft skin to the recipient wound area and its subsequent
vascularization. This process is identical to that of wound healing. Following
an initial rejection phase after the skin grafting procedure with massive
inflammation, revascularization of the graft starts after 24 to 48 hours. Initially
the graft is pale and white but subsequently adopts a pinkish colour which
indicates successful adoption in association with firm attachment to the bed.
Apart from immune compatibility, basic conditions for graft taking encompass
the ability for neoangiogenesis, good adherence of the graft to recipient areas,
and hence accurate immobilization of the graft. A graft can only be placed to
vital exposed dermis capable of producing granulation tissue. The recipient
area must not be infected or excessively exudative. In addition well-
functioning haemostasis is required. In fact, any accumulation of exudate or
blood underneath the graft jeopardizes its survival as it impedes adherence and
penetration of new capillaries. The consequent handling of the transplant is of
utter importance. In the first weeks after transplantation, complete removal of
pressure is essential. Protective footwear with dully formed inserts can secure
adequate offloading of the area of high pressure and protect the transplant.

2. Growth Factors
PDGF-beta (becaplermin; available as Regranex; Ortho-McNeil
Pharmaceutical, Inc., Titusville, NJ, USA; and Janssen-Cilag International
NV, Beerse, Belgium) has been developed as a topical therapy for the
treatment of noninfected diabetic foot ulcers. It is applied in the form of a
once-daily gel along with debridement on a weekly basis. Initial studies have
indicated a significant positive effect of becaplermin on ulcer healing;
however, more recent studies have reported an increased incidence of cancer
in patients treated with becaplermin, especially at high doses. Consequently,
the US Food and Drug Administration has published a warning of an
increased risk of cancer if more than three tubes of becaplermin are used.

Platelet-rich plasma (PRP) is an autologous product, extracted from the


patients plasma, which includes a high platelet concentration in a fibrin clot
that can be easily applied to the ulcer area. The fibrin clot is absorbed during
wound healing within days to weeks following its application. There are a few
studies reporting a shorter closure time and higher healing percentage in
patients using PRP and platelet-derived products. However, further studies are
required to support the possible beneficial effect of this method in ulcer
healing.
The results of the subcutaneous administration of granulocyte colony-
stimulating factor (GCFS) in patients with infected foot ulcers vary, with some
studies indicating faster resolution of the infection and faster healing, while
others did not report any significant difference. Basic fibroblast growth factor
(bFGF) is known to be beneficial in the formation of granulation tissue and
normal healing; however, one small study failed to prove any significant
difference between the intervention and the control group. Epidermal growth
factor (EGF) acts on epithelial cells, fibroblasts, and smooth muscle cells to
promote healing. Evidence for the use of EGF in diabetic ulcers is limited,
with only a small amount of data reporting a significantly higher rate of ulcer
healing with EGF use compared with placebo.

3. Bioengineered Skin Substitutes


In the recent years much attention has been paid to the use of tissue-
engineered human skin equivalents in the treatment of diabetic foot ulcers.
The first engineered skin substitutes were matrix-based products consisting of
cross-linked collagen and glycosaminoglycans. The matrix eventually
undergoes degradation, while simultaneously the hosts cells invade and
proliferate within it. Integra, a product of this category, has shown promising
results in deep wounds. The second generation of tissue-engineered skin
equivalents consisted of cell-based products, mostly keratinocytes. Marston et
al. demonstrated that dermagraft, a cryopreserved human fibroblast-derived
dermal substitute, is a safe and effective treatment for diabetic foot ulcers.
Veves et al. showed that the application of graft skin (Apligraf)a human
skin equivalent manufactured from cultured living dermis and sequentially
cultured epidermis of neonatal foreskinsresults in significantly improved
healing compared to other available treatments. Moreover, there were no
significant side effects. Nevertheless, both products are ultimately rejected, so
that their primary task appears to be a transient restoration of the dermis until
the patients keratinocytes can migrate and close the wound.

Tissue-engineered skin substitutes are classified into allogenic cell-containing


(Apligraf Graftskin, Organogenesis Inc., Canton, MA, USA; Dermagraft,
Advanced Biohealing Westport, CT, USA; OrCell, Ortec International Inc.,
New York, NY, USA), autologous cell-containing (Hyalograft 3D, Fidia
Advanced BioPolymers, Abano Terme, Italy; Laserskin, Fidia Advanced
BioPolymers, Abano Terme, Italy; TranCell, CellTran Ltd., Sheffield, UK),
and acellular (OASIS, Cook Biotech, West Lafayette, IN, USA;
GRAFTJACKET, Wright Medical Group Inc., Arlington, TN, USA;
AlloDerm, LifeCell Corporation, Branchburg, NJ, USA) matrices. The first
two types of matrix contain living cells, such as keratinocytes or fibroblasts, in
a matrix, while acellular matrices are free of cells and act by releasing growth
factors to stimulate neovascularization and wound healing.

Accumulating evidence shows that bioengineered skin substitutes may be a


promising therapeutic adjunct therapy to the standard wound care for the
management of noninfected diabetic foot ulcers. Nevertheless, more studies
need to be conducted in the future in order to confirm these results.

4. Bone Marrow-Derived Cells


Another very promising therapeutic option involves the use of bone marrow-
derived cells, and recent evidence indicates that bone marrow contains stem
cells with the potential for differentiation into a variety of tissues. For
example, patients with diabetes are known to have an impaired mobilization of
endothelial progenitor cells (EPCs) in the bone marrow and decreased
accumulation of these cells in wounds. Bone marrow-derived cells may thus
be a valuable and unlimited source of progenitor and/or stem cells. For
example, Badiavas and Falanga described that the local application of
autologous bone marrow-derived cells resulted in complete wound closure in
3 patients unresponsive to standard therapies including bioengineered skin
application and autologous skin grafting.

Furthermore, it is assumed that hyperbaric oxygen results in EPC recruitment


but does not improve migration of EPC to the wound site. However, in a
murine model of diabetes coadministration of stromal cell-derived factor-1-
alpha (SDF-1 ) resulted in homing of the activated EPCs to the wound site.
These data suggest that combining oxygen therapy with SDF-1 may improve
wound healing in patients with diabetes. Another novel interesting approach
consists of lineage commitment of stem cells to the keratinocyte lineage. This
can be achieved through exposure of the stem cells to a mixture of cytokines,
growth factors, and extracellular matrix components in vitro and has been
attempted with only moderate success. Another method is through genetic
modulation, in particular transfection of stem cells with recombinant DNA
encoding for proteins that regulate the commitment to the keratinocyte
lineage. Although this method presents with exciting new potential, one
cannot overlook the potential detrimental effects and safety concerns of
genetic manipulation of stem cells.

5. Extracellular Matrix Proteins


Hyaff (Fidia Farmaceutici, Abano Terme, Italy) is a semisynthetic ester of
hyaluronic acid which facilitates the growth and movement of fibroblasts, and
controls hydration. Other available products contain lyophilized collagen from
various sources (bovine, porcine), alone or in combination with alginates,
cellulose (Promogran, Johnson & Johnson, New Brunswick, NJ, USA), or
antibiotics. Collagen seems to induce the production of endogenous collagen
and to promote platelet adhesion and aggregation. It has been reported to be
safe and effective as an adjunctive therapy in the management of foot
ulceration; however, evidence is still limited.

6. MMP Modulators
Matrix metalloproteinases regulate the extracellular matrix components.
During normal wound healing, there is a balance between the construction and
the destruction of the extracellular matrix. In chronic wounds, a high
expression of MMP-2 in fibroblasts and the endothelium is detected and is
believed to favor destruction. Thus, downregulation of MMP-2 expression
may enhance the healing process. DerMax (Tyco Healthcare Group Lp,
North Haven, CT, USA) is a dressing containing metal ions and citric acid,
and its topical application is associated with a lower expression of MMP-2 by
fibroblasts and endothelial cells. Metal ions inhibit the production of reactive
oxygen species by polymorphonuclear cells, and citric acid acts as a scavenger
of superoxide anions. One pilot study provided encouraging results. Certainly,
randomized trials are necessary in order to establish the role of DerMax in the
treatment of diabetic ulcers.

7. Subatmospheric Pressure Dressings


The use of subatmospheric pressure dressings such as the commercially
available vacuum-assisted closure (VAC) device have been shown to be an
effective way in accelerating the healing of various wounds. This technique
optimizes blood flow, decreases local tissue edema, and removes excessive
fluid from the wound bed. Additionally, the cyclical application of sub-
atmospheric pressure alters the cytoskeleton of the cells in the wound bed
thereby triggering a cascade of intercellular signals that increases the rate of
cell division and formation of granulation tissue. The success rate of skin
grafting is significantly increased when VAC is used as bolster covering the
freshly skin-grafted wound. A recent review assessing current modalities in
the treatment of diabetic foot ulcers concluded that although vacuum
compression therapy has been linked to significant reduction in wound area
and time to healing, this treatment was not shown to be costeffective and
should therefore be used only in exceptional circumstances.

8. Negative-Pressure Wound Therapy


Negative-pressure wound therapy (NPWT) has emerged as a new treatment
for diabetic foot ulcers. It involves the use of intermittent or continuous
subatmospheric pressure through a special pump (vacuum-assisted closure)
connected to a resilient open-celled foam surface dressing covered with an
adhesive drape to maintain a closed environment. The pump is connected to a
canister to collect wound discharge and exudate. Experimental data suggest
that NPWT optimizes blood flow, decreases tissue edema, and removes
exudate, proinflammatory cytokines, and bacteria from the wound area. It
should be performed after debridement and continued until the formation of
healthy granulation tissue at the surface of the ulcer. Currently, NPWT is
indicated for complex diabetic foot wounds; however, it is contraindicated for
patients with an active bleeding ulcer. Two small studies and one larger study
provide some encouraging data concerning the possible benefit of NPWT in
the healing rate and time of diabetic foot ulcers. However, more randomized
trials are needed in order to confirm these results.

9. Hyperbaric Oxygen
There is strong evidence that fibroblasts, endothelial cells, and keratinocytes
are replicated at higher rates in an oxygen-rich environment. Moreover,
leukocytes kill bacteria more effectively when supplied by oxygen. It is also
known that fibroblasts from diabetic individuals show diminished cell
turnover in comparison with those from nondiabetic persons. Based on these
data, the idea was that the administration of oxygen at high concentrations
might accelerate wound healing in diabetes. Treatment with hyperbaric
oxygen therapy involves the intermittent administration of 100% oxygen at a
pressure greater than that at sea level. It is performed in a chamber with the
patient breathing 100% oxygen intermittently while the atmospheric pressure
is increased to 23 atmospheres for a duration of 12 h. A full course involves
3040 sessions. A small amount of data suggests significant reduction of the
ulcer area as well as reduction of the risk for major amputation. Hyperbaric
oxygen can be applied as an adjunctive therapy for patients with severe soft-
tissue foot infections and osteomyelitis who have not responded to
conventional treatment. Adverse effects include barotrauma to the ears and
sinuses, pneumothorax, transient changes in visual acuity, and seizures.
Furthermore, a recent systematic review by the National Institute for Health
and Clinical Excellence (NICE) Guidelines Development Group in the UK
concluded that the available data are insufficient to demonstrate that
hyperbaric oxygen therapy is cost-effective.

10. Amputations
Amputations are urgent or curative. Indications for an amputation include the
removal of infected or gangrenous tissue, controlling infection and creating a
functional foot or stump that can accommodate footwear or a prosthesis. The
preservation of leg length aids ambulation and decreases energy expenditure.
Yet the surgical site should heal primarily. A closed toe and metatarsal
amputation typically leave the patient with a functional foot for walking. If the
healing of a toe is in doubt, metatarsal amputations should be used liberally
after revascularisation. Piecemeal amputations should be avoided. In situations
involving extensive tissue loss and precluding a functional foot, as well as
when there are non-healing wounds despite patent revascularisation and for
controlling sepsis, amputation below the knee is necessary. According to the
IDF guideline, amputation should not be considered unless a detailed vascular
assessment has been performed by vascular staff. Amputation may be
indicated in the following circumstances:
Ischaemic rest pain that cannot be managed by analgesia or
revascularisation
A life-threatening foot infection that cannot be managed by other
measures
A non-healing ulcer that is accompanied by a higher burden of disease
than would result from amputation. In some cases, for example,
complications in a diabetic foot render it functionally useless and a well
performed amputation is a better alternative for the patient.

Around half of patients who undergo an amputation will develop a further DFU
on the contralateral limb within 18 months of amputation. The threeyear
mortality rate after a first amputation is 2050%. In a six-year follow-up study,
almost 50% of patients developed critical limb ischaemia in the contralateral limb,
but the severity of the DFU and amputation level was significantly lower than in
the unilateral limb. This may have been due to prompt intervention made possible
by increased patient awareness. Patients at high risk for ulceration (such as
patients who have undergone an amputation for a DFU) should be reviewed 13
monthly by a foot protection team. At each review patients' feet should be
inspected and the need for vascular assessment reviewed. Provision should be
made for intensified footcare education, specialist footwear and insoles, and skin
and nail care. Special arrangements should be made for people with disabilities or
immobility1. The Scottish Intercollegiate Guidelines Network (SIGN)
recommends specialist diabetes podiatrist input for patients with a history of
amputation and ulceration. Although amputation incidence may not reflect the
quality of local healthcare delivery, there is a need for more consistent delivery of
diabetes care, with the involvement of an MDFT and patient education.
III. CONCLUSION

1. The management of diabetic foot ulcers remains a major therapeutic


challenge which implies an urgent need to review strategies and treatments
in order to achieve the goals and reduce the burden of care in an efficient
and cost-effective way.

2. Prevention of diabetic foot ulceration is critical in order to reduce the


associated high morbidity and mortality rates, and the danger of
amputation. It is essential to identify the foot at risk, through careful
inspection and physical examination of the foot followed by neuropathy
and vascular tests.

3. Regular foot examination, patient education, simple hygienic practices,


provision of appropriate footwear, and prompt treatment of minor injuries
can decrease ulcer occurrence by 50% and eliminate the need for major
amputation in nonischemic limbs.

4. Diabetic foot ulcers should be carefully evaluated and the gold-standard


treatments should be strictly applied in order to prevent amputation.
Further clinical studies are needed to support the existing evidence
regarding the clinical benefit of new approaches for the treatment of
diabetic ulcers, and these approaches should be used only as add-on
therapies to the gold-standard wound care.

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