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DOI: 10.1111/j.1464-5491.2008.02573.x

Review Article
Blackwell Publishing Ltd

Unresolved issues in the management of ulcers of the foot

in diabetes

W. J. Jeffcoate, B. A. Lipsky*, A. R. Berendt†, P. R. Cavanagh‡, S. A. Bus§, E. J. G. Peters¶,

W. H. van Houtum††, G. D. Valk** and K. Bakker‡‡ on behalf of the three systematic review
working parties of the International Working Group on the Diabetic Foot
Foot Ulcer Trials Unit, Nottingham University Hospitals Trust, Nottingham, UK, *VA Puget Sound HCS and University of Washington, Seattle, WA, USA, †Bone
Infection Unit, Nuffield Orthopaedic Centre NHS Trust, Oxford, UK, ‡Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, WA,
USA, §Department of Rehabilitation, Academic Medical Center, University of Amsterdam, Amsterdam, ¶Department of Internal Medicine and Infectious Diseases
and **Department of Internal Medicine, University Medical Center Utrecht, Utrecht, ††Department of Internal Medicine, Spaarne Hospital, Hoofddorp and
‡‡IWGDF, Heemstede, the Netherlands

Accepted 13 August 2008

Abstract
Management of diabetic foot ulcers presents a major clinical challenge. The response to treatment is often poor and
the outcome disappointing, while the costs are high for both healthcare providers and the patient. In such circumstances,
it is essential that management should be based on firm evidence and follow consensus. In the case of the diabetic foot,
however, clinical practice can vary widely. It is for these reasons that the International Working Group on the Diabetic
Foot has published guidelines for adoption worldwide. The Group has now also completed a series of non-systematic and
systematic reviews on the subjects of soft tissue infection, osteomyelitis, offloading and other interventions designed to
promote ulcer healing. The current article collates the results of this work in order to demonstrate the extent and quality
of the evidence which is available in these areas. In general, the available scientific evidence is thin, leaving many issues
unresolved. Although the complex nature of diabetic foot disease presents particular difficulties in the design of robust
clinical trials, and the absence of published evidence to support the use of an intervention does not always mean that the
intervention is ineffective, there is a clear need for more research in the area. Evidence from sound clinical studies is
urgently needed to guide consensus and to underpin clinical practice. It is only in this way that patients suffering with
these frequently neglected complications of diabetes can be offered the best hope for a favourable outcome, at the least
cost.
Diabet. Med. 25, 1380–1389 (2008)
Keywords diabetic foot, infection, osteomyelitis, systematic review, wound healing
Abbreviations EGF, epidermal growth factor; G-CSF, granulocyte colony stimulating factor; HBO, hyperbaric oxygen;
IWGDF, International Working Group on the Diabetic Foot; MMPs, matrix metalloproteinases; PDGF, platelet-derived
growth factor; RCT, randomised controlled trial; TIMP, tissue inhibitor of matrix metalloproteinases

associated with serious impairment of lifestyle and mood [4]

Introduction
Disorders of the foot affect about 15% of all people who have
diabetes [1] and are associated with considerable morbidity,
mortality and cost [2,3]. While the spectrum of diabetes-related
foot disease comprises chronic ulceration (with or without
associated infection of soft tissue or bone), critical ischaemia
and acute Charcot foot, most attention is focused on the manage-
ment of the chronic, non-healing ulcer. This delay in healing is
Correspondence to: William Jeffcoate, Foot Ulcer Trials Unit, Department of
Diabetes and Endocrinology, Nottingham University Hospitals Trust, City
Hospital Campus, Nottingham NG5 1PB, UK. E-mail: wjeffcoate@futu.co.uk
and exposes the patient to limb-threatening complications,
such as the development of secondary infection and gangrene.
Management is frequently unrewarding: the median time to
healing exceeds 2 months [5] and only two-thirds of diabetic
foot ulcers will eventually heal without surgery [6– 8]. Unfor-
tunately, few of the interventions available have been shown to
enhance ulcer healing [9–13]. Not surprisingly, in the absence
of interventions of proven effectiveness, many clinicians resort
to a wide variety of unproven remedies.
Many treatments for diabetic foot complications are currently
promoted and the likelihood of being used may depend on
factors other than robust evidence of effectiveness, including

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approval for reimbursement. The weak evidence base for most
interventions results in clinical practice that is based largely on
clinician opinions and these often differ widely. In 1999, the
International Working Group of the Diabetic Foot (IWGDF;
a consultative section of the International Diabetes Federation)
launched guidelines intended to summarise available evidence
and make recommendations for care and these have been recently
updated [14,15]. Recognising the need for the guidelines
to be based on the available scientific evidence, the IWGDF
completed a non-systematic review on the management of
infection [16] and, more recently, three systematic reviews
covering: footwear and offloading in the prevention and
treatment of ulcers; the management of osteomyelitis; and all
other interventions that have been reported in the management
of established ulcers [17–19]. The conclusions of these reviews
echo the work and the conclusions of previous authors; in
general, the quality of available research is poor and didactic
statements on management are not supported by high-quality
evidence.
This article is aimed at collating the key findings of these
four reviews, augmented by selected papers published since
December 2006. We wish to highlight not only what is known,
but more importantly the areas in which major uncertainties
persist and for which robust evidence is urgently needed to
inform good clinical practice.
Soft tissue infection
Accepted practice and available evidence
Soft tissue infection in the foot of a patient with diabetes nearly
always represents a complication of a disruption of the skin
envelope—occasionally a recent break in the skin, but most
often a chronic ulcer—rather than a primary process [20,21].
When infection complicates a pre-existing wound, however, it
often triggers a deterioration in that wound, which may be slowly
or rapidly progressive. Unchecked infection can precipitate
tissue necrosis and gangrene, especially in an ischaemic limb.
It follows that, although infection does not cause ulceration, it
can impair healing or lead to further tissue loss. Thus, infection
is a major precipitating factor leading to limb loss, especially in
developing nations [8,22].
The first priority of management of the newly presenting
ulcer is, therefore, to diagnose or exclude bacterial infection
and to administer appropriate antibiotic therapy when indicated.
The diagnosis of infection is essentially clinical, based on the
presence of signs of inflammation, not microbiological. Both
the Infectious Diseases Society of America (IDSA) and the
IWGDF have suggested that it should be graded into mild,
moderate and severe [16,20] and some evidence has validated
this approach [23,24]. The purpose of obtaining a culture of a
wound is not to diagnose infection but to define the identity
and antibiotic sensitivity of possible infecting organisms. Wound
samples should be obtained by curettage or biopsy to obtain
tissue, if possible, as surface swabs are often contaminated
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with colonising flora and fail to identify deep pathogens [20].
Antibiotic regimens should be targeted at the organisms found
to be responsible for the infection and should be continued for
the minimum duration needed (generally not more than
2 weeks for soft tissue infection) to reduce both the incidence
of side effects and the emergence of resistant organisms.
Aerobic Gram-positive cocci are the most important pathogens,
but numerous studies have shown that, with properly obtained
specimens for culture, multiple organisms will be isolated
from the majority of clinically infected ulcers [25]. Isolation of
these organisms, however, does not necessarily indicate that
each is behaving as a pathogen, rather than a coloniser. Current
guidelines for the management of newly presenting, acute, mild
or moderate infections of soft tissue recommend using agents
active against Gram positive cocci (especially Staphylococcus
aureus) as these are the most common pathogens. For chronic
ulcers in which infection has been unresponsive to primary
therapy, a broad spectrum regimen, such as a beta-lactam
plus beta-lactamase inhibitor combination or clindamycin
plus a quinolone, is recommended. Clinicians should consider
covering obligate anaerobes when the wound is ischaemic
or gangrenous and covering antibiotic-resistant organisms
(especially methicillin-resistant Staphylococcal aureus; MRSA)
when local experience or culture results suggest the need
[16,20].
Unresolved issues
The significance of colonisation and critical colonisation
Uncertainty persists over the significance of micro-organisms
colonising the surface of a wound that is not clinically infected.
Some have argued for using systemic antibiotic treatment in
the belief that high levels of surface colonisation may inhibit
healing or that clinical signs of infection may be obscured by
neuropathy or ischaemia [26]. This view is not shared by the
majority of experts and there are no supportive published
data. Others have suggested using either topical or systemic
antimicrobial agents for a wound colonised by more than 105
colony-forming units of organisms—in the belief that this
so-called ‘critical colonization’ will inhibit wound healing per
se and is likely to evolve into clinical infection of soft tissue.
Although there are some data to confirm an inverse associa-
tion between the level of colonisation of diabetic foot ulcers
and healing [27], this does not prove a causal relationship.
As it is possible that both poor outcome and the extent of
colonisation are themselves the consequence of a third factor
(such as ischaemia, wound chronicity or prior antibiotic use),
the issue can only be resolved by a prospective study designed
to determine the effect of reducing the bacterial load on wound
healing.
Choice of antibiotic regimen
There is uncertainty about the optimal choice of antimicrobial
therapy in the management of clinically overt infection of soft
tissue. This includes questions on route of therapy (topical,
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oral, parenteral), specific agents and duration of treatment.
Randomised trials are needed to assess the effectiveness and
safety of broad spectrum compared with targeted antibiotic
regimens. Randomised controlled trials (RCTs) are also needed
to determine the optimal route and minimum effective duration
of antimicrobial therapy in various types of infection, as well
as to assess the relative value of clinical signs, microbiological
sampling and biochemical measures such C-reactive protein
(CRP) and procalcitonin [24] in determining which wounds
are infected and when treatment can be discontinued.
Infection of bone—osteomyelitis
Data from several studies show that bone is infected in some
20% of patients with a foot wound attending specialist clinics
in both the USA and the UK [28,29]. Because evidence suggests
that infection of bone markedly increases the likelihood of
lower extremity amputation (either minor or major) [21], it is
imperative that clear protocols are developed for defining and
treating osteomyelitis of the foot in diabetes.
Accepted practice and available evidence
Infection of bone usually occurs by contiguous spread of infec-
tion from overlying soft tissue. The diagnosis of osteomyelitis is
generally based on the combination of clinical signs of infection
with evidence of underlying bone disruption or inflammation
on specific imaging tests. Management is based on the use of
appropriate antibiotic therapy and, in some situations, on the
surgical removal of necrotic bone.
Unresolved issues
Diagnosis, including differentiation from acute
Charcot disease
Diagnosing osteomyelitis is often difficult. The diagnosis may
be unequivocal if pus is observed within bone tissue, but in most
circumstances it is based on suggestive evidence, including the
clinical appearance of the overlying soft tissue (usually a digit),
bone fragmentation on X-ray and oedema of bone marrow
on magnetic resonance imaging (MRI). Most believe that a com-
bination of microbiological and histological examination of a
bone biopsy sample is the criterion standard for diagnosing
osteomyelitis [18], but even this technique is associated with
both false positive and false negative results—especially in
those who have already been treated with antibiotics (as is
commonly the case). Furthermore, most clinicians and many
institutions do not have access to bone biopsy. Thus, the
IWGDF has proposed a scheme based on combinations of
clinical, imaging and laboratory results to classify the likelihood
of osteomyelitis in individual cases as ‘definite’, ‘probable’,
‘possible’ or ‘unlikely’ [18]. This scheme remains to be validated.
The greatest diagnostic difficulty lies in differentiating
osteomyelitis from acute Charcot disease, as both disorders are
most commonly observed in a similar patient population and
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Management of diabetic foot ulcers • W. J. Jeffcoate et al.
both are associated with local inflammation and with bone
fragmentation [31]. Furthermore, the two entities may coexist,
as an ulcerated Charcot foot may be complicated by secondary
infection and acute osteomyelitis may also trigger the onset of
the Charcot process. Thus, more robust diagnostic criteria are
required for these disorders, as the treatments for each are
substantially different.
The role of early surgery in treatment
As far as treatment of osteomyelitis is concerned, the major
continuing controversy centres on the relative roles of surgery
and antibiotics. Traditionally, authorities have suggested that
the type of contiguous, chronic osteomyelitis seen in the
diabetic foot requires that all necrotic bone, and most (if not
all) infected bone, should be surgically removed. This was
based on the understanding that antibiotics do not penetrate
necrotic tissue and early experience that antibiotic treatment
of infected bone was frequently unsuccessful [32,33]. Some
non-randomised studies suggest a better outcome with surgical
than solely antibiotic therapy [34,35]. However, many groups
have produced observational evidence that bone infection may
be apparently eradicated in the majority of cases following
the use of newer antibiotic regimens, such as those including
quinolones or beta-lactam plus beta-lactamase inhibitor
combinations [36–38]. The optimal treatment will inevitably
depend on a judicious combination of non-surgical and surgical
treatments, but we do not currently know which patients
with which types of infection would benefit from a specific
approach.
The role of bone biopsy in diagnosis and antibiotic selection
Bone can be sampled either at the time of an open procedure
or percutaneously (usually under imaging guidance), but must
be obtained without traversing microbially contaminated
tissue. Data are urgently needed to determine the place of bone
biopsy, for both histological and microbiological analysis, in
the diagnosis and directed therapy of osteomyelitis. We need
to determine the meaning of a bone biopsy obtained in a
patient with a non-healing ulcer who has no clinical signs of
bone infection but a positive bone culture. A number of
authors interpret this finding as diagnostic of osteomyelitis,
whereas other possibilities, such as non-infective colonisation
of bone, may need to be considered. Finally, while bone biopsy
appears to be safe, at least in the hands of those experienced in
the procedure, we need to ensure it remains safe when the use
of the technique becomes more widespread.
Choice of antibiotic regimen
There are limited data on which to establish the best choice of
antibiotic therapy for diabetic foot osteomyelitis. The usual
recommended duration of antibiotic therapy for bone infection
is about 6 weeks, but most of the reports of using antibiotics
alone for diabetic foot osteomyelitis have treated for about
3 months or longer. Some evidence suggests the outcome may
be improved when the antibiotic choice is based on the results
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of culture of bone [39], but this needs to be validated in a
randomised study.
Debridement
Accepted practice and available evidence
Once the issue of infection has been dealt with, the next priority
is to ensure that the surface and edges of the wound are
prepared in such a way as to encourage healing. The main
purpose of this wound bed management is to remove necrotic
and highly bacterially contaminated tissue from the surface and
edges of the wound. This can be accomplished most quickly
and most effectively by sharp (i.e. surgical) debridement. Other
methods of debridement include using larvae (maggots), chemical
agents, antiseptics (see below) and some newer technologies.
Unresolved issues
Sharp debridement
Only two published studies have attempted to demonstrate the
effectiveness of sharp debridement and both were of weak
design, i.e. subset analyses of patients included in other studies
[40,41]. A robust prospective assessment is required because
various clinical teams differ in their approach: in the extent to
which debridement is primarily directed at the wound margin
or the wound bed, the regularity with which they will pare the
surface of the wound to leave freely bleeding soft tissue and the
frequency with which debridement is repeated. Many providers
do not have the training, the equipment or the time during an
outpatient visit to perform the sharp debridement that other
specialists would regard as important.
Other methods
Two controlled studies have addressed the effectiveness of
larvae [42,43] but both had methodological weaknesses and
more data are required to assess benefit. No controlled trials
using other methods of debridement have been published. If
the effectiveness of either larvae or other methods in cleaning
the wound bed is confirmed, it will be important to know how
long the effect remains and whether the change is associated
with an improved rate of eventual healing.
Topical antiseptics, applications and
dressings
Accepted practice and available evidence
Open wounds require regular inspection, repeated cleansing
and re-dressing. The main purposes of dressings are to provide
a warm moist environment which is believed to be optimal
for wound healing, as well as to absorb excess exudate and to
protect the wound bed from trauma. Clinicians also hope that
both the speed and success of healing will be improved by
applying specific agents to the surface of the wound or by
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the use of dressing products that incorporate or release such
an agent.
Unresolved issues
There are some data suggesting a significant benefit for
hydrogel dressings in wound healing but these derive from
studies of relatively poor quality [19]. A more robust study has
reported benefit from using a carboxymethylcellulose dressing
[44]. No other trial data indicate that the use of any other
topical antiseptic, wound preparation or dressing has a
beneficial effect on the healing of diabetic foot ulcers [19]. A
single RCT on the use of a silver impregnated dressing showed
no difference between groups for the primary endpoint [45]
and a systematic review of the use of silver-containing
products concluded that there was insufficient evidence to
recommend their use [46].
Growth factors and other agents designed
to correct abnormalities of wound bed
metabolism
Accepted practice and available evidence
A number of approaches that attempt to modify the bio-
chemistry of the wound bed or surrounding cells have been
described, but many are experimental and there is no consensus
on their place in clinical practice. These approaches include
applying or injecting various types of platelet-derived products,
granulocyte-colony stimulating factor (G-CSF), platelet-derived
growth factor (PDGF, becaplermin) and epidermal growth factor
(EGF). Some advocate dressing products designed to correct
imbalances in the wound of the expression of matrix metallo-
proteinases (MMPs) and their inhibitors (tissue inhibitors of
matrix metalloproteinases, TIMPs) [19].
Although a variety of platelet-derived products have been
advocated over the last two decades [47–51], the effectiveness
and cost-effectiveness of this approach has yet to be established
in rigorous trials. Several randomised trials have explored the
use of G-CSF in treating diabetic foot ulcers complicated by
infection and the results suggest the possibility of an overall
improvement in limb salvage [52]. Because, however, of the
small size of these studies, the various G-CSF preparations and
regimens used and the variable quality of the study designs, this
possibility needs to be confirmed. An apparent benefit of PDGF
was observed in one large RCT conducted on neuropathic foot
ulcers in diabetes [53], but the results of a follow-up US study
were inconclusive [54]. The results of an equivalent European
study were not published, suggesting that the promise of
the first study was not confirmed. Early work on EGF has
suggested that it may hasten healing, but this remains to be
confirmed in appropriately powered studies. The results of a
single large trial designed to demonstrate an effect of a dressing
product aimed at modulating expression of MMPs and TIMPs
(Promogran®) were essentially negative [55], although a recent
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study by Kakagia and colleagues has suggested that this product
exhibited a synergistic effect when used in combination with
PDGF [56].
Unresolved issues
There are currently insufficient data to support the use of
growth factor preparations in routine clinical practice.
Bioengineered skin substitutes
Accepted practice and available evidence
Healing of clean, neuropathic ulcers may be enhanced by the
application of bioengineered skin substitutes, comprised of
sheets of cultured cells derived from neonatal skin. Of five ran-
domised controlled studies on skin substitutes, three involved
dermal fibroblast culture and one each fibroblast/keratinocyte
co-culture and culture of keratinocytes alone. One RCT of the
use of dermal fibroblasts reported a significant difference from
control patients, although control subjects responded very
poorly with only 18% of neuropathic ulcers healing by 12 weeks
[57]. The performance of fibroblast/keratinocyte co-culture
was better [58], but was still inferior (in both control and
intervention groups) to results obtained in offloading studies
of a similar group of patients [59]. The fibroblast/keratinocyte
co-culture was also assessed in a large, non-US, study but the
results were never published. The study on keratinocytes did
not report full results [60]. A single report of the use of a skin
substitute for patients with relatively large ulcers based on
autologous cells reported no benefit overall, but a weakly
significant benefit in a subgroup [61]. Another recent systematic
review of the evidence to support the use of bioengineered
skin substitutes concluded that identified trials were of
questionable quality and that recommendations for the use of
skin substitutes could not be made until further high-quality
studies were performed [62].
Unresolved issues
The place of bioengineered skin substitutes has yet to be estab-
lished and we need further evidence of both the effectiveness
and cost-effectiveness of this approach. Such studies should
select appropriate populations, excluding those most likely to
heal with less costly interventions [19].
Negative pressure wound therapy
Accepted practice and available evidence
The application of negative pressure to the surface of wounds
(especially of those which are post-operative or newly debrided)
has been shown to improve healing [63,64]. This technique
has been heavily marketed and is being widely adopted. Both
of the published large trials of this technique reported signifi-
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Management of diabetic foot ulcers • W. J. Jeffcoate et al.
cantly enhanced healing in the intervention group, although
they were limited by being necessarily non-blinded, as well as
by including patients who had surgical closure in the ‘healed’
group. Compression therapy has also been shown to be of
benefit in one single trial [65].
Unresolved issues
While there is evidence to support the use of negative pressure
therapy [66], especially in clean post-operative wounds, a
more recent systematic review has emphasized that it is not
strong [67]. Its place in the management of non-surgical
wounds, including those with less good blood supply, is far
from clear. The most widely available commercial equipment
is relatively expensive and it is not known if the intervention
should be reserved for a particular subgroup that is less likely
to heal with simpler measures. More information is needed on
patient (and wound) selection, the duration of treatment and its
optimal combination with other approaches, such as grafting
or surgical closure. Rozen et al. [68] have recently reported
successfully using a form of negative pressure wound therapy
that is cheaper than commercially available devices.
Hyperbaric oxygen
Accepted practice and available evidence
Hyperbaric oxygen (HBO) has been promoted for the manage-
ment of non-healing wounds for decades, but is endorsed
mainly by those with ready access to (and often ownership of)
the necessary facilities. An earlier systematic review concluded
that there are insufficient data to justify the routine use of
systemic HBO [69]. Most reported studies have been anecdotal
reports, leaving many sceptical of the need for this expensive
intervention [70], but there have been a number of RCTs
undertaken to examine the effectiveness of HBO, including one
which was double-blinded, although unfortunately rather small
[71]. All of these suggest possible clinical benefit. There are no
data to support the use of topical, as opposed to systemic, HBO.
Unresolved issues
More data are required from larger, controlled trials to confirm
the effectiveness of HBO for diabetic foot wounds and to define
which types of lesion may benefit. These trials must, such as that
by Abidia et al. [71] be double-blinded and use hyperbaric air
in the control group to eliminate the possible beneficial effect
of compression. Formal cost–benefit analyses are also needed.
Revascularisation
Accepted practice and available evidence
Revascularisation should be considered in patients with clinical
evidence of impaired lower limb blood flow resulting from
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macrovascular disease that is amenable to intervention, but
this practice is based on clinical experience rather than evidence
from controlled trials. Observational data have shown that
the benefit of attempted revascularisation is much reduced in
patients with chronic renal failure [72–74].
Unresolved issues
The lack of evidence results in continuing uncertainty over
case selection, with many centres attempting intervention only
for occlusions of the larger arteries of the leg, while others
advocate angioplasty for arteries of the calf and foot. The
benefit of distal revascularisation procedures should be
established in controlled trials but clinical circumstances and
ethical issues make this difficult (but not impossible), and
most data derive from observational series. Many such series
report the apparent benefit of an intervention in terms of ‘limb
salvage’, but this term should be used and interpreted with
caution. The term implies that the limb would have been
inevitably lost if the intervention had not been adopted,
but this can only be conclusively demonstrated if there was
a control population.
Offloading in the management of chronic
wounds
Accepted practice and available evidence
One of the factors responsible for the failure of chronic ulcers
to heal is continued mechanical trauma to the bed of the
healing wound, often occurring during the normal activities of
daily life. This occurs because the area is insensate as a result
of underlying distal symmetrical neuropathy. The regenerating
wound bed can, however, be protected by a variety of pressure
offloading methods, including casting, bracing, footwear and
surgical offloading.
Compared with other methods, the use of non-removable
devices, such as a plaster or fibreglass total contact cast or a
walking brace that has been rendered non-removable, results
in a higher proportion of plantar ulcers being healed and in
a shorter time [75–78]. Remarkably, ulcer patients have
been shown to take an average of 72% of their daily steps
unprotected when given a device which they can remove
[79].
Other forms of footwear, such as cast shoes or half shoes,
may result in rates of healing that are better than standard
care [80–84], but this remains to be substantiated in con-
trolled studies. Surgical procedures, such as excision of bony
prominences, joint arthroplasty and Achilles tendon lengthening
do not improve the proportion of ulcers that eventually heal
when compared with total contact casting, but may reduce
healing time [85–90]. The benefit, cost–benefit and safety of
surgical interventions has yet to be demonstrated, especially as
relatively little is known of their long-term consequences, and
of the incidence of associated transfer ulcers.
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No studies on the effects of bed rest, crutches, canes,
wheelchairs, offloading dressings and soft midsole plugs on
ulcer healing were located in the literature. Unfortunately,
there is also little evidence for the effectiveness of low
technology approaches to offloading, such as felted foam
dressings [91] or other techniques that may be suitable for
use in less-developed parts of the world [92].
Unresolved issues
While effective offloading is largely recognized as a cornerstone
of management of the chronic wound, uncertainties surround
the optimal means of implementing this strategy. The application,
and repeated replacement, of casting devices has historically
been an expensive and time-consuming task and further infor-
mation is needed on the minimum training and optimal setting
required to ensure delivery of safe and effective offloading.
Additional investigations should also be directed at establishing
what place special footwear has in ulcer healing and on the
effectiveness of surgical procedures in accelerating the healing
of ulcers overlying bone deformity or joints with reduced
mobility. Other issues that need to be addressed are the relative
advantages and disadvantages of non-removable vs. removable
offloading devices. While non-removable devices appear to be
more effective [59,75], they may be associated with secondary
ulceration on both the affected and contralateral foot, as
well as with inconvenience and distress (caused by immobility
and reduced ability to wash), and with muscle wasting and
backache. Removable devices are more convenient, but less
effective because of issues relating to patient non-adherence.
Simple, reliable, unobtrusive and reasonably priced methods
to monitor adherence to offloading interventions are urgently
needed to inform the results of future clinical trials.
Discussion
Disease of the foot remains a major complication of diabetes,
one that is difficult and expensive to treat and which is
associated with potentially devastating medical, social and
psychological consequences [2–4]. Thus, a climate of evidence-
based intervention is imperative, notwithstanding the fact that
design of trials in this field is difficult. Studies designed to
assess the management of infection—whether of soft tissue
or bone—pose particular problems. These derive from (i) the
need to rely mainly on clinical signs to make the diagnosis
and the lack of objective measures of these signs, (ii) the
importance of surgical interventions in many infections, (iii)
the difficulty in objectively defining the eradication of
infection and (iv) the fact that placebo-controlled trials are
almost always unethical once the diagnosis of infection is
made.
Trial design is also made difficult by the multiplicity of
factors involved in the pathogenesis of chronic ulcers and
which underlie the failure to heal. The condition of an ulcer
may vary with time and treatment and this means that the
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relative contribution made to delayed healing by different
pathological processes will also vary. It may therefore be hard
to demonstrate that any one intervention has on its own an
effect on the desired clinical outcome, which is ulcer healing,
with improved function and well-being. The absence of a
demonstrable clinical benefit does not necessarily mean that
the intervention is ineffective. The choice of appropriate
outcome measures requires special care.
Careful consideration must also be given to definition of the
selected study population (both of ulcers and patients) because
the effectiveness of interventions will vary depending on the
type of ulcer (as characterized by area, depth, site and the
presence of infection, peripheral arterial disease, neuropathy)
as well as in different groups of people (characterised by age,
co-morbidities, glycaemic control, social factors and access to
effective primary health care). The issue of population selection
is especially relevant to the assessment of newer, more costly,
interventions. Many such interventions are currently assessed
in patients in whom the likelihood of healing is relatively high:
those with uncomplicated neuropathic ulcers of relatively
well-perfused feet. However, this population is one in which
healing can be readily achieved with proper attention to simple
issues, such as offloading, and is not the one for which most
clinicians will select newer, and generally more expensive,
advanced wound therapies. Such therapies will generally be
reserved for patients who have proved unresponsive to
established methods and it is in this group that they should
properly be tested. Clinicians have to be cautious in extra-
polating into routine practice the results of some commercially
funded studies.
Investigators should consider other options if the complexity
of the presentation of diabetic foot ulcers, or their variability
over several months of management, is such that it is not
possible to design a robust randomised trial that will reasonably
assess the effectiveness of an intervention. One of these is to
compare outcomes (of ulcers or people: healed, unhealed,
amputation, death) between centres, whilst acknowledging
the many factors that may differ between them [8,93]. If one
service is associated with a substantially better outcome, using
clinically meaningful and patient-centred measures [5], a
search should be undertaken for the specific aspects of care
which may make that service superior. Ultimately, the aim is to
demonstrate that the adoption by a specialist unit of protocols
of care linked to a battery of interventions of proven efficacy
is associated with improved long-term clinical outcome, at
justifiable cost, in a carefully defined population.
Because the current paucity of robust scientific evidence
to inform treatment choices, and of validated protocols for
management of diabetic foot ulcers, is unacceptable, we
challenge all those involved in the care of the diabetic foot to
work together to resolve these issues. The absence of evidence
has allowed a culture to develop in which clinical management
is determined primarily by professional opinion and belief,
and in which attempts are made by industry to influence
these by the promotion of new, usually more expensive, inter-
1386
Management of diabetic foot ulcers • W. J. Jeffcoate et al.
ventions of unproven efficacy. Properly designed trials are
needed to demonstrate effectiveness of recommended inter-
ventions. Until effectiveness has been demonstrated in this
way, it is the responsibility of professional groups, as well as
of those authorising reimbursement, to favour the use of
the simplest, most economical and most acceptable therapies
in the treatment of this serious and much neglected complica-
tion of diabetes.
Competing interests
None of the authors has a duality of interest relevant to the
content of this review to declare, although ARB has received
honoraria from Pfizer and Merck for advisory board member-
ship and speakers’ bureau, and BAL has received research
funding from or served as a consultant to: Merck, Pfizer,
Wyeth-Ayerst, Bayer, Cubist, Ortho-McNeill/Johnson &
Johnson, Oculus. PRC owns stock in DIApedia LLC and is an
inventor on US patents 6 610 897 6 720 470 and 7 206 718
which elucidate a load-relieving dressing and a method of
insole manufacture for offloading diabetic feet. DIApedia
receives royalties from a licensing agreement with Acor
Orthopaedic. PRC has also received honoraria from Merck,
Eli Lilly and ConvaTec and is a recipient of grants from
the National Institutes of Health.
Acknowledgements
Systematic review working parties for the international working
group on the diabetic foot. Footwear and off-loading: Peter
Cavanagh, Chair, Seattle, USA; Sicco Bus, Secretary, Amsterdam,
the Netherlands; David Armstrong, Chicago, USA; Karel Bakker,
Heemstede, the Netherlands; Carlo Caravaggi, Milano, Italy;
Robert van Deursen, Cardiff, UK; Petr Hlavacek, Zlin, the
Czech Republic; Gerlof Valk, Utrecht, the Netherlands.
Wound management: William Jeffcoate, Chair, Nottingham,
UK; William van Houtum, Secretary, Hoofddorp, the Nether-
lands; Jan Apelqvist, Lund/Malmö, Sweden; David Armstrong,
Chicago, USA; Karel Bakker, Heemstede, the Netherlands;
Fran Game, Nottingham, UK; Agnès Hartemann-Heurtier,
Paris, France; Rob Hinchliffe, Nottingham, UK; Magnus Lön-
dahl, Lund, Sweden; Patricia Price, Cardiff, UK; Gerlof Valk,
Utrecht, the Netherlands. Osteomyelitis: Tony Berendt, Chair,
Oxford, UK; Edgar Peters, Secretary, Leiden, the Netherlands;
Karel Bakker, Heemstede, the Netherlands; Magnus Eneroth,
Malmö, Sweden; John Embil, Winnipeg, Canada; Rob Hinch-
liffe, Nottingham, UK; William Jeffcoate, Nottingham, UK;
Benjamin Lipsky, Seattle, USA; Eric Senneville, Tourcoing,
France; James Teh, Oxford, UK; Gerlof Valk, Utrecht, the
Netherlands.
References
1 Reiber GE, Lipsky BA, Gibbons GW. The burden of diabetic foot
ulcers. Am J Surg 1998; 176: 5S–10S.
© 2008 The Authors.
Journal compilation © 2008 Diabetes UK. Diabetic Medicine, 25, 1380–1389
dme(02)_2573.fm Page 1387 Friday, November 21, 2008 10:06 AM
Review article
2 Boulton AJ, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J. The
global burden of diabetic foot disease. Lancet 1985; 366: 1719–1724.
3 Tennvall GR, Apelqvist J, Eneroth M. Costs of deep foot infections
in patients with diabetes mellitus. Pharmacoeconomics 2000; 18:
225–238.
4 Nabuurs-Franssen MH, Huijberts MS, Nieuwenhuijzen Kruseman
AC, Willems J, Schaper NC. Health-related quality of life of diabetic
foot ulcer patients and their caregivers. Diabetologia 2005; 48:
1906–1910.
5 Jeffcoate WJ, Chipchase SY, Ince P, Game FL. Assessing the outcome
of diabetic foot ulcers using ulcer-related and person-related measures.
Diabetes Care 2006; 29: 1784–1787.
6 Apelqvist J, Larsson J, Agardh CD. Long-term prognosis for diabetic
patients with foot ulcers. J Intern Med 1993; 233: 485–491.
7 Oyibo SO, Jude EB, Tarawneh I, Nguyen HC, Harkless LB, Boulton
AJ. A comparison of two diabetic foot ulcer classification systems:
the Wagner and the University of Texas wound classification systems.
Diabetes Care 2001; 24: 84–88.
8 Ince P, Abbas ZG, Lutale JK, Basit A, Mansoor Ali S, Chohan F et al.
Use of the SINBAD classification system and score in comparing
outcome of foot ulcer management in three continents. Diabetes Care
2008; 31: 964–967.
9 Mason J, O’Keeffe C, Hutchinson A, McIntosh A, Young R, Booth
A. A systematic review of foot ulcer in patients with Type 2 diabetes
mellitus. II: treatment. Diabet Med 1999; 16: 889–909.
10 Eldor R, Raz I, Ben Yehuda A, Boulton AJ. New and experimental
approaches to treatment of diabetic foot ulcers: a comprehensive
review of emerging treatment strategies. Diabet Med 2004; 21:
1161–1173.
11 O’Meara S, Cullum N, Majid M, Sheldon T. Systematic reviews of
wound care management: (3) antimicrobial agents for chronic wounds;
(4) diabetic foot ulceration. Health Technol Assess 2000; 4: 1–237.
12 Cullum N, Nealson EA, Flemming K, Sheldon T. Systematic reviews
of wound care management: (5) beds; (6) compression; (7) laser
therapy, therapeutic ultrasound, electrotherapy and electromagnetic
therapy. Health Technol Assess 2001; 5: 1–221.
13 Nelson EA, O’Meara S, Craig D, Iglesias C, Golder S, Dalton J et al.
A series of systematic reviews to inform a decision analysis for
sampling and treating infected diabetic foot ulcers. Health Technol
Assess 2006; 10: 1–221.
14 Boulton AJM, van Houtum WH (eds). The diabetic foot: Proceedings
of the 5th International Symposium on the Diabetic Foot, 9–12 May
2007, Noordwijkerhout, The Netherlands. Diabet Metab Res Rev
2008; 24: Issue S1.
15 International Working Group on the Diabetic Foot. International
Consensus on the Diabetic Foot. 2003. Available at www.idf.org/
bookshop Last accessed 6th September 2008.
16 Lipsky BA. International Consensus Group on diagnosing and
treating the infected diabetic foot. Diabet Metab Res Rev 2004; 20:
S68–S77.
17 Bus SA, Valk GD, van Deursen RW, Armstrong DG, Caravaggi C,
Hlavacek P et al. The effectiveness of footwear and offloading
interventions to prevent and heal foot ulcers and reduce plantar
pressure in diabetes: a systematic review. Diabetes Metab Res Rev
2008; 24: S162–S180.
18 Berendt AR, Peters EJG, Bakker K, Embil JM, Eneroth M, Hinchliffe
RJ et al. Diabetic foot osteomyelitis: a progress report on diagnosis
and a systematic review of treatment. Diabet Metab Res Rev 2008;
24: S145–S161.
19 Hinchliffe R, Valk GD, Apelqvist J, Armstrong DG, Bakker K, Game
FL et al. A systematic review of the effectiveness of interventions to
enhance the healing of chronic ulcers of the foot in diabetes. Diabet
Metab Res Rev 2008; 24: S119–S144.
20 Lavery LA, Armstrong DG, Wunderlich RP, Mohler MJ, Wendel CS,
Lipsky BA. Risk factors for foot infections in individuals with
diabetes. Diabetes Care 2006; 29: 1288–1293.
© 2008 The Authors.
Journal compilation © 2008 Diabetes UK. Diabetic Medicine, 25, 1380–1389
DIABETICMedicine
21 Lipsky BA, Berendt AR, Deery HG, Embil J, Joseph WS, Karchmer
AW et al. Infectious Disease Society of America. Diagnosis and
treatment of diabetic foot infections. Clin Infect Dis 2004; 39:
885–910.
22 Morbach S, Lutale JK, Viswanathan V, Möllenberg J, Ochs HR,
Rajashekar S et al. Regional differences in risk factors and clinical
presentation of diabetic foot lesions. Diabet Med 2004; 21: 91–95.
23 Lavery LA, Armstrong DG, Murdoch DP, Peters EJ, Lipsky BA.
Validation of the Infectious Diseases Society of America’s diabetic foot
infection classification system. Clin Infect Dis 2007; 44: 562–565.
24 Jeandrot A, Richard JL, Combescure C, Jourdan N, Finge S, Rodier
M et al. Serum procalcitonin and C-reactive protein concentrations
to distinguish mildly infected from non-infected diabetic foot ulcers:
a pilot study. Diabetologia 2008; 51: 347–352.
25 Citron DM, Goldstein EJ, Merriam CV, Lipsky BA, Abramson MA.
Bacteriology of moderate-to-severe diabetic foot infections and in
vitro activity of antimicrobial agents. J Clin Microbiol 2007; 45:
2819–2828.
26 Edmonds M, Foster A. The use of antibiotics in the diabetic foot. Am
J Surg 2004; 187: 25S–28S.
27 Xu L, McLennan SV, Lo L, Natfaji A, Bolton T, Liu Y et al. Bacterial
load predicts healing rate in neuropathic diabetic foot ulcers.
Diabetes Care 2007; 30: 378–380.
28 Shone A, Burnside J, Chipchase S, Game F, Jeffcoate W. Probing the
validity of the probe to bone test in the diagnosis of osteomyelitis of
the foot in diabetes. Diabetes Care 2006; 29: 945.
29 Lavery LA, Armstrong DG, Peters EJ, Lipsky BA. Probe-to-bone test
for diagnosing diabetic foot osteomyelitis: relaible or relic? Diabetes
Care 2007; 30: 270–274.
30 Butalia S, Palda VA, Sargeant RJ, Detsky AS, Mourad O. Does this
patient with diabetes have osteomyelitis of the lower extremity? J Am
Med Assoc 2008; 99: 806–813.
31 Berendt AR, Lipsky BA. Is this bone infected or not? Differentiating
neuro-osteoarthropathy from osteomyelitis in the diabetic foot. Curr
Diab Rep 2004; 4: 424–429.
32 Lipsky BA. Osteomyelitis of the foot in diabetic patients. Clin Infect
Dis 1997; 25: 1318–1326.
33 Lazzarini L, Lipsky BA, Mader JT. Antibiotic treatment of
osteomyelitis: what have we learned from 30 years of clinical trials?
Int J Infect Dis 2005; 9: 127–138.
34 Ha Van GH, Siney H, Danan JP, Sachon C, Gimaldi A. Treatment of
osteomyelitis in the diabetic foot. Contribution of conservative
surgery. Diabetes Care 1996; 19: 1257–1260.
35 Henke PK, Blackburn SA, Wainess RW, Cowan J, Terando A,
Proctor M et al. Osteomyelitis of the foot and toe in adults is a
surgical disease: conservative management worsens lower extremity
salvage. Ann Surg 2005; 241: 885–892.
36 Jeffcoate WJ, Lipsky BA. Controversies in diagnosing and managing
osteomyelitis in diabetes. Clinl Inf Dis 2004; 39: S115–S122.
37 Embil JM, Rose G, Trepman E, Math MC, Duerksen F, Simonsen JN
et al. Oral antibiotic therapy for diabetic foot osteomyelitis. Foot
Ankle Int 2006; 27: 771–779.
38 Game F, Jeffcoate WJ. Primarily non-surgical management of
osteomyelitis of the foot in diabetes. Diabetologia 2008; 51: 962–967.
39 Senneville E, Lombart A, Beltrand E, Valette M, Legout L, Cazaubiel
M et al. Outcome of diabetic foot osteomyelitis treated non-surgically:
a retrospective cohort study. Diabetes Care 2008; 31: 637–642.
40 Steed DL, Donohoe D, Webster MW, Lindsley L. Effect of extensive
debridement and treatment on the healing of diabetic foot ulcers.
J Am Coll Surg 1996; 183: 61–64.
41 Saap LJ, Falanga V. Debridement performance index and its correlation
with complete closure of diabetic foot ulcers. Wound Repair Regen
2002; 10: 354–359.
42 Sherman RA. Maggot therapy for treating diabetic foot ulcers
unresponsive to conventional therapy. Diabetes Care 2003; 26:
446–451.
1387
dme(02)_2573.fm Page 1388 Friday, November 21, 2008 10:06 AM
DIABETICMedicine
43 Armstrong DG, Salas P, Short B, Martin BR, Kimbriel HR, Nixon BP
et al. Maggot therapy in ‘lower-extremity hospice’ wound care. J Am
Pod Med Assoc 2005; 95: 254–257.
44 Piaggesi A, Baccetti F, Rizzo L, Romanelli M, Navalesi R, Benzi L.
Sodium carboxyl-methyl-cellulose dressings in the management of
deep ulcerations of diabetic foot. Diabet Med 2001; 18: 320–324.
45 Jude EB, Apelqvist J, Spraul M, Martini J, Silver Dressing Study Group.
Prospective controlled study of Hydrofiber dressing containing ionic
silver or calcium alginate dressings in non-ischaemic diabetic foot
ulcers. Diabet Med 2007; 24: 280–288.
46 Vermeulen H, van Hattem JM, Storm-Versloot MN, Ubbink DT.
Topical silver for treating infected wounds. Cochrane Libr Issue
2007; 4: 1–36.
47 Krupski WC, Reilly LM, Perez S, Moss KM, Crombleholme PE, Rapp
JH. A prospective randomized trial of autologous platelet-derived
wound healing factors for treatment of chronic nonhealing wounds:
a preliminary report. J Vasc Surg 1991; 14: 526–532.
48 Steed DL, Goslen JB, Holloway GA, Malone JM, Bunt TJ, Webster
MW. Randomized prospective double-blind trial in healing chronic
diabetic foot ulcers. CT-102 activated platelet supernatant, topical
versus placebo. Diabetes Care 1992; 15: 1598–1604.
49 Margolis DJ, Kantor J, Santanna J, Strom BL, Berlin JA. Effectiveness
of platelet release for the treatment of diabetic neuropathic foot
ulcers. Diabetes Care 2001; 24: 483–488.
50 Feng J, Du WH, Wang J. Clinical study of various growth factors
on the improvement of impaired healing ulcers in patients with
diabetic disease. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 1999;
13: 273–277.
51 Driver VR, Hanft J, Fylling CP, Beriou JM. Autogel Diabetic Foot
Study Group. A prospective, randomized, controlled trial of
autologous platelet-rich plasma gel for the treatment of diabetic
foot ulcers. Ostomy Wound Manage 2006; 52: 68–70.
52 Cruciani M, Lipsky BA, Mengoli C, de Lalla F. Are granulocyte
colony-stimulating factors beneficial in treating diabetic foot
infections?: A meta-analysis. Diabetes Care 2005; 28: 454–460.
53 Wieman TJ, Smiell JM, Su Y. Efficacy and safety of a topical gel
formation of recombinant human platelet-derived growth factor-BB
(becaplermin) in patients with chronic neuropathic diabetic ulcers.
A Phase III randomized placebo-controlled double-blind study.
Diabetes Care 1998; 21: 822–827.
54 Robson MC, Payne WG, Garner WL, Biundo J, Giacolone VF,
Cooper DM et al. Intergating the results of phase IV (post-marketing)
clinical trial with four previous trials reinforces the position that
Regranex (becaplermin) gel 0.01% is an effective adjunct to the
treatment of diabetic foot ulcers. J Appl Res 2005; 5: 35–45.
55 Veves A, Sheehan P, Pham HT. A randomized, controlled trial of
Promogran (a collagen/oxidized regenerated cellulose dressing) vs
standard treatment in the management of diabetic foot ulcers. Arch
Surg 2002; 137: 822–827.
56 Kakagia DD, Kazakos KJ, Xarchas KC, Karanikas M, Georgiadis
GS, Tripsiannis G et al. Synergistic action of protease-modulating
matrix and autologous growth factors in healing of diabetic foot
ulcers. A prospective randomized trial. J Diabetes Complications
2007; 21: 387–391.
57 Marston WA, Hanft J, Norwood P, Pollak R. Dermagraft Diabetic
Foot Ulcer Study Group. The efficacy and safety of Dermagraft in
improving the healing of chronic diabetic foot ulcers: results of
a prospective randomized trial. Diabetes Care 2003; 26: 1701–
1705.
58 Veves A, Falanga V, Armstrong DG, Sabolinski ML; Apligraf
Diabetic Foot Ulcer Study. Graftskin, a human skin equivalent, is
effective in the management of non-infected neuropathic diabetic
foot ulcers: a prospective randomized multicenter clinical trial.
Diabetes Care 2001; 24: 290–295.
59 Katz IA, Harlan A, Miranda-Palma B, Prieto-Sanchez L, Armstrong
DG, Bowker JH et al. A randomized trial of two irremovable off-
1388
Management of diabetic foot ulcers • W. J. Jeffcoate et al.
loading devices in the management of plantar neuropathic diabetic
foot ulcers. Diabetes Care 2005; 28: 555–559.
60 Bayram Y, Deveci M, Imirzalioglu N, Soysal Y, Sengezer M. The cell
based dressing with living allogenic keratinocytes in the treatment of
foot ulcers: a case study. Br J Plast Surg 2005; 58: 988–996.
61 Caravaggi C, De Giglio R, Pritelli C, Sommaria M, Dalla Noce S,
Faglia E et al. HYAFF 11-based autologous dermal and epidermal
grafts in the treatment of non-infected diabetic plantar and dorsal
foot ulcers: a prospective, multi-center, controlled, randomized
clinical trial. Diabetes Care 2003; 26: 2853–2859.
62 Blozik E, Scherer M. Skin replacement therapies for diabetic foot
ulcers. Diabetes Care 2008; 31: 693–694.
63 Armstrong DG, Lavery LA; Diabetic Foot Study Consortium. Negative
pressure wound therapy after partial diabetic foot amputation: a multi-
centre, randomised controlled trial. Lancet 2005; 388: 1704–1710.
64 Blume PA, Walters J, Payne W, Ayala J, Lantis J. Comparison of
negative pressure wound therapy utilizing vacuum-assisted closure to
advance moist wound therapy in the treatment of diabetic foot ulcers.
A multi-center randomized controlled trial. Diabetes Care 2008; 31:
631–636.
65 Armstrong DG, Nguyen HC. Improvement in healing with aggressive
edema reduction after debridement of foot infection in persons with
diabetes. Arch Surg 2000; 135: 1405–1409.
66 Andros G , Armstrong DG, Attinger CE, Boulton AJ, Frykberg RG,
Joseph WS et al. Consensus statement on negative pressure wound
therapy (VAC therapy) for the management of diabetic foot wounds.
Ostomy Wound Manage 2006; S1–32.
67 Gregor S, Maegele M, Sauerland S, Krahn JF, Peinemann F, Lange S.
Negative pressure wound therapy: a vacuum of evidence ? Arch Surg
2008; 143: 189–196.
68 Rozen WM, Shahbaz S, Morsi A. An improved alternative to vacuum-
assisted closure (VAC) as a negative pressure dressing in lower limb
split skin grafting: a clinical trial. J Plast Reconstr Anaesthet Surg
2008; 61: 334–337.
69 Kranke P, Bennett M, Roeckl-Wedemann I, Debus S. Hyperbaric
oxygen therapy for chronic wounds. Cochrane Database Syst Rev
2004; CD004123.
70 Berendt AR. Counterpoint: hyperbaric oxygen for diabetic foot
wounds is not effective. Clin Infect Dis 2006; 43: 193–198.
71 Abidia A, Laden G, Kuhan G, Johnson BF, Wilkinson AR, Renwick
PM et al. The role of hyperbaric oxygen therapy in ischaemic diabetic
lower extremity ulcers: a double-blind randomised-controlled trial.
Eur J Vasc Endovasc Surg 2003; 25: 513–518.
72 Johnson BL, Glickman MH, Bandyk DF, Esses GE. Failure of foot
salvage in patients with end-stage renal disease after surgical
revascularization. J Vasc Surg 1995; 22: 280–285.
73 Reddan DN, Marcus RJ, Owen WF Jr, Szczech LA, Landwehr DM.
Long-term outcome of revascularization for peripheral vascular
disease in end-stage renal disease patients. Am J Kidney Dis 2001;
38: 57–63.
74 Leers SA, Reifsnyder T, Delmonte R, Caron M. Realistic expectations
for pedal by-pass grafts in patients with end-stage renal disease.
J Vasc Surg 1998; 28: 976–980.
75 Mueller MJ, Diamond JE, Sinacore DR, Delitto A, Blair VP 3rd,
Drury DA et al. Total contact casting in treatment of diabetic plantar
ulcers. Controlled clinical trial. Diabetes Care 1989; 12: 384–388.
76 Armstrong DG, Nguyen HC, Lavery LA, Van Schie CHM, Boulton
AJM, Harkless LB. Off-loading the diabetic foot wound: a randomized
clinical trial. Diabetes Care 2001; 24: 1019–1022.
77 Armstrong DG, Lavery LA, Wu S, Boulton AJ. Evaluation of
removable and irremovable cast walkers in the healing of diabetic
foot wounds: a randomized controlled trial. Diabetes Care 2005;
28: 551–554.
78 Piaggesi A, Macchiarini S, Rizzo L, Palumbo F, Tedeschi A, Nobili
LA et al. An off-the-shelf instant contact casting device for the
management of diabetic foot ulcers: a randomized prospective
© 2008 The Authors.
Journal compilation © 2008 Diabetes UK. Diabetic Medicine, 25, 1380–1389
dme(02)_2573.fm Page 1389 Friday, November 21, 2008 10:06 AM
Review article
trial versus traditional fiberglass cast. Diabetes Care 2007; 30: 586–
590.
79 Armstrong DG, Lavery LA, Kimbriel HR, Nixon BP, Boulton AJ.
Activity patterns of patients with diabetic foot ulceration: patients with
active ulceration may not adhere to a standard pressure off-loading
regimen. Diabetes Care 2003; 26: 2595–2597.
80 Chantelau E, Breuer U, Leisch AC, Tanudjaja T, Reuter M.
Outpatient treatment of unilateral diabetic foot ulcers with ‘half
shoes’. Diabet Med 1993; 10: 267–270.
81 Hissink RJ, Manning HA, van Baal JG. The MABAL shoe, an
alternative method in contact casting for the treatment of neuropathic
diabetic foot ulcers. Foot Ankle Int 2000; 21: 320–323.
82 Knowles EA, Armstrong DG, Hayat SA, Khawaja KI, Malik RA,
Boulton AJ. Offloading diabetic foot wounds using the scotchcast
boot: a retrospective study. Ostomy Wound Manage 2002; 48: 50–53.
83 Ha Van G, Siney H, Hartmann-Heurtier A, Jacqueminet S, Greau F,
Grimaldi A. Non-removable, windowed, fiberglass cast boot in the
treatment of diabetic plantar ulcers: efficacy, safety, and compliance.
Diabetes Care 2003; 26: 2848–2852.
84 Margolis DJ, Allen-Taylor L, Hoffstad O, Berlin JA. Healing diabetic
neuropathic foot ulcers: are we getting better? Diabet Med 2005; 22:
172–176.
85 Patel VG, Wieman TJ. Effect of metatarsal head resection for diabetic
foot ulcers on the dynamic plantar pressure distribution. Am J Surg
1994; 167: 297–301.
86 Piaggesi A, Schipani E, Campi F, Romanelli M, Baccetti F, Arvia C
et al. Conservative surgical approach versus non-surgical management
© 2008 The Authors.
Journal compilation © 2008 Diabetes UK. Diabetic Medicine, 25, 1380–1389
DIABETICMedicine
for dianetic neuropathic foot ulcers: a randomized trial. Diabet Med
1998; 15: 412–417.
87 Armstrong DG, Stacpoole-Shea S, Nguyen H, Harkless LB.
Lengthening of the Achilles tendon in diabetic patients who are
at high risk for ulceration of the foot. J Bone Joint Surg Am 1999;
81: 535–538.
88 Armstrong DG, Lavery LA, Vazquez JR, Short B, Kimbriel HR,
Nixon BP et al. Clinical efficacy of the first metatarsophalangeal
joint arthroplasty as a curative procedure for hallux interphalangeal
joint wounds in patients with diabetes. Diabetes Care 2003; 26:
3284–3287.
89 Mueller MJ, Sinacore DR, Hastings MK, Strube MJ, Johnson JE.
Effect of Achilles tendon lengthening on neuropathic plantar
ulcers. A randomized clinical trial. J Bone Joint Surg Am 2003; 85-
A: 1436–1445.
90 Armstrong DG, Rosales MA, Gashi A. Efficacy of fifth metatarsal
head resection for treatment of chronic diabetic foot ulceration. J Am
Pod Med Assoc 2005; 95: 353–356.
91 Zimny S, Schatz H, Pfohl U. The effects of applied felted foam on
wound healing and healing times in the therapy of neuropathic—
diabetic foot ulcers. Diabet Med 2003; 20: 622–625.
92 Abbas ZG, Archibald LK. Challenges for management of the diabetic
foot in Africa: doing more with less. Int Wound J 2007; 4: 305–313.
93 Prompers L, Huijberts M, Apelqvist J, Jude E, Piaggesi A, Bakker K
et al. High prevalence of ischaemia, infection and serious co-morbidity
in patients with diabetic foot disease in Europe. Baseline results from
the Eurodiale study. Diabetologia 2007; 50: 18–25.
1389