REVIEW

Evidence-based Management of PAD & the Diabetic Foot

a,*
J.R.W. Brownrigg , J. Apelqvist b, K. Bakker c, N.C. Schaper d, R.J. Hinchliffe a

a
St George’s Vascular Institute, St George’s Healthcare NHS Trust, London, UK
b
Department of Endocrinology, University Hospital of Malmö, Sweden
c
IWGDF, Heemstede, The Netherlands
d
Division of Endocrinology, MUMCþ, CARIM and CAPHRI Institute, Maastricht, The Netherlands

WHAT THIS PAPER ADDS

Despite their widespread use, the evidence to support many interventions in the diabetic foot derives from
studies of poor quality. We highlight the need for separate reporting of outcomes in patients with diabetes
undergoing revascularisation for critical limb ischaemia and challenge current classification systems for
peripheral arterial disease in this cohort. The review focuses on evidence-based strategies for diabetic foot
ulceration (DFU) to promote healing and preserve life and limb. We emphasize the importance of referring all
patients presenting with DFU to a multidisciplinary team involving vascular surgeons and interventional
radiologists.

Diabetic foot ulceration (DFU) is associated with high morbidity and mortality, and represents the leading cause
of hospitalization in patients with diabetes. Peripheral arterial disease (PAD), present in half of patients with DFU,
is an independent predictor of limb loss and can be difficult to diagnose in a diabetic population. This review
focuses on the evidence for therapeutic strategies in the management of patients with DFU. We highlight the
importance of timely referral of patients presenting with a new foot ulcer to a multidisciplinary team, which
includes vascular surgeons and interventional radiologists.
Ó 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.
Article history: Received 14 November 2012, Accepted 19 February 2013, Available online 27 March 2013
Keywords: Diabetic foot ulceration, Diabetes, Peripheral arterial disease

INTRODUCTION/EPIDEMIOLOGY diabetes have failed. It is therefore timely to review the

The dramatic increase in the worldwide prevalence of dia- evidence for the management of peripheral arterial disease
betes mellitus (DM) has resulted in an inevitable rise in (PAD) and the diabetic foot, highlighting recent guidelines
diabetes-related complications. In 2011, there were an produced by the International Working Group on the Dia-
estimated 366 million adults with diabetes worldwide and betic Foot (IWGDF) and the European Society of Vascular
projections indicate this figure will rise to 552 million by Surgery (ESVS).6,7
2030.1 Amputation is a largely preventable complication of Foot lesions carry high morbidity and mortality and
diabetes and >85% of major amputations in patients with represent the most common cause of hospitalization in
diabetes are preceded by foot ulceration.2 Despite evidence patients with diabetes. The lifetime risk of foot ulceration in
to suggest that targeted interventions resulting from patients with diabetes lies between 15% and 25%,8,9 with
multidisciplinary care can reduce limb loss, progress to date an annual incidence of around 2%.10 The risk of a person
has been slow.3 Whilst the number and incidence of with diabetes undergoing a lower extremity amputation is
amputations have fallen in an ageing population without estimated to be 23 times that of a person without dia-
diabetes, those in patients with type 2 diabetes have risen betes,11 and the National Diabetes Audit estimates that
in some countries.4 Twenty years on from the St Vincent’s every 7 out of 10 000 people with diabetes in England and
Declaration,5 attempts to achieve 5-year targets to halve Wales underwent a major amputation in 2008e2009. In
the number of lower limb amputations in patients with 2010e2011 there were 72 459 hospital admissions for
diabetes-related foot complications,12 at an estimated cost
of between £639 million and £662 million to the National
To access continuing medical education questions on this Health Service in England and Wales.13
paper, please go to www.vasculareducation.com and click on ‘CME’ PAD is an independent risk factor for subsequent ulcer-
* Corresponding author. ation and limb loss in diabetes. It is present in 50% of
E-mail address: [email protected] (J.R.W. Brownrigg).
1078-5884/$ e see front matter Ó 2013 European Society for Vascular
patients with diabetic foot ulceration (DFU), a proportion
Surgery. Published by Elsevier Ltd. All rights reserved. which may be increasing.14,15 Those with DFU and PAD are
http://dx.doi.org/10.1016/j.ejvs.2013.02.014 less likely to heal and more likely to require amputation
674 European Journal of Vascular and Endovascular Surgery Volume 45 Issue 6 June/2013

compared to patients without PAD. It is therefore essential DIAGNOSIS OF PAD

that PAD is identified in all patients with diabetes. Identification of PAD in patients with diabetes may be
difficult because symptoms and signs are frequently masked
by co-existing distal symmetrical polyneuropathy. Further-
more, most patients with DFU present to primary care,
PATHOLOGY IN DFU podiatry or internal medicine clinicians who are not experts
The aetiology of DFU is multifactorial and involves in the diagnosis of PAD. IWGDF guidelines suggest that, in
a complex interplay between distal polyneuropathy (motor, addition to a thorough history for symptoms of arterial
sensory and autonomic), abnormal foot anatomy, functional insufficiency, all patients with a diabetic foot ulcer should
changes in the microcirculation and PAD. The pathway to undergo hand-held Doppler evaluation of both pedal pul-
ulceration typically follows abnormal loading or trauma of ses, measurement of ABI and, in cases of diagnostic
the painless neuropathic foot, which may be poorly uncertainty, measurement of toe-brachial index (TBI) or
perfused due to PAD, rendering it less able to heal. Both transcutaneous pressure of oxygen (TcPO2).6 Importantly
ulceration and infection in the foot will increase the these screening tools, whilst highly sensitive in the non-
demand for oxygen and, as such, vascular intervention may diabetic population, may be less efficacious in diabetes,
be required to achieve healing in cases where objective especially in the presence of peripheral and autonomic
measures of perfusion suggest that PAD is only of mild neuropathy.26,27 Those patients with signs and symptoms of
severity. The wound repair process may be further impaired PAD, including claudication, rest pain, absent foot pulses,
by virtue of various biological factors inherent to diabetes, monophasic Doppler signals, ABI <0.9 or TBI <0.7 should
including impaired humoral immunity and abnormal be referred to a vascular surgeon for imaging of the vascular
inflammatory responses.16,17 tree and to consider revascularisation options as part of an
Early descriptions of diabetes as an occlusive small vessel interdisciplinary approach. However, vascular specialists
disease were disproven by histological staining of ampu- might wish to be involved in the diagnosis and management
tated limbs,18 and subsequently by arterial casting studies. of any new patient presenting with DFU given that the
This led to the identification of several functional abnor- majority will have PAD.
malities of the microvasculature including an increase in Once a diagnosis of PAD is established, it is important to
arterio-venous shunting and impaired vasoreactivity.19 In assess the severity of the perfusion deficit and what impact
patients with type 2 diabetes these changes lead to capil- this may have on ulcer healing. With respect to ankle
lary hypoperfusion, probably further impairing wound pressures, an ABI of <0.6 corresponds to a significant
healing.20 Furthermore, the development of collateral impairment in wound healing (Fig. 1).28 A low probability of
vessels is impaired in patients with diabetes.21 Conse- wound healing due to poor perfusion should prompt
quently arterial occlusions may result in more severe further investigations to establish the distribution of PAD.
perfusion deficits in those with diabetes compared to those Guidelines published by the National Institute for Clinical
without diabetes. The distribution of PAD in patients with Excellence (NICE) in the UK recommend offering duplex
diabetes is characteristically distal and diffuse, with ultrasound as first-line imaging to all people with PAD
a greater prevalence of crural disease and long arterial where revascularisation is being considered.29 Evaluation of
occlusions.22e24 The distribution of PAD in diabetes may the below-knee vessels is particularly important in patients
relate to the presence of somatic neuropathy, which has with diabetes and the sensitivity of DUS for detecting
been implicated in the development of medial arterial a high-grade stenosis (50%) are 90% for the anterior and
calcification.25 posterior tibial arteries and 82% for the peroneal artery.30
Although DUS is non-invasive and relatively inexpensive
compared with other imaging modalities, its reliability is
dependent on operator expertise. The evaluation of below-
knee vessels with haemodynamic parameters alone does
not provide adequate information for preoperative plan-
ning, but may serve as a useful and intermediate adjunct to
other, more invasive modalities.31
Digital subtraction angiography (DSA) remains the gold
standard imaging modality for evaluating the distribution of
PAD when revascularisation is planned and has the advan-
tage of allowing simultaneous endovascular intervention. Its
Figure 1. Schematic estimate of the probability of healing of foot main drawback in patients with diabetes and a high prev-
ulcers and minor amputations in relation to ankle blood pressure, alence of renal insufficiency is the risk of contrast-induced
toe blood pressure, and transcutaneous oxygen pressure (TcPo2) nephropathy. As a precaution, patients with renal impair-
based on selected reports. From Bakker K, Apelqvist J, Schaper NC. ment should receive peri-procedural intravenous volume
Practical guidelines on the management and prevention of the expansion and metformin should be stopped prior to DSA
diabetic foot 2011. Diabetes Metab Res Rev, 2012;28 Suppl as it may cause a lactic acidosis.32 The visualization of pedal
1:225e31.
J.R.W. Brownrigg et al. 675

vessels with DSA may be limited in patients with severe required. If it is felt that PAD is contributing towards
occlusive disease, where the concentration of contrast falls impaired wound healing then patients, if ambulatory,
short of the sensitivity threshold. In such instances, a hand- should be considered for revascularisation with the excep-
held Doppler probe can be useful in unmasking pedal target tion of the severely frail or functionally impaired and those
arteries not visible on DSA. with an unsalvageable foot. Importantly, where PAD is likely
Contrast-enhanced magnetic resonance angiography (CE- to compromise healing of a major amputation wound,
MRA) is a low-invasive modality capable of imaging calcified interventions to optimize inflow should be considered.
vessels without artifact and avoids the need for nephrotoxic Revascularisation in patients with diabetes can be tech-
iodinated contrast. Temporally resolved hybrid CE-MRA nically difficult by virtue of the distal distribution of disease,
using an aortoiliac and femoral bolus-chase achieves the impaired collateral formation and vessel calcification. Data
best diagnostic performance. In a study of patients with pooled by the IWGDF from 19 studies of patients with DFU
diabetes, the sensitivity and specificity for time-resolved CE- and PAD showed a median limb salvage rate of 85% at 1-
MRA of crural vessels was 79% and 90% respectively.33 year.38 Half of patients with DFU and PAD can expect to
Disadvantages of MRA include limited spatial resolution be alive at 5-years and mortality rises to 50% in 2-years
and a relative contraindication for the use of gadolinium in following a major amputation.39 Patients with co-existing
patients with severe renal insufficiency (creatinine clear- chronic kidney disease (CKD) fare worse and the severity
ance <30 ml/min), which has been linked to the develop- of CKD has been shown to correspond with poor outcomes
ment of nephrogenic systemic fibrosis.34 In addition, the and mortality following revascularisation.40
occurrence of stent artefacts in MRA limit its use for the There are no randomized trial data comparing surgical
detection of in-stent stenosis. bypass and endovascular interventions in selected patients
Computed tomography angiography (CTA) should be with diabetes or infrageniculate disease, however, in
offered where MRA is contraindicated,29 and has several patients with diabetes and an ischaemic foot ulcer, these
advantages over MRA with respect to the speed of exami- techniques appear to offer equivalent outcomes where
nation and spatial resolution. It is limited by image inter- revascularisation is successful.41,42 The BASIL trial,43 which
ference from calcified arteries, which can make randomized patients with severe limb ischaemia (rest pain
interpretation difficult. A systematic review comparing or tissue loss for >2 weeks) to bypass or balloon-
sensitivity and specificity of DUS, contrast enhanced MRA angioplasty, demonstrated similar outcomes in terms of
and multidetector-row CTA reported similar accuracies health-related quality of life and amputation-free survival,
across these modalities for detecting high-grade stenoses although less than half of randomized patients had diabetes
above and below the knee.35 and no sub-group analyses were performed. Endovascular
techniques performed under local anaesthesia are lower-risk
REVASCULARISATION than bypass surgery and cost considerably less; however, an
Data from the EURODIALE Study (a prospective study of increased re-intervention rate following angioplasty in the
newly presenting patients with DFU to 14 experienced BASIL trial reduced any overall cost difference.44 Data from
European diabetic foot centres) would seem to suggest that the BASIL trial suggest they are also associated with lower
many patients are not having vascular imaging nor being short-term morbidity and, as such, endovascular therapy is
considered for revascularisation.36 Of those patients with probably justified as the initial approach to restoring
severe ischaemia (ABPI <0.5) appropriate vascular imaging perfusion. Surgical bypass has the advantage of increased
was performed in just 56%, and only 43% of those imaged durability when autologous vein is used but patients with
were revascularised. It is quite possible that the picture is multiple comorbidities and a short life expectancy (6e12
even bleaker for patients outside specialist centres. Retro- months) are unlikely to realize this benefit.
spective review of the Eurodiale data suggests there are The distal distribution of PAD in diabetes has brought
various reasons why revascularisation was not performed, about innovation and development in both endovascular
including spontaneous wound healing, poor clinical condi- techniques and open bypass surgery. Distal endovascular
tion of the patient or surgeon preference. interventions and distal origin bypass grafts arising from the
The decision to revascularise the ulcerated foot is SFA, popliteal or crural vessels show good outcomes in
complex. Multiple factors influence wound healing in dia- selected patients. Identifying the optimal artery for angio-
betes in addition to PAD. Patients with mild PAD and plasty or run-off vessel for bypass requires careful scrutiny
adequate perfusion measurements (ABI 0.6, TcPO2 of anatomic and haemodynamic factors and some authors
>50 mmHg) should be initially managed with optimal advocate revascularisation based on the angiosome model
wound care (debridement, treatment of infection and off- of perfusion, where the target artery corresponds to the
loading) and a 6-week period of observation. There is area of tissue loss.45 It is important to note that angiosomes
level II evidence to suggest the healing response to ‘best are a representation of normal anatomy and changes to the
medical therapy’ during this period gives a good indication collateral circulation that result from PAD mean the success
as to the adequacy of perfusion.37 In large ulcers and in of this technique in reconstructive surgery will not neces-
those with the combination of PAD and infection, the ex- sarily extrapolate to revascularization in cases of DFU. The
pected outcome of conservative treatment is poor (level I available evidence for the angiosome concept is limited, but
evidence) and earlier vascular intervention may be it does seem a logical step to achieve healing in diabetic
676 European Journal of Vascular and Endovascular Surgery Volume 45 Issue 6 June/2013

foot ulcers. In a series of patients with DFU treated by directing the resources of specialized foot clinics towards
angiosome-guided endovascular techniques, rates of limb the minority of patients at medium- or high-risk.
salvage and healing at 1-year were encouraging, at 91% and Primary care physicians in the UK undertake annual foot
85% respectively.46 Interestingly, a meta-analysis of 31 checks and stratify patients with diabetes according to their
studies reporting results of popliteal to distal vein bypasses risk of ulceration, however, the effectiveness of screening
has demonstrated greater limb salvage rates than corre- programmes and complex interventions (education, podi-
sponding patency data.41 Primary patency at 1 and 5-years atry, orthoses) in reducing both the risk of foot ulceration
was 82% and 63% respectively with corresponding foot and mortality is difficult to confirm.50,51 While the evidence
salvage rates of 89% and 78%. This observation suggests for specific interventions is sparse, it is clear that patients
that long-term graft patency is not always necessary for with an established diabetic foot ulcer benefit from prompt
a successful outcome in patients with diabetes, providing recognition and early referral to a limb salvage team.
that wound healing precedes graft failure. Following the introduction of a multidisciplinary foot team
A meta-analysis of crural angioplasty performed by the at Ipswich hospital, UK, Krishnan et al. observed a 62%
same group reported comparable limb salvage rates of 93% reduction in major amputations in a catchment general
and 82% at 1 and 36 months respectively.42 As with surgical population.3 Larger ulcers are more difficult to manage
bypass, long term patency is less relevant, providing wound hence the need for early identification and intervention;
healing is achieved following an intervention. The devel- data from another established foot clinic demonstrated
opment of drug-eluting stents and balloons offers the a direct relationship between cross-sectional area (and
potential to reduce rates of re-stenosis following endovas- ulcer duration) at first assessment and time to healing.52
cular therapy, however, there is currently insufficient Despite the prognostic performance of neuropathy and
evidence to support the use of these devices in patients PAD in predicting ulceration, a risk stratification tool that
with DFU. Some contemporary series report a combined uses routinely available demographic and clinical data
surgical and endovascular approach to the problem of would be more practical on a population level. The training
inflow disease47 which may be most useful in patients with required for accurate clinical assessment of PAD and
concomitant SFA and distal arterial occlusive disease. A neuropathy may not be feasible outside well-resourced
hybrid approach is particularly attractive in patients with settings. Reallocating resources towards evidence based
limited availability of vein conduit, which may otherwise multidisciplinary foot clinics may offer a better alternative
necessitate the use of prosthetic grafts. We expect that to primary care-led screening.
both endovascular and bypass techniques will remain
widely used and complementary in the foreseeable future. MEDICAL OPTIMIZATION
DM is recognized as a key risk factor for the development of
PREVENTION OF ULCERATION/SCREENING cardiovascular disease (CVD) and mortality from CVD causes
Foot examination focussing on the presence of peripheral is z2-fold higher compared with individuals without DM.53
neuropathy, PAD and abnormal foot anatomy can predict Recent evidence suggests that a history of foot ulceration
risk of developing a diabetic foot ulcer.10,48 Diverse risk may increase this risk further still, showing excess all-cause
stratification systems exist incorporating these and addi- mortality in patients with DFU, compared with patients with
tional risk factors, although none has been universally diabetes without a history of DFU.54 Accordingly, the
adopted (Table 1). In a Scottish study which stratified foot benefits of CVD risk modification in reducing morbidity and
ulcer risk in 3526 patients with diabetes, foot ulceration mortality have been shown in populations with diabetes
was 83 times more common in high-risk patients, compared and DFU.
with low-risk patients.49 During a mean follow-up duration The Steno-2 study randomized patients with type 2 dia-
of 1.7 years, the risk of foot ulceration was 0.36% in low-risk betes and persistent microalbuminaemia to intensive CV
patients (64% of the population), 2.3% in moderate-risk risk management, which corresponded to an absolute risk
patients and 29.4% in high-risk patients. The negative reduction for all-cause mortality of 20% after a mean follow
predictive value of a low-risk score may be useful in up of 13.3 years (7.8 years of multifactorial intervention and

Table 1. Variables included in the diverse stratification systems.

Stratification Variables
DN PAD Foot deformity Previous ulcer Previous amputation Visual impairment
UTFRS90 U U U U
IWGDF15 U U U U U
SIGN10 U U U U U U
ADA91 U U U U U
Boyko et al.92 U U U U
UTFRS: University of Texas Foot Risk Stratification; IWGDF: International Working Group on the Diabetic Foot; SIGN: Scottish Intercollegiate
Guideline Network; ADA: American Diabetes Association; DN: diabetic neuropathy; PAD: peripheral arterial disease.
Adapted from Monteiro-Soares M, Boyko EJ, Ribeiro J, Ribeiro I, Dinis-Ribeiro M. Risk stratification systems for diabetic foot ulcers: a systematic review.
Diabetologia 2011;54:1190e1199.
J.R.W. Brownrigg et al. 677

an additional 5.5 years of follow-up).55 Participants were demonstrated favourable results in a prospective RCT
selected for the presence of microalbuminuria which is involving more than 300 patients receiving a dermal
associated with microvascular disease and therefore fibroblast culture69 A greater proportion of patients
neuropathy and ulceration, and is itself a strong predictor of receiving the bioengineered skin achieved complete heal-
CV events.56,57 In the setting of patients with DFU, Young ing at 12 weeks (30% vs 18%) compared with conventional
et al. reported improved survival of patients treated with therapy (dressings, offloading footwear and debridements),
intensive CV risk modification.58 In a foot clinic population, however the healing rates in the control group were lower
5-year mortality fell from 48% to 27% following introduction than expected. Although negative pressure wound therapy
of a protocol incorporating CV risk screening and adminis- (NPWT) is widely used in the treatment of chronic wounds,
tration of an antiplatelet agent, statin and antihypertensive much of the supporting evidence is based on industry
where indicated (level II evidence). funded trials and unpublished data are largely inacces-
No direct evidence supports a role for tight glycaemic sible.70 One well-designed, industry supported RCT of 342
control in preventing ulceration, although epidemiological patients with an ulcer >2 cm2 reported promising
data suggests that optimizing blood glucose levels can outcomes.71 NPWT was associated with reduced time to
prevent peripheral neuropathy and PAD in patients with wound closure, increased incidence of healing by 16 weeks
diabetes. In the UK Prospective Diabetes Study, a reduction and reduced incidence of minor amputation. Further study
in HbA1C of 1% was associated with a reduction in risk of is, however, needed to justify the use of NPWT in routine
43% for amputation or death from PAD.59 Similarly, there clinical practice. The evidence to support the use of
are no data to support aggressive glycaemic control to aid a particular dressing or topical therapy for the ulcer bed is
healing in active ulceration; however this is also likely to be thin. Providing a comprehensive environment to improve
important, not least because raised blood glucose encour- healing with antibiotics, debridement and offloading is
ages infection. Strict glycaemic control will increase the risk superior to the use of a novel, and often expensive,
of hypoglycaemic attacks and weight gain in some patients. dressing. It is what you take off the wound and not what
In the majority of frail and elderly patients with DFU, less you put on it that counts.
intensive glycaemic goals are probably indicated, with
target blood glucose levels between 6 and 10 mmol/l.
INFECTION/ANTIBIOTICS
ULCER/WOUND MANAGEMENT AND DRESSINGS The risk of infection in the diabetic foot increases with the
The quality of published reports supporting the use of local presence of PAD, recurrent or chronic wounds and those
interventions in DFU is poor but some principles guiding penetrating to bone.72 The majority of infections are con-
foot care can be derived from the available literature.60,61 tained within the soft tissue, but around a fifth involve
The cornerstone of early management in neuropathic underlying bone (osteomyelitis) which is associated with
ulcers is offloading pressure with appropriate footwear, a worse outcome. The diagnosis of diabetic foot infection is
removable devices or total contact casts (TCCs). The efficacy based on clinical findings; superficial wound cultures are not
of prescribed footwear and removable devices is dependent useful and should not be treated, as bacterial colonization
on patient compliance and, probably for this reason, the appears to be ubiquitous in diabetic foot ulcers. Bone biopsy
TCC has demonstrated superior results in randomized for histopathology and culture remains the “gold standard”
trials,62 and is recommended by the IWGDF as first-choice for diagnosing osteomyelitis, yet unfortunately this proce-
treatment.63 A perception of increased risk of falls with dure is not routinely performed in clinical practice.73
TCCs appears to be unfounded.64,65 Despite all this, only Infection of a foot ulcer can be a major threat to limb and
18% of approximately 600 patients with a plantar foot ulcer life and should be treated promptly. The IWGDF has
in the Eurodiale study were treated with TCCs.36 Callus produced guidelines for the treatment of diabetic foot
formation contributes to abnormal loading and failure to infections based on the severity of infection,28 which
heal, and debridement should be routinely provided by predicts amputation. Ulcers with superficial infection should
trained podiatrists. Evidence suggests that removal of be treated with debridement and oral antibiotics aimed at
calluses is beneficial for reducing plantar pressures,66,67 Staphylococcus aureus and streptococci. Targeted therapy
although this has yet to be confirmed in randomized trials. against gram positive cocci has been shown to be equally
Despite their widespread use there is a paucity of effective as broader spectrum regimens (level I evidence),74
evidence to support the use of topical therapies for dia- even in the presence of osteomyelitis which will respond to
betic foot ulcers. In agreement with the conclusions of an antimicrobial therapy in most cases. Deep infection, char-
earlier Cochrane review,68 the IWGDF identified no good acterized by purulent discharge or fullness in the plantar
quality randomized controlled trials (RCTs) reporting heal- space,75 necessitates urgent debridement of necrotic tissue
ing rate or infection outcomes from which to produce including infected bone, and revascularisation if indicated.
clinical guidelines.60 The application of factors which aim to Intravenous broad-spectrum antibiotics should target Gram-
promote healing by altering cell biology have failed to positive and negative micro-organisms, including anaer-
demonstrate consistent efficacy and there is insufficient obes. Signs of life and limb threatening infection include
evidence to justify the use of these expensive agents in bullae, ecchymoses, soft tissue crepitus and rapid spread of
routine practice. Bioengineered skin grafts have infection.76
678 European Journal of Vascular and Endovascular Surgery Volume 45 Issue 6 June/2013

In the Eurodiale cohort, investigators observed a mark- Group on the Diabetic Foot (IWDGF) was developed for
edly negative impact of infection on ulcer healing that was research purposes,84 but the grading of infection in this
confined to patients with PAD. These findings emphasize system according to its severity is also advocated for clinical
the need for studies comparing different antibiotic regi- use as it predicts outcome.85 A universal classification
mens in PAD and for those investigating the effects of early system of diabetic foot ulcers would enable consistent
revascularisation on control of infection.77 reporting among studies in DFU to guide the development
of novel therapies while increasing the external validity of
CLASSIFICATION AND OUTCOMES (REPORTING) research in this field and allowing fair comparison between
centres.86 To this end the European Wound Management
In studies of outcome following lower limb revascularisation
Association (EMWA) has produced a set of recommenda-
for critical limb ischaemia (CLI), patients with and without
tions for standardized reporting of outcomes in studies of
diabetes are typically reported as one group. The unique
wound management.87 Clearly there will be some overlap
characteristics of PAD in diabetes, in its distribution and
with the Society for Vascular Surgery standard reporting
presentation, make it difficult to extrapolate clinical signif-
criteria for the lower limb ischaemia,88 although some
icance from data on unselected patients. Additionally, CLI
important outcomes may be distinct. Ulcer healing has been
remains a problematic definition in patients with diabetes
shown to be of particular importance to patients with
as symptoms of ischaemic pain (claudication, rest pain) may
diabetes and is associated with improvements in health-
be masked by the presence of distal symmetric poly-
related quality of life (HRQOL).89 One study demonstrated
neuropathy, and ulceration may develop with very mild PAD
improvements in QOL in both the patient and caregiver
of little haemodynamic significance. In contrast, patients
following ulcer healing.90
without diabetes are unlikely to develop tissue loss in the
In a study of 449 patients with an index diabetic foot ulcer,
absence of a severe perfusion deficit. A haemodynamic
Jeffcoate et al. demonstrated how the use of ulcer-related
classification of PAD using ankle brachial index (ABI), toe
endpoints may underestimate morbidity and mortality in
pressures or transcutaneous oxygen tension is more useful
this cohort.15 At 12 months, ulcer healing without amputa-
in patients with diabetes with the caveat that ABIs may be
tion was achieved in 65.7% whereas only 45% of patients
falsely elevated due to arterial calcification and have a poor
were alive, without amputation and ulcer free. The authors
predictive value. Patients with diabetes need to be identi-
suggest that ulceration free survival may merit further
fied as an important subgroup in the PAD literature to allow
exploration as an outcome measure in diabetic foot disease.
pooling of results for systematic review and meta-analysis.
The balance of risk and benefit for interventions in diabetic
Several angiographic classification schemes exist to
foot disease is probably best assessed through a combina-
describe the anatomical distribution of disease in patients
tion of defined clinical endpoints including mortality,
with PAD. The limitations of the currently available schemes
amputation-free survival, healing and re-ulceration with
may, in part, explain the poor reporting of PAD distribution in
patient-reported outcome measures.
the literature. The Trans-Atlantic Inter-Society Consensus
(TASC) guidelines classify femoral popliteal lesions based on
their anatomical distribution,78 however, the classification of FUTURE PERSPECTIVES
infrapopliteal lesions is not specifically addressed. This is Better selection of patients for revascularisation procedures
significant given that the patency of the outflow artery is will rely on improvements in the reporting of outcome in
critical in determining the success of arterial bypass, and this diabetic foot disease. Whilst new data on the impact of
is especially true in diabetes where run-off is more likely to be revascularisation are awaited, there are encouraging
poor. The Bollinger score,79,80 albeit more cumbersome developments in other treatment modalities, including
clinically, describes the infrapopliteal arterial segments in stem cell and progenitor cell therapy. As discussed previ-
some detail and is advantageous in this respect. In the BASIL ously, PAD is present in around half of patients with DFU.
trial, below knee Bollinger scores were significantly greater in The impact of PAD on wound healing is compounded by
patients presenting with tissue loss; however the same impaired formation of new capillaries (angiogenesis) and
difference in above knee scores was not significant. Inter- proliferation of pre-existing micro-vessels into collateral
estingly there was a negative correlation between mean arteries (arteriogenesis) in patients with diabetes. Stimula-
above and below knee Bollinger scores, suggesting that the tion of angiogenesis and arteriogenesis represent attractive
TASC score, in its current form, may underestimate disease approaches in DFU and there is accumulating evidence to
severity in a cohort of patients with diabetes and relative confirm their efficacy in the treatment of critical limb
sparing of the above knee arterial segments. ischaemia.91 Pooled data from studies of autologous bone
Several validated scoring systems have been developed marrow mononuclear cell (BMMNC) therapy in patients
for use in diabetic foot ulcers. These include the University with PAD show increases in ABI values between 0.1 and 0.2
of Texas Wound Classification system and the Size (Area and points, TcPO2 increases between 10 and 20 mmHg O2 and
Depth), Sepsis, Arteriopathy, and Denervation (S(AD)SAD) improvements in walking distances. Although data in
score,81,82 the latter of which has been prospectively vali- selected populations with DFU are limited, one study in
dated in different ethnic groups and is a reliable predictor of China demonstrated improved ulcer healing rates with
healing.83 The PEDIS score of the International Working BMMNCs and bone marrow mesenchymal stem cells
J.R.W. Brownrigg et al. 679

compared with controls.92 Further research should clarify and risk factors for, new diabetic foot ulceration in a commu-
the role of cell therapies in DFU. nity-based cohort. Diabet Med 2002;19:377e84.
11 National diabetes audit executive summary 2009e10. The NHS
Information Centre 2011.
CONCLUSIONS 12 Holman N, Young RJ, Jeffcoate WJ. Variation in the recorded
The present review underlines the difficulty in diagnosing incidence of amputation of the lower limb in England. Dia-
PAD in patients with diabetes and the importance of referring betologia 2012;55:1919e25.
13 Kerr M. Foot care in diabetes: the economic case for change.
those presenting with a new foot ulcer to a multidisciplinary
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