doi: 10.1111/1346-8138.

13285 Journal of Dermatology 2016; 43: 591–619

GUIDELINE
The wound/burn guidelines – 3: Guidelines for the diagnosis
and treatment for diabetic ulcer/gangrene
Taiki ISEI,1 Masatoshi ABE,2 Takeshi NAKANISHI,3 Koma MATSUO,4 Osamu YAMASAKI,5
Yoshihide ASANO,6 Takayuki ISHII,7 Takaaki ITO,8 Yuji INOUE,9 Shinichi IMAFUKU,10
Ryokichi IRISAWA,11 Masaki OHTSUKA,5 Mikio OHTSUKA,12 Fumihide OGAWA,13
Takafumi KADONO,6 Masanari KODERA,14 Tamihiro KAWAKAMI,15 Masakazu
KAWAGUCHI,16 Ryuichi KUKINO,17 Takeshi KONO,18 Keisuke SAKAI,19 Masakazu
TAKAHARA,20 Miki TANIOKA,21 Yasuhiro NAKAMURA,22 Akira HASHIMOTO,23 Minoru
HASEGAWA,7 Masahiro HAYASHI,16 Manabu FUJIMOTO,7 Hiroshi FUJIWARA,24 Takeo
MAEKAWA,25 Naoki MADOKORO,26 Yuichiro YOSHINO,27 Andres LE PAVOUX,28 Takao
TACHIBANA,29 Hironobu IHN,9 The Wound/Burn Guidelines Committee
1
Department of Dermatology, Kansai Medical University, Osaka , 2Department of Dermatology, Gunma University Graduate School of
Medicine, Gunma , 3Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, 4Department of
Dermatology, The Jikei University School of Medicine, Tokyo, 5Department of Dermatology, Okayama University Graduate School of
Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, 6Department of Dermatology, Faculty of Medicine, University of Tokyo,
Tokyo, 7Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa
University, Ishikawa, 8Department of Dermatology, Hyogo College of Medicine, Hyogo, 9Department of Dermatology and Plastic
Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, 10Department of Dermatology, Faculty of Medicine, Fukuoka
University, Fukuoka, 11Department of Dermatology, Tokyo Medical University, Tokyo, 12Department of Dermatology, Fukushima
Medical University, Fukushima, 13Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki,
14
Department of Dermatology, Japan Community Health Care Organization Chukyo Hospital, Aichi, 15Department of Dermatology,
St. Marianna University School of Medicine, Kanagawa, 16Department of Dermatology, Yamagata University Faculty of Medicine,
Yamagata, 17Department of Dermatology, NTT Medical Center Tokyo, 18Department of Dermatology, Nippon Medical School, Tokyo,
19
Intensive Care Unit, Kumamoto University Hospital, Kumamoto, 20Department of Dermatology, Graduate School of Medical Sciences,
Kyushu University, Fukuoka, 21Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, 22Department of
Dermatology, University of Tsukuba, Ibaraki, 23Department of Dermatology, Tohoku University Graduate School of Medicine, Miyagi,
24
Department of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 25Department of
Dermatology, Jichi Medical University, Tochigi, 26Department of Dermatology, Mazda Hospital, Hiroshima, 27Department of
Dermatology, Japanese Red Cross Kumamoto Hospital, Kumamoto, 28Ichige Dermatology Clinic, Ibaraki, 29Department of Dermatology,
Osaka Red Cross Hospital, Osaka, Japan

ABSTRACT
We aimed to prepare guidelines for the management of diabetic ulcer/gangrene with emphasis on the diagnosis
and treatment of skin symptoms. They serve as a tool to improve the quality of the diagnosis and treatment in
each patient and, further, to improve the level of the care for diabetic ulcer in Japan by systematically presenting
evidence-based recommendations for clinical judgments by incorporating various viewpoints.
Key words: diabetic complications, diabetic gangrene, diabetic patients, diabetic skin ulcer, podiatrist.

BACKGROUND OF THE DRAFTING OF THE
GUIDELINES CONCERNING DIABETIC ULCER
Guidelines are “documents systematically prepared to support
medical experts and patients for making appropriate judgments
in particular clinical situations”, and those for diabetic ulcer/gan-
grene have been prepared and proposed in foreign countries.
However, in foreign countries, the medical system differs com-
pared with that in Japan, and a wider variety of medical profes-
sions may be engaged in the diagnosis and treatment for
diabetes than in Japan. For example, there are professionals
who perform the diagnosis and treatment for disorders from the

Correspondence: Hironobu Ihn, M.D., Ph.D., Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University,
1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan. Email: ihn-der@kumamoto-u.ac.jp
This is the secondary English version of the original Japanese manuscript for The wound/burn guidelines – 3: Guidelines for the diagnosis and
treatment for diabetic ulcer/gangrene published in the Japanese Journal of Dermatology 2012; 122(2): 281–319.
Received 1 December 2015; accepted 2 December 2015.

© 2016 Japanese Dermatological Association 591

T. Isei et al.
toes to the legs called podiatrists in addition to orthopedists in
some countries. The role of the podiatrist varies among coun-
tries, but they can perform even surgical treatments of the foot in
the USA. Thus, overseas medical situations differ markedly from
that in Japan. It is, therefore, unreasonable to directly apply
overseas guidelines to Japan without taking such differences in
the medical circumstances into consideration. In Japan, the
number of diabetic patients has increased markedly in recent
years with associated increases in the importance of the diagno-
sis and treatment for its complications, diabetic skin ulcer and
gangrene. We, therefore, aimed to prepare guidelines for the
management of diabetic ulcer/gangrene with emphasis on the
diagnosis and treatment of skin symptoms. Of course, as dia-
betic ulcer/gangrene are symptoms of diabetes, which is a sys-
temic disease, it is not sufficient to focus on skin symptoms
alone, and attention to diabetes per se and its complications is
always necessary. Needless to say, it is also necessary to man-
age diabetic patients in cooperation with all medical professions
involved in the diagnosis and treatment for diabetes and its com-
plications. In addition, as factors that delay wound healing are
always present in diabetic ulcer unlike acute wounds,
approaches to such exacerbating factors are necessary in treat-
ing it. For this reason, the present guidelines aim to serve as a
tool to improve the quality of the diagnosis and treatment in each
patient and, further, to improve the level of the care for diabetic
ulcer in Japan by systematically presenting evidence-based rec-
ommendations for clinical judgments by incorporating these
viewpoints.
POSITION OF THE GUIDELINES FOR THE
DIAGNOSIS AND TREATMENT FOR DIABETIC
ULCER/GANGRENE
The Wound/Burn Guidelines Committee consists of members
commissioned by the Board of Directors of the Japanese Der-
matological Association. It held several meetings and evalua-
tions in writing since October 2008 and drafted the Guidelines
for the Diagnosis and Treatment for Diabetic Ulcer/Gangrene
by taking opinions of the Scientific Committee and Board of
Directors of the Japanese Dermatological Association into con-
sideration. The present guidelines show the current standards
of the diagnosis and treatment for diabetic ulcer/gangrene in
Japan. However, individual patients vary in underlying diseases,
severity of symptoms and background including complications.
Therefore, the physicians who conduct the diagnosis and treat-
ment should determine the therapeutic approaches with the
patients, and the contents of their treatments are not required
to be in complete agreement with the present guidelines. Also,
the guidelines are not relevant for citation in lawsuits.
SPONSORS AND CONFLICTS OF INTEREST
All cost needed for drafting the present guidelines has been
borne by the Japanese Dermatological Association, and no
fund has been received from particular organizations, enter-
prises or pharmaceutical companies. If any members of the
committee have been involved in the development of particular
592
related drugs, they were excluded from the evaluation of the
recommendation level of the treatments in question. Each
member of the committee has no other conflict of interest to
disclose on drafting the present guidelines.
COLLECTION OF EVIDENCE
Databases used: Medline, PubMed, Japana Centra Revuo
Medicina Web and Cochrane database systematic reviews of
ALL EBM Reviews. References obtained by manual search of
each member were also added.
Search period: The published work that could be searched
between January 1980 and December 2008 was reviewed.
Recent published work of importance was added when appro-
priate.
Adoption criteria: Priority was placed on systematic reviews
of randomized controlled trials (RCT) and papers on individual
RCT. If they were not available, papers on cohort studies, case–
control studies and so forth were adopted. Although some
papers on case series studies were also used as references, the
published work on basic experiments was excluded.
CRITERIA FOR THE DETERMINATION OF THE
EVIDENCE AND RECOMMENDATION LEVELS
The criteria adopted in the Guidelines for the Diagnosis and
Treatment of Malignant Tumors edited by the Japanese Der-
matological Association mentioned below were used as refer-
ences.
 Evidence levels:
I. Systematic reviews/meta-analyses.
II. One or more RCT.
III. Non-RCT (including before/after comparative studies
with statistical analysis).
IVa. Analytical epidemiological studies (cohort studies).
IVb. Analytical epidemiological studies (case–control stud-
ies/cross-sectional studies).
V. Descriptive studies (case reports and case series stud-
ies).
VI. Opinions of special committees and individual experts.
 Recommendation levels:
A. Strongly recommended (There is at least one piece of
level I or good level II evidence indicating the effec-
tiveness).
B. Recommended (there is at least one piece of inferior
level II, good level III or very good level IV evidence).
C1. Recommended as an option despite the lack of good
evidence (there is inferior level III–IV evidence, several
pieces of good level V evidence or level VI evidence
endorsed by the committee).
C2. (Presently) not recommendable due to the lack of suf-
ficient evidence (there is no evidence indicating effec-
tiveness or there is evidence indicating
ineffectiveness).
© 2016 Japanese Dermatological Association

D. Not recommended (there is good evidence indicating
ineffectiveness or harmfulness).
The recommendation levels mentioned in the text are not nec-
essarily in agreement with the above, because they were deter-
mined at some points according to consensus of the committee
(by showing evidence levels) in consideration of the international
lack of evidence concerning the diagnosis and treatment of this
condition, inappropriateness of directly applying overseas evi-
dence to Japan, and practicality of the guidelines.
REVIEWS BEFORE DISCLOSURE
Prior to the disclosure of the guidelines, progress in drafting was
presented at the Annual Meetings of the Japanese Dermatologi-
cal Association from 2008 to 2011, opinions were invited from
the association members and necessary revisions were made.
UPDATING POLICIES
The present guidelines will be updated in 3–5 years. However,
if partial updating becomes necessary, update information will
be presented on the website of the Japanese Dermatological
Association when appropriate.
TERMINOLOGY
“Diabetes”: Diabetes is caused by continuation of chronic ele-
vation of the blood glucose level above the appropriate range
due to insulin deficiency. It causes various tissue and organ
disorders (complications). It is generally diagnosed according
to the diagnostic criteria of the Japanese Diabetes Society.
“Diabetic dermatopathy”: Skin disorders caused by patho-
logical changes in diabetic patients.
“Peripheral arterial disease (PAD)”: PAD is a general term
for peripheral arterial disorders including arteriosclerosis oblit-
erans (ASO) but is often used synonymously with ASO because
of its predominance. Recently, it has been shown to be closely
involved in not only leg amputation due to gangrene but also
cardiovascular diseases and associated deaths.
“Infection”: A state in which bacteria have grown above the
stage of colonization, which is a state in which bacteria are
present but do not grow on the ulcer surface, and the prolifera-
tive power of bacteria has surpassed the host immune capac-
ity and interferes with wound healing.
“Topical agents”: Drugs used for topical treatment through
the skin or by direct application to the focus in the skin. Pre-
pared by compounding various active agents with a base.
“Hammer toe”: Toe deformity caused by impairment of flex-
ion of the metatarsophalangeal joint and extension of interpha-
langeal joint.
“Claw toe”: Toe deformity due to flexion of the distal inter-
phalangeal joints. Caused by impairment of the extensor
aponeurosis.
“Charcot’s osteoarthropathy”: Bone destruction caused by
excessive use of a joint due to neuropathic impairment of pain
sensation. Occurs mostly in joints distal to the ankle in dia-
betes.
© 2016 Japanese Dermatological Association
Wound/Burn Guidelines – 3
“Foot corn”: Internally developing, localized hyperkeratosis
induced by long-standing external stimulation.
“Pressure ulcer”: External force applied to the body reduces
or arrests the blood flow in the soft tissue between the bone
and skin surface. If this state persists for a prolonged period,
the tissue receives irreversible ischemic damage and develops
a pressure ulcer.
“Pocket”: A wound cavity spreading beyond a skin defect.
The tissue covering a pocket is called the cover wall or cover lid.
“DESIGN”: A scale for the evaluation of the condition of
pressure ulcer announced by the Japanese Society of Pressure
Ulcers in 2002 and an assessment tool consisting of seven
items: (i) depth; (ii) exudates; (iii) size; (iv) inflammation/infec-
tion; (v) granulation tissue; (vi) necrotic tissue; and (vii) pocket.
There are two types, one for severity classification representing
severe and mild by capital and small letters, and the other for
quantitative follow-up evaluations of the healing process. In the
latter type, there is the 2002 version and DESIGN-R (2008
revised version) modified for more accurate rating of the sever-
ity as well as evaluation of the course of pressure ulcers.
“Bacterial colonization”: A state in which bacteria are only
present on the ulcer surface. The host immune capacity is bal-
anced with the proliferative ability of bacteria, and the birth
and death of bacteria are in equilibrium.
“Bacterial contamination”: A state in which bacteria are pre-
sent on the ulcer surface but do not divide or proliferate.
“Critical colonization”: Conventionally, the microbial environ-
ment of the wound was classified into infected and aseptic
states, but the current trend is to understand the two condi-
tions as continuous (the concept of bacterial balance). Infection
of the wound is understood as continuous stages of contami-
nation, colonization and infection, and infection may occur
depending on the balance between the bacterial burden on the
wound and host resistance. Critical colonization is a stage
between colonization and infection but tilted more to infection
with the number of bacteria exceeding that of colonization.
“Biofilm”: Bacteria that have colonized on the surface of a
foreign body or in necrotic tissue may produce polysaccha-
rides on their body surface. Polysaccharides around bacterial
bodies gradually fuse and form a membrane-like structure,
which wraps bacteria. This is called a biofilm. Bacteria
wrapped in a biofilm are protected from antibiotics in general
and leukocytes, and infection is likely to persist.
“Ankle brachial pressure index (ABI)”: The value indicated as
the ratio between the blood pressure measured in the leg (usu-
ally in the posterior tibial or dorsalis pedis artery) and upper arm
(lower limb blood pressure/brachial blood pressure). Because it
decreases with peripheral leg blood pressure due to stenosis or
obstruction of the leg artery, it is useful for the diagnosis of PAD.
However, caution is needed in dialysis patients with marked
sclerotic change due to calcification of the peripheral arterial
wall, as the ABI may be normal or elevated even when PAD is
present. According to the TASCII, international guidelines con-
cerning PAD, the ABI is considered normal when it is 0.91 or
more and 1.40 or less, and PAD is diagnosed when it is 0.90 or
less. The American Diabetes Association (ADA) considers the
ABI to be low when it is less than 0.9 and to be high when it is
593
T. Isei et al.
1.3 or more in diabetic patients. In outpatient care for diabetic
patients in Japan, a slightly higher cut-off index of the ABI (1.0)
has been reported to be appropriate. A special device for quick
measurement of the ABI (ABI/PWV) has become widely
adopted, and the discrimination of false and true values is possi-
ble by simultaneous measurement of the limb arterial pressures
and pulse wave velocity (PWV). This examination can be per-
formed relatively easily in the outpatient clinic without a special
device.
“Trans-Atlantic Inter-Society Consensus II (TASCII)”: Guideli-
nes concerning the diagnosis and treatment of PAD that were
prepared with the participation of societies related to blood
vessels in Europe, the USA, Japan, Australia and South Africa,
and have gained international consensus. They include items
related to the diagnosis and treatment of PAD complicating
diabetic ulcer.
“Peripheral arterial occlusive disease (PAOD)”: PAOD is a
general term for PAD in which stenosis or obstruction occurs
for some reason in limb arteries, causing circulatory disorders.
It includes Buerger’s disease and acute arterial obstruction as
well as ASO, but is often used synonymously with ASO or PAD
because of the predominance of ASO.
“Arteriosclerosis obliterans”: A disease in which chronic
stenosis or obstruction of limb arteries and consequent impair-
ment of the limb blood flow are caused by arteriosclerosis due
to dyslipidemia.
“Toe brachial pressure index (TBI)”: The value indicated as
the ratio between the brachial and toe blood pressure (toe blood
pressure / arm blood pressure). Because calcification is less
likely to occur in the toe arteries compared with lower leg ves-
sels, the TBI may be less affected by calcification than the ABI.
“Transcutaneous oxygen pressure (TcPO2) (measurement)”:
A non-invasive examination performed by directly measuring
the oxygen diffusing from the cutaneous microvessels on the
skin surface using a probe. The cutaneous blood flow can be
indirectly evaluated using information concerning the blood flow
and state of oxygenation in the cutaneous microcirculation.
“Skin perfusion pressure (SPP)”: The SPP, measured by the
laser Doppler technique, allows the evaluation of the cutaneous
microcirculation relatively easily. It may be closely correlated
with the toe pressure (TP) and is measurable even in patients
in whom the TP cannot be measured (those after toe amputa-
tion or with toe ulcer).
“Digital subtraction angiography (DSA)”: Angiography in
which images of structures other than the objects of interest
can be deleted by digital image processing. The accuracy of
the diagnosis can be enhanced by eliminating tissues including
bones.
“Computed tomography angiography (CTA)”: Angiography
using computed tomography.
“Angiography”: The procedure to obtain X-ray images by
injecting a contrast agent into blood vessels.
“Magnetic resonance angiography (MRA)”: Angiography by
magnetic resonance imaging (MRI). A contrast agent is often
used for examining peripheral arteries.
“Fontaine classification”: A scale for functional classification
of collaterals based on information obtained by medical inter-
594
views. Consists of stages I–IV. All diabetic ulcers/gangrenes
associated with chronic arterial obstruction are classified as
stage IV.
Fontaine stage I Chill and color changes in the leg
Fontaine stage II Intermittent claudication
Fontaine stage III Pain at rest
Fontaine stage IV Necrosis or skin ulcer in the leg
“Critical limb ischemia (CLI)”: A condition corresponding to
Fontaine stage III or IV.
“Moist wound healing”: A method to maintain the wound
surface in a moist environment. It retains polynuclear leuko-
cytes, macrophages, enzymes and cell growth factors on the
wound surface. It also promotes autolysis and contributes to
debridement and does not interfere with cell migration.
“Semmes–Weinstein monofilament test”: A testing technique
performed by applying a nylon filament to the skin with pres-
sure and examining the sensibility. Sensory nerve disorders
can be evaluated by semiquantitative measurements of pain
and pressure sensibilities using monofilaments different in
diameters. The 5.07 (10 g weight) monofilament is often used
for the diagnosis of diabetic neuropathy.
Evaluations Filament/converted to
pressure (g)
Normal 1.65–2.83: green/0.008–0.08
Reduced sensibility to touch 3.22–3.61: blue/0.172–0.217
Reduced protective sensibility 3.84–4.31: purple/0.445–2.35
Loss of protective sensibility 4.56–6.65: red/4.19–279.4
No response to 6.65
“Foot care”: A series of actions for the care of the foot
aimed at unloading, pressure reduction, mitigation of pain and
cleaning for the protection of the foot or prevention of wounds.
“Debridement”: A therapeutic action to clean the wound by
removing dead tissues, aged tissues that have ceased to react
to stimulation by promoters of wound healing such as growth
factors, foreign bodies and foci of bacterial infection, which are
often associated with the above. There are methods such as:
(i) autolytic debridement induced by occlusive dressing; (ii)
mechanical debridement (e.g. wet-to-dry dressing, high-pres-
sure lavage, hydrotherapy and ultrasonic lavage); (iii) debride-
ment using proteases; and (iv) surgical debridement.
“Surgical therapy”: Surgical treatments, surgical debride-
ment and invasive treatments of subcutaneous pockets. The
distinction between surgical treatments and surgical debride-
ment is unclear.
“Dressing materials”: Modern wound dressing materials for
creating moist environment for wounds. Conventional sterilized
gauze is excluded.
“Occlusive dressing”: All dressing methods used to avoid
drying of wounds for moist wound healing are called occlusive
dressing. This is a collective term for dressing using modern
wound dressing materials other than conventional gauze dressing.
“Wound dressing materials”: Wound dressing materials
can be classified into dressing materials (modern dressing
© 2016 Japanese Dermatological Association

materials) and medical materials such as gauze (classic dress-
ing materials). The former are medical materials aimed to pro-
vide conditions optimal for wound healing by maintaining a
moist environment and must be used selectively depending on
the state of the wound and amount of exudate. The latter allow
drying of the wound and cannot maintain a moist environment
if effusion is insufficient. Medical materials other than conven-
tional gauze that provide an environment optimal for wound
healing by covering the wound and maintaining moisture may
also be called wound dressing materials or dressing materials.
“Wound bed preparation”: Management of the wound sur-
face environment to promote wound healing. Specifically, it
consists of removing necrotic tissues, reducing bacterial load,
preventing wound drying, controlling excessive effusion, and
treating pockets and wound margins.
“Negative-pressure wound therapy”: A variation of physical
therapy. The wound is maintained in closed environment, and
suction is applied to adjust the pressure to 125–150 mmHg, in
principle. This directly eliminates bacteria and exotoxins
released from them, promotes vascularization and alleviates
edema of granulation tissue.
“Nutrition support team (NST)”: The Japan Council for Nutri-
tional Therapy calls nutritional management performed appro-
priately for individual patients and for the treatment of
individual disorders “nutrition support”, and defines a team of
several professions including the physician, nurse, pharmacist,
managerial dietician and clinical laboratory technician as an
NST.
“Hyperbaric oxygen therapy”: A therapy intended to elevate
the arterial dissolved oxygen concentration and relieve hypoxia
of skin tissue by placing the patient under an oxygen pressure
higher than the atmospheric pressure.
“Callosity”: Externally developing, localized hyperkeratosis
induced by long-standing external stimulation.
“Foot bathing”: Immersing the leg rather than the whole
body in warm water and washing it while warming.
“Physical therapy”: Treatments performed by applying stim-
ulation to the body using physical means, which include physi-
cal energies such as heat, water, light, ultrashortwave,
electricity, ultrasound, vibration, pressure and traction. Ther-
motherapy, cryotherapy, hydrotherapy, phototherapy, ultra-
shortwave therapy, electric stimulation therapy, ultrasound
therapy, negative-pressure wound therapy, hyperbaric oxygen
therapy and traction therapy are variations of physical therapy.
These physical therapies are performed to mitigate pain, pro-
mote wound healing or increase the elasticity of tissues such
as muscles and ligaments. Physical therapy is used as a gen-
eral term for all these therapies, and individual therapies are
referred to conventionally with the means for the treatment, or
physical agents, to avoid confusion.
“Lavage”: Removing chemical stimulants, infection sources
and foreign bodies from the skin or wound surface using the
hydraulic pressure or lysing effect of a liquid. Lavage may be
performed using physiological saline, tap water, or saline or
tap water combined with a surfactant such as soap and deter-
gent. The effect of lavage may be derived from the flow volume
or hydraulic pressure.
© 2016 Japanese Dermatological Association
Wound/Burn Guidelines – 3
DEFINITION OF THE DISEASE
Of the diabetic skin disorders observed in diabetic
patients, chronic or progressive ulcerating or necrotic
lesions based on diabetic neuropathy, PAD or both are
defined as diabetic ulcer/gangrene. Of these lesions, rever-
sible changes are defined as diabetic ulcer, and necro-
tized, non-reversible changes as gangrene. As a matter of
course, ulcerative or necrotic lesions due to other diseases
(collagen disease, leg varices, malignant neoplasms) are
excluded.
WOUND HEALING PROCESS AND ITS
INTERFERENCE IN DIABETES
The wound healing process in the skin can be divided into
three periods: (i) inflammation; (ii) cell proliferation; and (iii)
maturation/reconstruction. In each of these periods of the
wound healing process, the appearance and suppression of
functions of various cells and morphological changes are
observed, and growth factors and proteases are involved in
them in complicated manners. In healthy people, this wound
healing process advances smoothly, and wounds heal rapidly
(acute wounds). In diabetic patients, however, the healing
mechanism is inhibited by various inhibiting factors of wound
healing such as neuropathy, peripheral angiopathy, regional
hyperglycemia and reduced activity of the patient, delaying
wound healing (chronic wounds). In diabetes, a hypoxic state
occurs readily on the dermal level. Matrix metalloproteinase
(MMP)-1 with a collagen-decomposing activity derived from
fibroblasts may increase under a hypoxic condition and ham-
per wound healing.1 Hypoxia promotes infection of the lesion,
which further delays wound healing.2,3 Hyperglycemia also
affects the osmotic pressure and inhibits granulation in skin
ulcers. Moreover, basic research has also disclosed on the
gene level that hyperglycemia is involved in a delay of wound
healing.4
To correct this delay of wound healing, it is necessary to
promote wound healing using appropriate repairing factors as
well as eliminating exacerbating factors. Basic evaluations
using model mice have also demonstrated that improving the
wound healing mechanism leads to the acceleration of healing
in diabetic ulcer models.5–7 In various periods of the wound
healing process, the appearance and suppression of functions
of various cells and morphological changes are observed, and
growth factors and proteases are involved in them in compli-
cated manners. It is very important to understand these mech-
anisms for the selection of repairing factors appropriate for the
treatment.
However, in the actual treatment for diabetic ulcers, part of
the difficulty in healing is derived from not only the poor control
of the blood glucose level but also the involvement of a wide
variety of exacerbating and repairing factors. For this reason,
physicians diagnosing and treating diabetic skin ulcers/gan-
grenes must approach these conditions with rich knowledge
about wound healing and sufficient power of observation for
skin symptoms.
595
T. Isei et al.

ATTITUDES TO THE DIAGNOSIS AND In diabetic neuropathy, impairment of motor nerves causes
TREATMENT atrophy of muscles supplied by them and leads to toe or foot
deformities such as hammer toe and claw toe. Also, an
Diabetic ulcer/gangrene often occur on the basis of periph-
increase in the bone blood flow due to autonomic neuropathy
eral neuropathy, which is a complication of diabetes.8–12
causes a decrease in the bone mass, and if this is combined
Because many diabetic patients are hyperlipidemic, diabetes
with repeated stimulation by continuing walking without feeling
is often complicated by circulatory disorders of the limbs
pain due to sensory neuropathy, foot deformity called Char-
(PAD) due to arteriosclerotic stenosis or obstruction of
cot’s foot (joint) occurs. As such deformities abnormally
peripheral arteries, and diabetic ulcer/gangrene caused by
increase the pressure exerted to particular sites of the foot, the
circulatory insufficiency based on PAD accounts for approxi-
risk of skin disruption leading to ulcer is augmented. Also, the
mately 25% of all cases. Both peripheral neuropathy and
patients fail to notice foot corns, trauma, burns and skin infec-
PAD are involved in some cases. Moreover, ulcer may be
tions due to reduced protective sensibility caused by sensory
caused or exacerbated as infection is involved in addition to
neuropathy, leading to the development and exacerbation of
these factors.
the ulcer. PAD itself does not frequently cause ulcers, but once

Skin ulcer,Gangarene
CQ1

No iabetes ellitus
Glucose Intolerance

Yes

Infection Yes Infection Controle

CQ2,3 CQ2-6,10

No

Diagnosis and/or therapy

Peripheral Arterial Disese
Yes Diagnosis and therapy
for other disease
with skin ulcer (PAD) , CQ7 for PAD
CQ1,7,15
No

Yes Diagnosis and therapy

Diabetic peripheral
for DPN
neuropathy(DPN) CQ8,16,17,24,25
CQ8
No

Yes

No

conservative treatments ineffective Surgical procedures

CQ9-25 CQ10

effective

Cure

Recurrence prevention, Rehabilitation

CQ14,18-20,23-25

Figure 1. Assessment and treatment algorithm for diabetic ulcer/gangrene. CQ, clinical question.

596 © 2016 Japanese Dermatological Association


an ulcer develops, it prolongs the healing process and even
increases the risk of gangrene, possibly necessitating amputa-
tion of large joints.13
Because of these diabetic complications, the condition of a
diabetic ulcer is often expected not to be improved by conven-
tional topical agents for ulcer alone, and treatments for compli-
cations are frequently required. Because treatments vary
depending on the extent of involvement of different complica-
tions in the pathogenesis of ulcer, the clarification of the pres-
ence or absence and severity of diabetic neuropathy and PAD
is important for not only the diagnosis but also determination
of the therapeutic strategy. This approach is also regarded as
a principle of the management of diabetic ulcer/gangrene in
many overseas guidelines.9,14,15
As mentioned in the previous section, the mechanism of
wound healing is inhibited by various factors in diabetic ulcer,
and the lesions are in a state of chronic wound. A principle of
treatment for a chronic wound is to promptly convert it to an
acute wound by eliminating factors that interfere with the
mechanism of wound healing, and this is also important in
treating diabetic ulcers. Indeed, the prevalence of ulcers in dia-
betic patients is reported to be approximately 15%,16 while it
varies among reports. Diabetic patients tend to become inac-
tive in daily living due to the ulcers, and this further exacer-
bates diabetes, setting off a negative spiral.
In the present guidelines, the basic concept of the man-
agement of diabetic ulcer/gangrene is to first diagnose/assess
these diabetic complications and then to appropriately com-
bine their treatments with the diagnosis/assessment of, and
treatments for, the ulcer/gangrene per se. Algorithms and clin-
ical questions (CQ) were established on the basis of this con-
cept as signposts for the actual management of the
condition.
DIAGNOSTIC AND THERAPEUTIC
ALGORITHMS
Figure 1 shows algorithms for the management of diabetic
ulcer/gangrene.
REFERENCES
1 Kan C, Abe M, Yamanaka M, Ishikawa O. Hypoxia-induced
increase of matrix metalloproteinase-1 synthesis is not restored by
reoxygenation in a three-dimensional culture of human dermal
fibroblasts. J Dermatol Sci 2003; 32: 75–82.
2 Beer HD, Fa €ssler R, Werner S. Glucocorticoid-regulated gene
expression during cutaneous wound repair. Vitam Horm 2000; 59:
217–239.
3 Greif R, Akcß a O, Horn EP, Kurz A, Sessler DI. Supplemental peri-
operative oxygen to reduce the incidence of surgical-wound infec-
tion. Outcomes Research Group. N Engl J Med 2000; 342: 161–
167.
4 Fleischmann E, Lenhardt R, Kurz A et al. Nitrous oxide and risk of
surgical wound infection: a randomised trial. Lancet 2005; 366:
1101–1107.
5 Olerud JE. Models for diabetic wound healing and healing into per-
cutaneous devices. J Biomater Sci Polym Ed 2008; 19: 1007–1020.
6 Brem H, Tomoic-Canic M. Cellular and molecular basis of wound
healing in diabetes. J Clin Invest 2007; 117: 1219–1222.
© 2016 Japanese Dermatological Association
Wound/Burn Guidelines – 3
7 Liu ZJ, Velazquez OC. Hyperoxia, endothelial progenitor cell mobi-
lization, and diabetic wound healing. Antitoxid Redox Signal 2008;
10: 1869–1882.
8 International working group for diabetic foot disease: Kou Uchi-
mura et al. ed. International consensus of diabetic foot disease.
2000; 1–98.
9 Apelqvist J, Bakker K, van Houtum WH, Schaper NC, On behalf of
the International Working Group on the Diabetic Foot (IWGDF) Edi-
torial Board. Practical guidelines on the management and preven-
tion of the diabetic foot. Based upon the International Consensus
on the Diabetic Foot (2007) Prepared by the International Working
Group on the Diabetic Foot :. Diabetes Metab Res Rev 2008; 24:
S181–S187.
10 Mayfield JA, Reiber GF, Sanders LJ, Janisse D, Pogach LM.
Preventive foot care in people with diabetes. Diabetes Care 1998;
21: 2161–2177.
11 Abbott CA, Carrington AL, Ashe H et al. The North-west Diabetes
Foot Care Study : incidence of, and risk factors for, new diabetic
foot ulceration in a community-based patient cohort. Diabet Med
2002; 19: 377–384.
12 Reiber GE, Vileikyte L, Boyko EJ et al. Casual pathways for inci-
dent lower extremity ulcers in patients with diabetes from two set-
tings. Diabetes Care 1999; 22: 157–162.
13 Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic limb
amputation : basis for prevention. Diabetes Care 1990; 13: 513–
552.
14 Frykberg RG, Zgonis T, Armstrong DG et al. American College of
Foot and Ankle Surgeons Diabetic foot disorders. A clinical prac-
tice guideline 2006. J Foot Ankle Surg 2006; 45: S1–S66.
15 Steed DL, Attinger C, Colaizzi T et al. Guidelines for the treatment
of diabetic ulcers. Wound Repair Regen 2006; 14: 680–692.
16 Jeffcoate WJ, Harding KG. Diabetic foot ulcers. Lancet 2003; 361:
1545–1551.
CQ1: ARE THE WAGNER GRADING SYSTEM
AND UNIVERSITY OF TEXAS DIABETIC
WOUND CLASSIFICATION USEFUL AS
CLINICAL SEVERITY SCALES TO BE USED IN
DAILY PRACTICE FOR THE MANAGEMENT OF
DIABETIC ULCER/GANGRENE?
Remarks on recommendation: It is recommended to evaluate
the severity of diabetic ulcer/gangrene primarily using the Wag-
ner Grading System. It is also recommended to perform sever-
ity evaluation using the University of Texas Diabetic Wound
Classification.
Recommendation level: Wagner Grading System: B.
University of Texas Diabetic Wound Classification: B.
Comments:
 Concerning the Wagner Grading System, there is one cohort
study17 and the evidence level is IVa. However, the recom-
mendation level was set at B, because it has been widely
used and gained international consensus, and because it
has served as a standard for the development of new sever-
ity classifications. There is a non-randomized comparative
study and a cohort study18,19 concerning the University of
Texas Diabetic Wound Classification, and the evidence level
is III–IVa. Also, while it is more likely to reflect the actual
severity than the Wagner Grading System, it has a large
number of evaluation items and is relatively complex. There-
fore, its recommendation level set at a level comparable
with the Wagner Grading System.
597
T. Isei et al.
 The Wagner Grading System classifies diabetic ulcer/gan-
grene into five grades according to the depth of ulcer and
the presence or absence of osteomyelitis and gangrene.
Because it is simple and easy to understand, it is widely
used primarily in Western countries, but its validity in dia-
betic patients in Japan has not been evaluated. Also, the
presence or absence and severity of PAD are not included
in the evaluation criteria of the Wagner Grading System.
Therefore, in using this system, it is necessary to evaluate
the severity by taking the condition of the ulcer, state of
peripheral angiopathy or neuropathy, and the general condi-
tion including complications into consideration.
 The University of Texas Diabetic Wound Classification18,19
classifies diabetic ulcers of the leg into four grades accord-
ing to their depth in underlying tissues, and subclassifies
each grade into four stages according to the presence or
absence of infection and ischemia. Because this system
includes the states of infection and ischemia as evaluation
criteria, it is more likely to reflect the actual severity than the
Wagner Grading System. However, as it has a large number
of evaluation items and is complex, it may be somewhat
inconvenient for use at the outpatient clinic.
 As clinical severity scales for diabetes, some new criteria
have been proposed including S(AD)SAD,20 SINBAD,21
PEDIS22 and DUSS,23 but none of them has gained interna-
tional consensus. Also, as all these classifications are crite-
ria for severity evaluation including the general condition,
they are insufficient as evaluation criteria for the state of the
ulcer surface per se. They are, therefore, unsatisfactory to
be used for the selection of topical treatments for ulcer such
as topical agents.
 For the evaluation of the state of pressure ulcer for its man-
agement, the DESIGN, an assessment tool consisting of the
depth, exudates, size, inflammation/infection, granulation tis-
sue, necrotic tissue and pocket, has been proposed by the
Japanese Society of Pressure Ulcers.24 The follow-up type
DESIGN is applicable as a method for the evaluation of the
local state of diabetic ulcers and criteria for the selection of
topical treatments and can be used when appropriate.
REFERENCES
17 Wagner FW Jr. The dysvascular foot: a system for diagnosis and
treatment. Foot Ankle 1981; 2: 64–122 (Evidence level IVa).
18 Lavery LA, Armstrong DG, Harkless LB. Classification of diabetic
foot wounds. J Foot Ankle Surg 1996; 35: 528–531 (Evidence level
IVa).
19 Armstrong DG, Lavery LA, Harkless LB. Validation of a diabetic
wound classification system. The contribution of depth, infection,
and ischemia to risk of amputation. Diabetes Care 1998; 21: 855–
859 (Evidence level III).
20 Macfarlane RM, Jeffcoate WJ. Classification of diabeticfoot ulcers:
the S(AD)SAD system. Diabetic Foot 1999; 1962: 123–131.
21 Ince P, Abbas ZG, Lutale JK. et al. Use of the SINBAD classifica-
tion system and score in comparing outcome of foot ulcer man-
agement on three continents. Diabetes Care 2008; 31: 964–967.
22 Schaper NC. Diabetic foot ulcer classification system for research
purposes: a progress report on criteria for including patients in
research studies. Diabetes Metab Res Rev 2004; 20: S90–S95.
598
23 Beckert S, Witte M, Wicke C, Ko € nigsrainer A, Coerper S. A new
wound-based severity score for diabetic foot ulcers : a prospective
analysis of 1,000 patients. Diabetes Care 2006; 29: 988–992.
24 Moriguchi A, Miyachi Y, Sanada H. et al. DESIGN -A new assess-
ment tool for the classification and the healing Process in pressure
ulcers. Jpn J PU 2002; 4: 1–7 (in Japanese).
CQ2: HOW SHOULD BACTERIAL INFECTION
OF DIABETIC ULCERS BE DIAGNOSED?
Remarks on recommendation: For the diagnosis of bacterial
infection of diabetic ulcers, it is recommended to make judg-
ments based on comprehensive evaluation of clinical findings,
blood test results, imaging findings and results of bacterial cul-
tures.
Recommendation level: B.
Comments:
 For the diagnosis of infection of diabetic ulcers, it is essen-
tial to make judgments on the basis of comprehensive eval-
uation of clinical findings, blood test results, imaging
findings and results of bacterial cultures, but relevant reports
are limited to expert opinions, and the evidence level is VI.
However, the recommendation level was set at B in consid-
eration of the importance attached to clinical findings also in
foreign guidelines.25,26 Although there are two clinical com-
parative studies concerning the diagnosis of infection of dia-
betic ulcers and bacterial cultures,27,28 they are not reports
on the diagnosis of infections in general.
 Foot infections in diabetic patients are classified according
to clinical characteristics into non-limb threatening infec-
tions, which are mild and affect a limited area, and limb-
threatening infections, which are severe and may require
foot or limb amputation. Non-limb-threatening infection is
infection of a shallow ulcer with cellulitis restricted within
2 cm from its margin but not accompanied by fasciitis,
abscess or osteomyelitis. There is no ischemia, and the
blood glucose level is controlled adequately. Severe limb-
threatening infection is defined as deep ulcer with cellulitis
extending farther than 2 cm from its margin and accompa-
nied by deep infection (abscess, fasciitis or osteomyelitis).
It is in an ischemic state, and the blood glucose level is
poorly controlled.27,29
 For the diagnosis in general, the point is whether or not
there are findings indicating inflammation such as reddening
around the ulcer, swelling, pus discharge, exudates, smell,
local hot feeling and tenderness. Patients may be subjec-
tively asymptomatic because of neuropathy. Also, while a
sign of inflammation on blood tests (white blood cell count,
C-reactive protein [CRP], erythrocyte sedimentation rate) is
useful, an increase in white blood cells or CRP may not be
observed despite the presence of deep infection.
 Plain radiography may reveal no changes in bones in an
early stage of osteomyelitis, but plain radiography, CT and
MRI are useful for the evaluation of deep soft tissue infec-
tions and osteomyelitis, and they present gas images in gas
gangrene. Therefore, patients should be referred to medical
facilities capable of CT or MRI when necessary.
© 2016 Japanese Dermatological Association

 Bacterial cultures of samples from the infected wound and
susceptibility testing are necessary for appropriate antibiotic
therapy. Samples may be obtained by swabbing, curettage,
aspiration or biopsy, but samples from deeper tissues are
more reliable.28,30 The most important pathogenic microor-
ganisms are primarily aerobic Gram-positive cocci such as
Staphylococcus aureus and b-hemolytic streptococci, but
Gram-negative or anaerobic bacteria may cause infections,
and these species are often detected simultaneously.31–33
Samples for bacterial cultures should be collected after
debridement, and cultures for both aerobic and anaerobic
species should be performed as much as possible.25,29 In
bacterial cultures, understanding of concepts about bacterial
balance such as colonization, contamination and critical col-
onization, which represent the states of bacteria at the
wound and host. Also, antibiotics are generally ineffective
against bacteria contained in a biofilm.
REFERENCES
25 Frykberg RG, Zgonis T, Armstrong DG et al. Diabetic foot disor-
ders. A clinical practice guideline (2006 revision). J Foot Ankle Surg
2006; 45: S1–S66 (Evidence level VI).
26 Lipsky BA, Berendt AR, Deery HG et al. Infectious Diseases Soci-
ety of America. Diagnosis and treatment of diabetic foot infections.
Clin Infect Dis 2004; 39: 885–910 (Evidence level VI).
27 Lookingbill DP, Miller SH, Knowles RC. Bacteriology of chronic leg
ulcers. Arch Dermatol 1978; 114: 1765–1768.
28 Pellizzer G, Strazzabosco M, Presi S et al. Deep tissue biopsy vs.
superficial swab culture monitoring in the microbiological assess-
ment of limb-threatening diabetic foot infection. Diabet Med 2001;
18: 822–827.
29 Joshi N, Caputo GM, Weitekamp MR, Karchmer AW. Infections in
patients with diabetes mellitus. N Engl J Med 1999; 341: 1906–1912.
30 Cavanagh PR, Lipsky BA, Bradbury AW, Botek G. Treatment for
diabetic foot ulcers. Lancet 2005; 366: 1725–1735.
31 Wheat LJ, Allen SD, Henry M et al. Diabetic foot infections: bacte-
riologic analysis. Arch Intern Med 1986; 246: 1935–1940.
32 Sapico FL, Canawati HN, Witte JL, Montgomerie JZ, Wagner FW
Jr, Bessman AN. Quantitative aerobic and anaerobic bacteriology
of infected diabetic feet. J Clin Microbiol 1980; 12: 413–420.
33 Sapico FL, Witte JL, Canawati HN, Montgomerie JZ, Bessman AN.
The infected foot of the diabetic patient: quantitative microbiology
and analysis of clinical features. Rev Infect Dis 1984; 6: S171–
S176.
CQ3: ARE IMAGING FINDINGS USEFUL FOR
THE DIAGNOSIS OF OSTEOMYELITIS?
Remarks on recommendation: While it is possible to predict
osteomyelitis from bone exposure and positive findings on the
probe-to-bone test, imaging examinations, MRI in particular,
are recommended for more accurate diagnosis (B).
Among other imaging examinations, plain radiography, bone
scintigraphy and labeled white blood cell scintigraphy is rec-
ommended as an option (C1).
Recommendation level:
MRI: B.
Plain radiography, bone scintigraphy, labeled white blood
cell scintigraphy: C1.
© 2016 Japanese Dermatological Association
Wound/Burn Guidelines – 3
Comments:
 There are two meta-analyses concerning the diagnosis of
osteomyelitis.34,35 Among imaging examinations, MRI is the
most reliable modality, and the evidence level is I. However,
the recommendation level was set at B, because MRI can-
not be performed as a routine examination at all medical
facilities. Also, the recommendation level of plain radiogra-
phy, bone scintigraphy and labeled white blood cell scintig-
raphy was set at C1, because their sensitivity and specificity
are inferior to those of MRI.
 Osteomyelitis can also be diagnosed on the basis of clinical
findings. For example, bone exposure and a positive probe-
to-bone test (the tip of the probe hits the bone on the ulcer
floor) are its diagnostic markers.36,37
 The sensitivity and specificity of bone exposure and a posi-
tive probe-to-bone test for the diagnosis of osteomyelitis are
60% and 90%, respectively.34,35 Among imaging modalities,
MRI, plain radiography, bone scintigraphy and labeled white
blood cell scintigraphy have been evaluated, and their sensi-
tivity and specificity were 90% and 79%, 54% and 68%,
81% and 28%, and 74% and 68%, respectively.34,35
 A definitive diagnosis of osteomyelitis can also be made by
bone biopsy, but the examination is invasive and may
spread the infection.
REFERENCES
34 Dinn MT, Abad CL, Sfdar N. Diagnostic accuracy of the physical
examination and imaging tests for osteomyelitis underlying diabetic
foot ulcers: meta-analysis. Clin Infect Dis 2008; 47: 519–527 (Evi-
dence level I).
35 Kapoor A, Page S, Lavallet M, Gale DR, Felson DT. Magnetic reso-
nance imaging for diagnosing foot osteomyelitis: a meta-analysis.
Arch Intern med 2007; 167: 125–132 (Evidence level I).
36 Grayson ML, Gibbons GW, Balogh K, Levin E, Karchmer AW.
Probing to bone in infected pedal ulcers. A clinical sign of underly-
ing osteomyelitis in diabetic patients. JAMA 1995; 273: 721–723.
37 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.
CQ4: WHAT TOPICAL AGENTS ARE USEFUL
FOR CONTROLLING BACTERIAL INFECTION
OF DIABETIC ULCERS?
Remarks on recommendation:
 The use of cadexomer iodine, silver sulfadiazine and povi-
done iodine sugar is recommended for controlling bacterial
infection of mild diabetic ulcers (B).
 The use of ointments containing antibiotics (antibacterial
agents) cannot be recommended at present due to the lack
of sufficient evidence (C2).
Recommendation level:
Cadexomer iodine, silver sulfadiazine, povidone iodine
sugar: B.
Ointments containing antibiotics (antibacterial agents): C2.
599
T. Isei et al.
Comments:
 There are two RCT concerning the use of external antibacte-
rial drugs for bacterial infection of diabetic ulcers.38,39 These
trials indicated the efficacy of saccharose38 and cadexomer
iodine,39 and the recommendation level of cadexomer iodine
is B. However, there have been no evaluations concerning
other topical agents in general or reports of evaluations of
the effects of individual drugs on diabetic ulcers.
 Although there are no reports concerning silver sulfadiazine
or povidone iodine sugar, their recommendation level for the
treatment of pressure ulcer, a similar chronic trauma of the
skin, is comparable to that of cadexomer iodine. Therefore,
their recommendation level was set at the same level as
cadexomer iodine on the basis of consensus of the commit-
tee.
 There are no reports indicating the advantage of ointments
containing antibiotics (antibacterial agents). Moreover, once
they are used for the control of infection of skin damages in
the chronic period, their use tends to be prolonged, possibly
causing microbial substitution. Therefore, their recommen-
dation level was set at C2.
 Povidone iodine gel, iodoform, iodine ointments and silver-
containing Hydrofiberâ are not recommended as there are
few reports about them, but their recommendation level for
the treatment of pressure ulcer is C1, and their use for the
treatment of diabetic ulcer is not excluded.
 Cadexomer iodine produces its bactericidal effect by slowly
releasing iodine.40 Dextrin polymer absorbs not only exu-
dates but also bacteria.40–42 Therefore, while it is useful for
the treatment of wounds with a large amount of exudate or
pus, old polymer beads must be completely washed off at
dressing changes, and it should not be used for pockets
that are difficult to wash.43 If used for wounds deficient in
effusion, it may cause drying of the wound surface and
delay wound healing. In a stage with well-developed granu-
lation tissue, iodine may damage it. Also, caution for iodine
allergy is needed.43
 Silver sulfadiazine produces an infection-controlling effect
on the wound surface due to the antibacterial action of the
silver it contains on the cell membrane and cell wall.44,45 It
also suppresses the formation of biofilm by S. aureus
including methicillin-resistant S. aureus (MRSA).46 Moreover,
as an emulsion base is used, it exerts a cleaning effect on
the wound surface by softening/lysing necrotic tissue. How-
ever, caution is necessary as its efficacy is attenuated when
used with povidone iodine, and its concomitant use with
external enzyme preparations, in particular, must be
avoided.43
 Povidone iodine sugar produces an infection-controlling
effect due to the antibacterial effect of the iodine it con-
tains.47 White sugar inhibits the growth of bacteria and sup-
presses the formation of biofilm by S. aureus including
MRSA.48 White sugar alleviates edema of the wound surface
due to its water-absorbing property and exerts an excellent
granulation-promoting effect by stimulating collagen synthe-
sis by fibroblasts.48 However, if effusion is deficient, it may
600
induce drying of the wound surface and delay wound heal-
ing.43 In the red period with well-developed granulation tis-
sue, povidone iodine may damage granulation tissue. Also,
caution for iodine allergy is necessary.43
REFERENCES
38 Rhaiem BB, Ftouhi B, Brahim SB et al. A comparative study of
saccharose use in the treatment of cutaneous lesions in diabetic
patients: about 80 cases. Tunisie Med 1998; 76: 19–23 (in French)
(Evidence level II).
39 Apelqvist J, Ragnarson-Tennvall G. Cavity foot ulcers in diabetic
patients: a comparative study of cadexomer iodine ointment and
standard treatment. Acta Derm Venereol 1996; 76: 231–235 (Evi-
dence level II).
40 Kurosaki T, Noto Y, Takemori M. Bacteriocidal activity and iodine
release of Cadex ointment 0.9%. Jpn Phamacol Ther, 2001; 29:
839–847 (in Japanese).
41 Hellgen L, Vincent J. Absorption effect in vitro of iodophor gel on
debris fractions in leg ulcers: Private documents for references of
Perstorp Pharma.
42 Lawrence JC. Studies on the distribution of bacteria within two
modern synthetic dressings using an artificial wound : Private doc-
uments for references of Perstorp Pharma.
43 Japanese society of pressure ulcers ‘Guideline for prevention and
management of pressure ulcers’ decision committee: Change ‘I’ to
‘i’ -control of infection and inflammation. Tokyo, Shorinsha: 2009;
134–137 (in Japanese) (Evidence level VI).
44 Rosenkranz HS, Carr HS. Silver sulfadiazine: effect on the growth
and metabolism of bacteri. Antimicrob Ag Chemother 1972; 2:
362–372.
45 Coward JE, Carr HS, Rosenkranz HS. Silver sulfadiazine: effect on
the ultrastructure of Pseudomonas aeruginosa. Antimicrob Ag Che-
mother 1973; 3: 621–624.
46 Akiyama H, Tada J, Arata J. Biofilm. Jpn J Clin Dermatol 1999; 53:
59–63 (in Japanese).
47 Asada Y, Usui T, Fukui I. Antimicrobial activity of KT-136 against
clinical isolate strains. Jpn Pharmacol Ther 1991; 19: 3851–3854 (in
Japanese).
48 Nakao H, Tsuboi R, Ogawa H. Wound-healing promotion mecha-
nism of sugar and povidone-iodine ointment -Analysis using cul-
tured cells and animal model. Ther Res 2002; 23: 1625–1626 (in
Japanese).
CQ5: IS SYSTEMIC ADMINISTRATION OF AN
ANTIBACTERIAL DRUG USEFUL FOR THE
CONTROL OF LOCAL ACUTE INFECTION OF
DIABETIC ULCER?
Remarks on recommendation: Systemic administration of
antibacterial drugs such as piperacillin/tazobactam, imipenem,
cefazolin, cephatolexin, ampicillin/sulbactam, linezolid, amoxi-
cillin/clavulanate, clindamycin and cephalexin is recommended
for infected moderate to severe diabetic foot ulcer.
Recommendation level: B.
Comments:
 There are 10 RCT concerning infected diabetic ulcer and
systemic administration of antibacterial drugs, and the evi-
dence level is II. The treatment has been shown to be effec-
tive, while there are differences in the effect. Antibacterial
drugs are administrated out of necessity, and the recom-
mendation level of each was made B.
© 2016 Japanese Dermatological Association

 In 586 patients with moderate to severe diabetic foot infec-
tion, the efficacy rates of ertapenem and piperacillin/ta-
zobactam were 94% and 92%, respectively, on a multi-
facility, double-blind comparative study.49 Ertapenem is not
marketed in Japan. Piperacillin/tazobactam is not covered
by the Japanese national medical insurance system when
used for the treatment of infection of cutaneous soft tissue.
There are also imipenem, piperacillin/clindamycin, cefazolin,
cephatolexin, ampicillin/sulbactam and linezolid, and there
are RCT concerning amoxicillin/clavulanate, clindamycin and
cephalexin, though on a small scale, reporting their effi-
cacy.50–57
 As severe infections are often mixed infections of Gram-
positive, Gram-negative and anaerobic bacteria, the admin-
istration of broad-spectrum antibacterial agents is neces-
sary. The administration period is recommended to be
1–2 weeks for mild infections and 2 weeks or longer for sev-
ere infections.58
REFERENCES
49 Lipsky BA, Armstrong DG, Citron DM, Tice AD, Morgenstern DE,
Abramson MA. Entrapenem versus piperacillin/tazobactam for dia-
betic foot infections(SIDESTEP): prospective, randomized, con-
trolled, double-blinded, multicentre trial. Lancet 2005; 366: 1695–
1703 (Evidence level II).
50 Chantelau E, Tanudjaja T, Altenhofer F, Ersanli Z, Lacigova S, Met-
zger C. Antibiotic treatment for uncomplicated neuropathic forefoot
ulcers in diabetes: a controlled trial. Diabet Med 1996; 13: 156–159
(Evidence level II).
51 Lipsky BA, Pecoraro RE, Larson SA, Hanley ME, Ahroni JH. Outpa-
tient management of uncomplicated lower-extremity infections in
diabetic patients. Arch In- tern Med 1990; 150: 790–797 (Evidence
level II).
52 Lipsky BA, Itani K, Norden C, Linezolid Diabetic Foot Infections
Study Group. Treating foot infections in diabetic patients: a ran-
domized, multicenter, open-label trial of linezolid versus ampicillin-
sulbactam/amoxicillin-clavulanate. Clin Infectious Dis 2004; 38: 17–
24 (Evidence level II).
53 Tan JS, Wishnow RM, Talan DA, Duncanson FP, Norden CW.
Treatment of hospitalized patients with complicated skin and skin
structure infections: double-blind, randomized, multicenter study
of piperacillin/tazobactam versus ticarcillin-clavulanate. The Piper-
acillin/Tazobactam Skin and Skin Structure Study Group. Antimi-
crobial Agents Chemother 1993; 37: 1580–1586 (Evidence level
II).
54 Bouter KP, Visseren FLJ, Van Loenhout RMM, Bartelink AKM,
Erkelens DW, Diepersloot RJA. Treatment of diabetic foot infection:
an open randomised comparison of imipenem/cilastatin and piper-
acillin/clindamycin combination therapy. Int J Antimicrobial Agents
1996; 7: 143–147 (Evidence level II).
55 Erstad BL Jr, McIntyre KE Jr, Mills JL. Prospective, randomized
comparison of ampicillin/sulbactam and cefoxitin for diabetic
foot infections. Vascular Surg 1997; 31: 419–426(Evidence level
II).
56 Grayson ML, Gibbons GW, Habershaw GM et al. Use of ampicillin/
sulbactam versus imipenem/cilastatin in the treatment of limb-
threatening foot infections in diabetic patients. Clin Infectious Dis
1994; 18: 683–693 (Evidence level II).
57 Bradsher RW Jr, Snow RM. Ceftriaxone treatment of skin and soft
tissue infections in a once daily regimen. Am J Med 1984; 77: 63–
67 (Evidence level II).
58 Lipsky BA. Evidence-based antibiotic therapy of diabetic foot
infections. FEMS Immunol Med Microbiol 1999; 26: 267–276.
© 2016 Japanese Dermatological Association
Wound/Burn Guidelines – 3
CQ6: HOW LONG SHOULD SYSTEMIC
ADMINISTRATION OF ANTIBACTERIAL DRUGS
BE CONTINUED FOR THE TREATMENT OF
OSTEOMYELITIS?
Remarks on recommendation: For osteomyelitis associated
with diabetic foot infection, it is recommended to administrate
antibacterial dugs for at least 2–4 weeks after removal of
infected bones.
Recommendation level: B.
Comments:
 There is one RCT concerning diabetic foot infection (includ-
ing osteomyelitis) and systemic administration of antibacte-
rial drugs,59 and the evidence level is II. Linezolid and
ampicillin/sulbactam have been shown to be effective, and
the mean treatment period for osteomyelitis has been
reported to be 19 days. Also, antibacterial drugs are admin-
istrated for 2–4 weeks after removal of infected bones for
osteomyelitis,60–62 and because this approximate period is
considered to be the minimum for the administration of
antibiotics, the recommendation level was set at B.
 There is one systematic review and two RCT concerning
osteomyelitis and infections, but the subjects were not
restricted to those with diabetic osteomyelitis.60–62
 In diabetic ulcer, in which the immune function and regener-
ative ability of the skin are depressed, exacerbation of
osteomyelitis may lead to a serious outcome. Therefore, it is
necessary to administrate antibacterial drugs at least over a
period necessary for the treatment of osteomyelitis in gen-
eral. If infected bones cannot be sufficiently removed, the
administration of antibacterial drugs at least over 6 weeks is
necessary.63
REFERENCES
59 Lipsky BA, Itani K, Norden C, Linezolid Diabetic Foot Infections
Study Group. Treating foot infections in diabetic patients: a ran-
domized, multicenter, open-label trial of linezolid versus ampicillin-
sulbactam/amoxicillin-clavulanate. Clin Infect Dis 2004; 38: 17–24
(Evidence level II).
60 Stengel D, Bauwens K, Sehouli J, Ekkernkamp A, Porzsolt F. Sys-
tematic review and meta-analysis of antibiotic therapy for bone
and joint infections. Lancet Infect Dis 2001; 1: 175–188.
61 Lazzarini L, Lipsky BA, Mader JT. Antibiotic treatment of
osteomyelitis: what have we learned from 30 years of clinical tri-
als? Int J Intect Dis 2005; 9: 127–138.
62 Swiontkowski MF, Hanel DP, Vedder NB, Schwappach JR. A com-
parison of short- and long-term intravenous antibiotic therapy in
the postoperative management of adult osteomyelitis. J Bone Jt
Surg Br 1999; 81: 1046–1050.
63 Jeffcoate WJ, Lipsky BA. Controversies in diagnosing and manag-
ing osteomyelitis of the foot in diabetes. Clin Infect Dis 2004; 39:
S115–S122.
CQ7: HOW SHOULD LIMB ISCHEMIA BE
DIAGNOSED ON THE INITIAL OUTPATIENT
EXAMINATION?
Remarks on recommendation:
601
T. Isei et al.
 On the outpatient examination, it is strongly recommended
to diagnose ischemia by careful inquiries about symptoms
including numbness, cold feeling and intermittent claudica-
tion, palpation for weakening or disappearance of pulses of
peripheral arteries and a decrease in the skin temperature,
and visual examination for changes in the skin color (A).
 In addition to the above, it is recommended to measure the
ABI (B).
Recommendation level: A for signs and symptoms B for the
measurement of the ABI.
Comments:
 There is one systematic review that signs and symptoms
are useful for the diagnosis of ischemia due to PAD,64 but
the subjects are not restricted to diabetic patients in this
review. However, as there is international consensus that
clinical symptoms are useful for the diagnosis of ischemia,
that examination of clinical symptoms is recommended by
many guidelines65,65 and that diabetes underlies PAD in
many patients,67,68 the recommendation level was set at A.
 There are two large-scale cross-sectional studies evaluating
the usefulness of the ABI measurement for the initial care of
diabetes or diabetic skin ulcer,69,70 and the evidence level is
IVb. Considering that the ABI can be measured by a rela-
tively simple procedure and readily at the outpatient clinic,
that its usefulness as a non-invasive examination for PAD
has been established,71 and that it is recommended in over-
seas and domestic guidelines and protocols,65,66,72,73 the
recommendation level was set at B.
 Diabetic ulcer is often complicated by PAD, particularly
PAOD, namely, a condition that used to be called ASO.66 As
ischemia progresses, symptoms such as numbness, pain,
cold feeling and intermittent claudication, and signs includ-
ing weakening or disappearance of pulses of peripheral
arteries, a decrease in the skin temperature, and changes in
the skin color appear, eventually leading to refractory ulcer
or gangrene. In such cases, ulcer often occurs at multiple
sites at the ends of the toes and fingers or between the
toes.74 According to the above review, it is possible to diag-
nose leg ischemia by detecting these symptoms through
inquiry, visual examination or palpation, and, on the other
hand, the possibility of PAD is lower with multiple normal
clinical findings than with a single normal clinical finding.64
By the Fontaine Classification used for functional assess-
ment of PAD (PAOD), diabetic ulcer corresponds to grade IV
when it is accompanied by chronic arterial obstruction and,
inevitably, to CLI.
 Patients may be asymptomatic in an early stage of PAD due
to compensation for ischemia. In diabetic patients, there
may be no clear symptom due to reduced motor abilities
caused by complications such as neuropathy and cardiac
disease.75 Moreover, the appearance of symptoms of PAD
may be delayed by hypoesthesia due to neuropathy. There-
fore, for the diagnosis of PAD, it is necessary to assess the
blood flow using an objective index in addition to examina-
tions for signs and symptoms.
602
 The ABI, the ratio between the systolic blood pressures at
the ankle and upper arm, is an objective index of the periph-
eral arterial blood flow for the diagnosis of limb ischemia. A
large number of clinical studies have been conducted on the
measurement of the ABI for the diagnosis and treatment of
PAD, and its usefulness has been nearly established. In dia-
betic patients, also, the usefulness of the ABI has been eval-
uated by clinical studies, but many of them have aimed to
clarify its relationships with the severity of coronary artery
disease and survival state. However, as PAD is based on
diabetes in many patients, the ABI has been recommended
as a standard non-invasive examination for diabetic ulcers
by foreign guidelines on the assumption that its usefulness
for the diagnosis of PAD in diabetic patients has been
established.65,66,72,73 In Japan, there is a large case series
study in which the ABI was measured in 3906 outpatients
with diabetes,69 reporting that the ABI was reduced in 7.6%
of the patients but that only 24.4% of them had been diag-
nosed with PAD before its measurement and suggesting the
usefulness of the ABI for screening (see the glossary for
details about normal value).
Notes:
 When the ABI cannot be measured accurately: Examinations
such as measurements of the TBI, ABI before and after
exercising, TcPO2 and SPP are performed. The SPP is
strongly correlated with the TP regardless of the presence
or absence of diabetes and is reported to be measurable in
some patients in whom the measurement of the TP is
impossible (those after toe amputation and with toe ulcer).76
 Examinations that should be performed after the initial diag-
nosis: If abnormalities are noted on the above examinations
for the initial diagnosis, imaging examinations are performed
to evaluate the sites and severity of circulatory disorders to
determine the therapeutic strategy including the evaluation
of indications for revascularization.64 Among the imaging
examinations, vascular ultrasonography is particularly useful
because of the simplicity, low invasiveness and possibility of
simultaneous evaluation of the blood flow, but it is disadvan-
tageous in that it requires skill and experience and that it
does not provide information about the entire leg. Angiogra-
phy, which is radiography performed after injecting an
iodine-based contrast agent through an intra-arterial cathe-
ter, has the highest resolution and is appropriate for mor-
phological examination. Recently, DSA, providing even
clearer images, has also become increasingly available.
Angiography has been performed widely, but it is relatively
invasive due to catheter insertion and the use of a contrast
agent. For this reason, it is often performed in expectation
of revascularization as well as for the diagnosis. In contrast,
CTA and MRA are less invasive, can be performed more
easily and allow examination of calcification of the vascular
wall. However, CTA using an iodine-based contrast agent
cannot be performed in patients with iodine hypersensitivity,
and caution for exacerbation of the renal function due to the
contrast agent is necessary in patients with renal
© 2016 Japanese Dermatological Association

dysfunction. Gadolinium-based contrast agents used for
MRI cause no problem at a conventional dose, but they
must be used carefully as they have been reported to
increase the risk of nephrogenic systemic fibrosis in patients
with kidney disorders.77
REFERENCES
64 Khan NA, Rahim SA, Anand SS, Simel DL, Panju A. Does the clini-
cal examination predict lower extremity peripheral arterial disease?
JAMA 2006; 295: 536–546 (Evidence level I).
65 Steed DL, Attinger C, Colaizzi T et al. Guidelines for the treatment
of diabetic ulcers. Wound Repair Regen 2006; 14: 680–692 (Evi-
dence level VI).
66 Uchimura I, Atsumi Y. International working group of the diabetic
foot: International consensus on diabetic foot:. Noordwijkerhou,
Netherlands, 1999, Ishiyaku Publishers Inc., Tokyo, 2000; 1–98 (in
Japanese) (Evidence level VI).
67 Melton LJ III, Macken KM, Palumbo PJ, Elveback LR. Incidence
and prevalence of clinical peripheral vascular disease in a popula-
tion based cohort of diabetic patients. Diabetes Care 1980; 3: 650–
654.
68 Kannel WB, McGee DL. Update on some epidemiologic features of
intermittent claudication: the Framingham Study. J Am Geriatr Soc
1985; 33: 13–18.
69 Maeda Y, Inoguchi T, Tsubouchi H et al. High prevalence of
peripheral arterial disease diagnosed by low anklebrachial index in
Japanese patients with diabetes: The Kyushu Prevention Study for
Atherosclerosis. Diabetes Res Clin Pract 2008; 82: 378–382.
70 Rhee SY, Guan H, Liu ZM et al. Multi-country study on the preva-
lence and clinical features of peripheral arterial disease in Asian
type 2 diabetes patients at high risk of atherosclerosis. Diabetes
Res Clin Pract 2007; 76: 82–92.
71 Mohler ER 3rd, Treat-Jacobson D, Reilly MP et al. Utility and barri-
ers to performance of the ankle-brachial index in primary care
practice. Vasc Med 2004; 9: 253–260.
72 Norgren L, Hiatt WR, Dormandy JA et al. Inter-society consensus
for the management of peripheral arterial disease (TASC II). J Vasc
Surg 2007; 45: S5–S67 (Evidence level VI).
73 Peripheral Arterial Disease in People with Diabetes. American Dia-
betes Association. Diabetes Care 2003; 26: 3333–3341 (Evidence
level VI).
74 Sueki H. Cutaneous Manifestations of Systemic Diseases: Skin
Manifestations of Diabetes Melitis or Metabolic Disorders, Compre-
hensive Handbook of Clinical Dermatology. Vol. 18, Tokyo:
Nakayama shoten, 2003; 42–56 (in Japanese).
75 Hirsch AT, Criqui MH, Treat-Jacobson D et al. Peripheral arterial
disease detection, awareness, and treatment in primary care.
JAMA 2001; 286: 1317–1324.
76 Tsai FW, Tulsyan N, Jones DN, Abdel-Al N, Castronuovo JJ Jr,
Carter SA. Skin perfusion pressure of the foot is a good substitute
for toe pressure in the assessment of limb ischemia. J Vasc Surg
2000; 32: 32–36.
77 Hosoya T, Okada H, Horio M et al. Guidelines for administering
gadolinium-based contrast agents to patients with renal dysfunc-
tion : second edition. Jap J Nephrology 2009; 51: 839–842 (in
Japanese).
CQ8: WHAT EXAMINATIONS ARE USEFUL FOR
THE DIAGNOSIS OF DIABETIC PERIPHERAL
NEUROPATHY?
Remarks on recommendation: The sensory examination by the
Semmes–Weinstein monofilament test, examination of the
vibration sensibility by the tuning fork method and test of
© 2016 Japanese Dermatological Association
Wound/Burn Guidelines – 3
Achilles tendon reflex are useful for the clinical diagnosis of
peripheral neuropathy due to diabetes, and they are recom-
mended. It is better to perform them in combination to improve
the diagnostic accuracy.
Recommendation level: B for the monofilament test, tuning
fork method and Achilles tendon reflex test.
Comments:
 There is one meta-analysis concerning the monofilament
test,78 and the evidence level is I. Although the test is recog-
nized to be useful, it cannot be performed at all facilities as
they are often not equipped with the testing instruments in
Japan, so the recommendation level was set at B. There are
two case reports concerning the vibration sensibility testing
using a tuning fork, and the evidence level is IVb. However,
according to them, its results were comparable with those
of the monofilament test,79 and the diagnostic accuracy was
comparable when it was performed alone or in combination
with other tests,80 so the recommendation level was set at
B. Concerning the test of Achilles tendon reflex, there is one
cohort study81 and one case–control study,82 and the evi-
dence level is IVa, but its recommendation level was set
similarly to the monofilament and tuning fork tests, because
it is a test that can be performed readily and is widely
adopted.
 For the management of patients with diabetic ulcer, it is
necessary to diagnose the presence or absence and sever-
ity of neuropathy. However, there is no symptom or exami-
nation specific to diabetic neuropathy, and while some
diagnostic criteria have been proposed, none has gained a
wide international consensus.
 In diabetic peripheral neuropathy, depression of the tactile
sensibility is noted from an early stage, but approximately
half the neuropathy patients are not aware of the disorder,83
and the diagnosis is often impossible according to clinical
symptoms alone.84 Also, symptoms and severity of neuropa-
thy vary among patients, and there is no specific symptom.
To avoid overlooking signs of neuropathy, it is necessary to
perform multiple tests aimed to detect neuropathy in combi-
nation and make judgments comprehensively rather than
relying on a single examination.
 The monofilament test is a simple test of the tactile sen-
sibility using a 5.07 monofilament, with which a pressure
of 10 g can be applied. If the patient is insensible to this
stimulation, the possibility of severe neuropathy is high.
Concerning this test, there are four cohort studies81,85–87
and one each case–control study,88 cross-sectional
study84 and meta-analysis,78 all of which reported its
usefulness.
 Neuropathy observed in many diabetic patients is primar-
ily symmetrical polyneuropathy that progresses chroni-
cally due to hyperglycemia and is called distal symmetric
polyneuropathy (DPN).89 Diagnostic criteria for DPN,
which are based on the vibration sensibility testing using
a C128 tuning fork and bilateral Achilles tendon reflex in
addition to symptoms, have also been proposed in
Japan.90
603
T. Isei et al.
REFERENCES
78 Feng Y, Schlo € sser FJ, Sumpio BE. The Semmes Weinstein
monofilament examination as a screening tool for diabetic periph-
eral neuropathy. J Vasc Surg 2009; 50: 675–682 (Evidence level I).
79 Oyer DS, Saxon D, Shah A. Quantitative assessment of diabetic
peripheral neuropathy with use of the clanging tuningfork test.
Endocr Pract 2007; 13: 5–10 (Evidence level IVa).
80 Meijer JW, Smit AJ, Lefrandt JD, van der Hoeven JH, Hoogenberg
K, Links TP. Back to basics in diagnosing diabetic polyneuropathy
with the tuning fork!. Diabetes Care 2005; 28: 2201–2205 (Evidence
level IVb).
81 Boyko EJ, Ahroni JH, Stensel V, Forsberg RC, Davi-gnon DR,
Smith DG. A prospective study of risk factor for diabetic foot ulcer.
The Seattle diabetic Foot Study. Diabetes Care 1999; 22: 1036–
1042 (Evidence level IVa).
82 McNeely MJ, Boyko EJ, Ahroni JH et al. The independent contri-
butions of diabetic neuropathy and vasculopathy in foot ulceration.
How great are the risks? Diabetes Care 1995; 18: 216–219 (Evi-
dence level IVb).
83 The transactions for actual conditions of diabetic foot and diabetic
neuropathy in Japan. Japan Promotion Council for Diabetes
Prevention and Countermeasures, (in Japanese) Available from
URL: http://www.med.or.jp/tounyoubyou/diabetes080312.pdf
84 Smieja M, Hunt DL, Edelman D, Etchells E, Cornuz J, Simel DL.
Clinical examination for the detection of protective sensation in the
feet of diabetic patients. International Cooperative Group for Clini-
cal Examination Research. J Gen Intern Med 1999; 14: 418–424.
85 Litzelman DK, Marriott DJ, Vinicor F. Independent physiological
predictors of foot lesions in patients with NIDDM. Diabetes Care
1997; 20: 1273–1278.
86 Peters EJ, Lavery LA, International Working Group on the Diabetic
Foot. Effectiveness of the diabetic foot risk classification system of
the International Working Group on the Diabetic Foot. Diabetes
Care 2001; 24: 1442–1447.
87 Pham H, Armstrong DG, Harvey C, Harkless LB, Giur-ini JM, Veves
A. Screening techniques to identify people at high risk for diabetic
foot ulceration: a prospective multicenter trial. Diabetes Care 2000;
23: 606–611.
88 Rith-Najarian SJ, Stolusky T, Gohdes DM. Identifying diabetic
patients at high risk for lower-extremity amputation in a primary
health care setting. A prospective evaluation of simple screening
criteria. Diabetes Care 1992; 15: 1386–1389.
89 Thomas PK. Classification, differential diagnosis, and staging of
diabetic peripheral neuropathy. Diabetes 1997; 46: S54–S57.
90 Japanese study group of diabetic neuropathy. Simplified diagnostic
criteria of diabetic distal symmetric polyneuropathy. Peripheral
nerve, 2009; 20: 76–77 (in Japanese).
CQ9: HOW LONG SHOULD THE OBSERVATION
PERIOD BE FOR THE EVALUATION OF THE
USEFULNESS OF CONSERVATIVE
TREATMENT IN DIABETIC ULCER PATIENTS?
Remarks on recommendation: It is recommended to evaluate
the usefulness of conservative treatment for diabetic ulcers in
the chronic period within 4 weeks at the maximum and to
compare it with other treatments when appropriate. However,
it is desirable to examine diabetic ulcers in the acute period at
least approximately once a week.
Recommendation level: B.
Comments:
 With conservative treatments, in observing the course of a
diabetic ulcer that has entered the chronic period from the
acute period it is also necessary to evaluate the effects of the
604
treatment at appropriate times and its superiority or inferiority
compared with other treatments. However, changing treat-
ments one after the other in a short period may lead to errors
in judgment, and the usefulness of each treatment must be
evaluated on the basis of observation over a sufficient period.
There are two analytical epidemiological studies evaluating
the assessment intervals in this period,91,92 and their evidence
levels are IVa and IVb. According to these studies, another
treatment should be considered unless a 53% or greater
decrease in the ulcer area is observed 4 weeks after the
beginning of one treatment. Because this interval is appropri-
ate from the realities of treatment plans and frequency of hos-
pital visits in patients in the chronic period, its
recommendation level was made B. However, as symptoms
may change every minute in the acute period of a diabetic
ulcer, in which the condition is exacerbated progressively,
treatment by frequent hospital visits or hospitalization is nec-
essary. Because evaluation of the usefulness of the treatment
is necessary on each of these occasions, examination at least
once a week is desirable in such situations.
 Because frequent examination naturally leads to early detec-
tion of exacerbation of the condition at the lesion, foot care
including periodic checking of foot deformities, skin ulcers,
nail plate deformities, sensibility, ischemia and footwear is
important.
 In treating a diabetic ulcer, it is important to serially evaluate
and record the patient’s clinical history, history of ulcers,
sites of their occurrence, conditions of the wound surface
(size, color, infection, effusion and necrotic materials) and
treatments. In diabetic patients, it is important to periodically
examine the skin even if there is no ulcer and to detect it
early should it occur.
 Diabetic ulcers may be controlled adequately by scoring the
condition of the wound and following it up serially.93,94
REFERENCES
91 Sheehan P, Jones P, Giurini JM, Caselli A, Veves A. Percent
change in wound area of diabetic foot ulcers over a 4-week period
is a robust predictor of complete healing in a 12-week prospective
trial. Plast Reconstr Surg 2006; 117: S239–S244 (Evidence level
IVa).
92 Sheehan P, Jones P, Caselli A, Giurini JM, Veves A. Percent
change in wound area of diabetic foot ulcers over a 4-week period
is a robust predictor of complete healing in a 12-week prospective
trial. Diabetes Care 2003; 26: 1879–1882 (Evidence level IVb).
93 Falanga V, Saap LJ, Ozonoff A. Wound bed score and its correla-
tion with healing of chronic wounds. Dermatol Ther 2006; 19: 383–
390.
94 Saap LJ, Falanga V. Debridement performance index and its corre-
lation with complete closure of diabetic foot ulcers. Wound Repair
Regen 2002; 10: 354–359.
CQ10: IS SURGICAL DEBRIDEMENT USEFUL
FOR REMOVING NECROTIC TISSUE FROM A
DIABETIC ULCER?
Remarks on recommendation: It is recommended to perform
surgical debridement as the initial debridement to remove
© 2016 Japanese Dermatological Association

necrotic tissue and crust that adhere to the ulcer, and kera-
tinized materials in and around the ulcer. However, if there is
underlying PAD, symptomatic improvements may not be
expected, or the condition of the ulcer/gangrene may be exac-
erbated, by surgical debridement. Therefore, surgical debride-
ment should be performed carefully in the limb, particularly in
its distal parts.
Recommendation level: B.
Comments:
 Concerning evaluations of surgical debridement for removing
necrotic tissue, there are two systematic reviews,95,96 but
their usefulness has not been demonstrated. However, surgi-
cal debridement is prompt, convenient and most desirable as
the initial debridement to be performed in an early period with
tightly adhering necrotic tissue. Also, international consensus
that, for wound bed preparation, surgical debridement should
be performed in combination with other debriding methods
for maintenance debridement in routine clinical practice has
been reached, and this approach has also been recom-
mended by foreign guidelines and treatment protocols.97–100
The recommendation level was set at B in consideration of
these circumstances.
 If there are clear signs of infection, and if infection is causing
necrotizing soft tissue infection such as necrotizing fasciitis
or sepsis, emergency surgical debridement is essential to
save the patient, and amputation is inevitable in some
cases.
 The objective of debridement is to remove necrotic tissue
that provides media for bacterial infection and inhibits gran-
ulation tissue proliferation or epidermal regeneration, tissues
that have developed bacterial infection and hyperkeratotic
tissue interfering with epidermal regeneration, not to allow
them to inhibit wound recovery. It is also necessary to
determine the wound depth accurately.101–103 Debridement
can be divided according to its objective into initial debride-
ment performed early to remove adhering necrotic tissue
and maintenance debridement performed in daily practice
for wound bed preparation to maintain the wound bed in a
favorable condition for recovery.101 According to the
method, it is classified into surgical or sharp debridement
using a scalpel or surgical scissors104 and mechanical, auto-
lytic, enzymatic and biological (chemical [antiseptic])
debridement.98
 Maintenance debridement performed after necrotic tissue or
keratotic tissue has been reduced by initial debridement is
often performed by a combination of surgical and non-surgi-
cal methods.
 Among non-surgical methods, there is one RCT105 and two
cohort studies106,107 concerning autolytic debridement using
hydrogel, and the procedure has been suggested to be sig-
nificantly more effective than conventional procedures
including wet-to-dry dressing, a method for mechanical
debridement using gauze and physiological saline.
 As for biological debridement, there is maggot therapy using
aseptically cultured maggots.108,109 Relatively low invasive-
ness is an advantage of this method.
© 2016 Japanese Dermatological Association
Wound/Burn Guidelines – 3
 Regarding enzymatic debridement using enzyme preparations
or polysaccharide beads, there is one RCT evaluating the
debriding effect of bromelain on chronic ulcers,110 but its effec-
tiveness against diabetic ulcers has not been established.
 If there is ischemia due to circulatory impairment of periph-
eral arteries such as PAD, surgical debridement of limb
extremities in ischemic patients used to be contraindicated,
because surgical manipulation may enlarge necrosis or gan-
grene. Therefore, surgical debridement should be performed
carefully in patients with PAD, and the assessment of the
blood flow of the peripheral skin is necessary before its
implementation.
 If a large amount or area of tissue is removed by surgical
debridement, the procedure is highly invasive to the patient,
and postoperative exacerbation of the general condition is
possible.111 Preoperative evaluation of the general condition
including the presence or absence of anemia, hypoproteine-
mia and hemorrhagic tendency, and the state of medications
including antiplatelets and anticoagulants, which may affect
the clotting ability, is necessary. Guidelines concerning car-
diovascular disorders recommend continuation of these med-
ications for minor operations in which bleeding is highly
controllable.112 Guidelines concerning cerebral infarction also
state that “continuation of oral” warfarin therapy is “desir-
able” and that antiplatelet therapy “may be continued”.113
However, as these medications can be suspended in some
patients, it is desirable to first consult the attending physician
and manage the patients individually. Also, if anticoagulants
cannot be suspended, restricting debridement within the area
of necrotic tissue and causing no bleeding (which causes little
stress including pain to the body) is an alternative, although
this is insufficient as surgical debridement.
REFERENCES
95 Edwards J, Stapley S. Debridement of diabetic foot ulcers
(Review). Cochrane Database Syst Rev 2010: CD003556 (Evidence
level I).
96 Hinchliffe RJ, Valk GD, Apelqvist J, Bakker AK, Game FL, Harte-
mann-Heurtier A. Systematic review of the effectiveness of inter-
ventions to enhance the healing of chronic ulcers of the foot in
diabetes. Diabetes Metab Res Rev 2008; 24: S119–S144 (Evidence
level I).
97 Steed DL, Attinger C, Colaizzi T et al. Guidelines for the treatment
of diabetic ulcers. Wound Repair Regen 2006; 14: 680–692 (Evi-
dence level VI).
98 Frykberg RG, Zgonis T, Armstrong DG, et al. Diabetic foot disor-
ders. A clinical practice guideline (2006 revision). J Foot Ankle Surg
2006; 45: S1–S66 (Evidence level VI).
99 Wraight PR, Lawrence SM, Campbell DA, Colman PG. Creation of
a multidisciplinary, evidence based, clinical guideline for the
assessment, investigation and management of acute diabetes
related foot complications. Diabet Med 2005; 22: 127–136 (Evi-
dence level VI).
100 Brem H, Sheehan P, Rosenberg HJ, Schneider JS, Boulton AJ.
Evidence-based protocol for diabetic foot ulcers. Plast Reconstr
Surg 2006; 117: S193–S209 (Evidence level VI).
101 Saap LJ, Falanga V. Debridement performance index and its corre-
lation with complete closure of diabetic foot ulcers. Wound Repair
Regen 2002; 10: 354–359.
605
T. Isei et al.
102 Steed DL, Donohoe D, Webster MW, Lindsley L. Diabetic Ulcer
Study Group. Effect of extensive debridement and treatment on
the healing of diabetic foot ulcers. J Am Coll Surg 1996; 183: 61–
64.
103 Hess CT, Kirsner RS. Orchestrating wound healing : assessing and
preparing the wound bed. Adv Skin Wound Care 2003; 16: 246–
257.
104 Sieggreen MY, Maklebust J. Debridement choices and challenges.
Adv Wound Care 1997; 10: 32–37.
105 Jensen JL, Seeley J, Gillin B. Diabetic foot ulcerations. A con-
trolled, randomized comparison of two moist wound healing proto-
cols: carrasyn Hydrogel wound dressing and wet-to-moist saline
gauze. Adv Wound Care 1998; 11: S1–S4.
106 Cangialosi CP. Synthetic skin : A new adjunct in the treatment of
diabetic ulcers. J Am Podiatry Assoc 1982; 72: 48–52.
107 Capasso VA, Munro BH. The cost and efficacy of two wound treat-
ments. AORN J 2003; 77: 984–992.
108 Sherman RA. Maggot therapy for treating diabetic foot ulcers unre-
sponsive to conventional therapy. Diabetes Care 2003; 26: 446–
451.
109 Armstrong DG, Salas P, Short B et al. Maggot therapy in “lower-
extremity hospice “wound care: fewer amputations and more
antibiotic-free days. J Am Podiatr Med Assoc 2005; 95: 254–257.
110 Ansai T, Tomisawa T, Muramatsu M et al. Clinical efficacy of
Bromelain ointment for necrotic tissues. Results of a double blind
study. Jpn J Plast Surg 1972; 15: 456–462 (in Japanese).
111 Kurita M, Oshima M, Ichioka S, Owada A, Aoi N. The effect of sur-
gical invasion on general condition of patients with pressure ulcers
(Assessment with the POSSUM score). Jpn J PU 2005; 2: 178–183
(in Japanese).
112 Report of the Joint Research Group. Guidelines for management of
anticoagulant and antiplatelet therapy in cardiovascular disease
(JCS 2004). Circ J 2004; 68: S1153–1219 (in Japanese).
113 Shinohara Y, Ogawa A, Suzuki N, Suzuki N, Katayama Y, Kimura
A. Japanese Guidelines for the Management of Stroke 2009: The
Joint Committee on Guidelines for the Management of Stroke. Ther
Res 2010; 18: 205–206 (in Japanese).
CQ11: WHAT TOPICAL AGENTS SHOULD BE
USED FOR DIABETIC ULCERS WITH NO
SIGNS OF INFECTION?
Remarks on recommendation: As topical agents for diabetic
ulcers, the use of trafermin or prostaglandin E1 (PGE1) is rec-
ommended for wounds with appropriate or deficient effusion.
The use of tretinoin tocopherol is recommended for wounds
deficient in effusion. The use of bucladesine sodium is recom-
mended for wounds with excessive effusion or marked edema.
Recommendation level: B for trafermin, PGE1, tretinoin
tocopherol and bucladesine sodium.
Comments:
 Clinical studies focusing on diabetic ulcer have been car-
ried out with trafermin (basic fibroblast growth factor:
bFGF) alone, and there are two RCT with an evidence
level of II.114,115 There are only case reports concerning
PGE1, bucladesine sodium and tretinoin tocopherol,116–119
and the evidence level is V. However, as the recommen-
dation levels of these three preparations are comparable
with that of trafermin in guidelines concerning pressure
ulcer, which is also a chronic wound of the skin, the
recommendation levels of these external preparations were
determined similarly to that of trafermin based on consen-
sus of the committee.
606
 The recommendation levels of topical agents such as alu-
minum chlorohydroxy allantoinate, lysozyme chloride, azu-
lene, calf blood extract, white petrolatum and dimethyl
propyl azulene are C1 for the treatment of pressure ulcers,
but they are not recommended for the treatment of diabetic
ulcers due to deficiency of reports. However, their use for
the treatment of diabetic ulcers is not excluded.
 Trafermin promotes wound healing due to its angiogenesis-
and granulation-promoting actions.120–122 Despite a strong
wound healing effect, the moist environment of the wound is
difficult to maintain with trafermin alone as only a spray type
preparation is available, so its use with other topical agents
or dressing materials is recommended.123 Also, as it is mar-
keted as a spray type preparation, and as its effectiveness
depends largely on its concentration, it is necessary to have
the patients sufficiently understand the method for its appli-
cation when it is prescribed to those with diabetic ulcer for
outpatient treatment. Moreover, modifications of the therapy
to maintain a moist environment such as the concomitant
use of an ointment with an oleaginous base such as white
petrolatum are necessary. As trafermin has recently been
reported unlikely to cause hypertrophic scars, it is also
expected to improve the quality of life (QOL) of patients with
diabetic ulcer.124
 Prostaglandin E1 promotes wound healing by its cutaneous
blood flow-increasing125 and angiogenesis-promoting126,127
actions. It also acts on fibroblasts and promotes their prolif-
eration128,129 and stimulates proliferation of keratinized cells
by increasing the interleukin-6 release from fibrob-
lasts.130,131 Because oleaginous Plastibase is used as the
base, PGE1 is appropriate for wounds with appropriate or
deficient effusion but not for wounds with rich effusion or
marked edema.
 Tretinoin tocopherol produces granulation- and angiogene-
sis-promoting effects by promoting migration and prolifera-
tion of cells including fibroblasts.130–133 Because an
emulsion base with a water content of 70% is used, the
preparation is appropriate for wounds with a strong ten-
dency to dry,123 but not for wounds with rich effusion or
marked edema.
 Bucladesine sodium promotes wound healing by improving
the regional blood flow and promoting angiogenesis, granu-
lation and epidermal formation.134–137 Because macrogol
used as the base is hygroscopic, the drug should be used
for wounds with excessive effusion or marked edema. How-
ever, caution is necessary as it may cause drying of wounds
with deficient effusion.
 Recently, the effects of various growth factors on wound
healing are attracting attention, and there are reports with a
high evidence level concerning the use of platelet-derived
growth factor (PDGF) for the treatment of diabetic ulcer.
While PDGF is already in clinical use in the USA, it is still
unavailable in Japan.
 While silver-containing dressing agents and topical silver
preparations are widely used for the treatment of diabetic
ulcer, there have been no RCT evaluating their clinical
efficacy.138
© 2016 Japanese Dermatological Association

 There are a few reports that ointments not marketed in
Japan are effective for the treatment of diabetic ulcer, but
their evidence levels are all low.139–142
REFERENCES
114 Uchi H, Igarashi A, Urabe K et al. Clinical efficacy of basic fibrob-
last growth factor (bFGF) for diabetic ulcer. Eur J Dermatol 2009;
19: 461–468 (Evidence level II).
115 Richard JL, Parer-Richard C, Daures JP et al. Effect of topical
basic fibroblast growth factor on the healing of chronic diabetic
neuropathic ulcer of the foot. A pilot, randomized, double-blind,
placebo-controlled study. Diabetes Care 1995; 18: 64–69 (Evidence
level II).
116 Kawahara S. The practice of topical treatments on diabetic foot
ulcer. Angiology Frontier 2008; 7: 30–35 (in Japanese) (Evidence
level VI).
117 Fujii K, Owada A, Hayashi Y. Successful occrusive treatment with
Fibrast Spray and Prostandin Ointment for the serious diabetic
ulcer on dorsum of pedis. J New Remedies & Clinics 2005; 42:
977–979 (in Japanese) (Evidence level V).
118 Kishimoto S, Wakabayashi T, Kobayashi K et al. Efficacy of dibu-
tyryl cyclic AMP in various skin ulcers. Acta Dermatol Kyoto 1989;
84: 127–139 (in Japanese) (Evidence level V).
119 Akiyama M. Verrucous skin lesions on the feet in diabetic neuropa-
thy (VSLDN). MB Derma 2004; 85: 25–29 (in Japanese) (Evidence
level V).
120 Okumura M, Okuda T, Nakamura T, Yajima M. Acceleration of
wound heeling in diabetic mice by basic fibroblast growth factor.
Biol Pharm Bull 1996; 19: 530–535.
121 Okumura M, Okuda T, Okamoto T, Nakamura T, Yajima M.
Enhanced angiogenesis and granulation tissue formation by basic
fibrobrast growth factor in healing-impaired animals. Arzneimit-
telforschung 1996; 46: 1021–1026.
122 Okumura M, Okuda T, Nakamura T, Yajima M. Effect of basic
growth factor of wound healing in healing-impaired animal models.
Arzneimittelforschung 1996; 46: 547–551.
123 Japanese Society of Pressure Ulcer. Pressure Ulcer Prevention
and Treatment Guideline. Tokyo: Shorinsha, 2009; 114–125 (in
Japanese).
124 Akita S, Akino K, Imaizumi T, Hirano A. A basic fibroblast growth
factor improved the quality of skin grafting in burn patients. Burns
2005; 31: 855–858 (Evidence level V).
125 Shiraishi T, Matsumoto R, Matsumoto N et al. The effects of an
ointment containing prostaglandin E1. ALPHA-cyclodextrin clath-
rate compound (PGE1 CD ointment) on wound healing in various
types of experimental wounds. Nishinihon J Derm 1994; 53: 499–
507 (in Japanese).
126 Matsumoto R. Effect of PO-41483-a-CD, a prostacyclin analog, on
a clamp-induced endothelial injury in rats. Life Science 1994; 53:
893–900.
127 Yuzuriha S, Matsuo K, Noguchi M. Topical application of prosta-
glandin E1 ointment to cutaneous wounds in ischemic rabbit ears.
Eur J Plast Surg, 1999; 22: 225–229.
128 Zhang JZ, Maruyama K, Iwatsuki K, Ono I, Kaneko F. Effects of
prostaglandin E1 on human keratinocytes and dermal fibroblasts: a
possible mechanism for the healing of skin ulcers. Exp Dermatol
1994; 3: 164–170.
129 Ono I, Gunshi Y, Cyou K, Maruyama K, Kaneko F. Expression
mechanism of wound healing promoting effects of prostaglandin.
Prog Med 1994; 14: 2506–2508 (in Japanese).
130 Hamada H, Sakyou K, Tanaka H, Ogawa O, Nishiki K. Effect of
tocoretinate on migration of cells. Pharmacometrics 1992; 43: 97–
102 (in Japanese).
131 Sakyou K, Ishikawa T, Nishiki K, Otsuka N, Ito A, Mori Y. Stimulat-
ing effect of tocoretinate on granulation and angiogenesis. Pharma-
cometrics 1992; 43: 87–95 (in Japanese).
© 2016 Japanese Dermatological Association
Wound/Burn Guidelines – 3
132 Sakyou K, Otsuka N, Hamada H, Nakaya N, Nakazawa S. Effect of
tocoretinate on proliferation of normal human skin fibroblasts.
Pharmacometrics 1992; 43: 103–110 (in Japanese).
133 Sakyou K, Ishikawa T, Masukawa Y, Urano Y, Hamada H. Effect of
tocoretinate ointment on experimental burn, open wound, and
incised wound in rat skin. Pharmacometrics 1992; 43: 121–127 (in
Japanese).
134 Okasa T, Koya K. Influence of bucladesine sodium containing oint-
ment on post-traumatic revasculalization. Study using vasculo-
molding method. Acta Dermatol Kyoto 1990; 85: 119–127 (in
Japanese).
135 Masuzawa M, Okawa T, Hujimura T, Asai T, Nishiyama S. Study of
cell proliferation effects of DBcAMP on a microvascular endothelial
cell of the human skin. Acta Dermatol Kyoto 1990; 85: 453–456 (in
Japanese).
136 Falanga V, Katz MZ, Alvarez AF. Dibutyryl cyclic AMP by itself or
in combination with growth factors can stimulate or inhibit growth
of human keratinocytes and dermal fibroblasts. Wounds 1991; 3:
70–78.
137 Iwasaki T, Chen JD, Kim JP, Wynn KC, Woodley DT. Dibutyryl cyc-
lic AMP modulates keratinocyte migration without alteration of inte-
grin expression. J Invest Dermatol 1994; 102: 891–897.
138 Bergin SM. Silver based wound dressings and topical agents for
treating diabetic foot ulcers. Cochrane Database Syst Rev 2006;
25: CD005082 (Evidence level I).
139 Lipsky BA, Holroyd KJ, Zasloff M. Topical versus systemic antimi-
crobial therapy for treating mildly infected diabetic foot ulcers: a
randomized, controlled, double-blinded, multicenter trial of pexi-
ganan cream. Clin Infect Dis 2008; 15: 1537–1545.
140 Abdelatif M, Makoot M, Etmaan M. Safety and efficacy of a new
honey ointment on diabetic foot ulcers: a prospective pilot study. J
Wound Care 2008; 17: 108–110.
141 Cassino R, Ricci E. Effectiveness of topical application of amino
acids to chronic wounds: a prospective observational study. J
Wound Care 2010; 19: 29–34.
142 El-Nahas M, Gawish H, Tarshoby M, State O. The impact of topical
phenytoin on recalcitrant neuropathic diabetic foot ulceration. J
Wound Care 2009; 18: 33–37.
CQ12: WHAT DRESSING MATERIALS SHOULD
BE USED FOR DIABETIC ULCERS WITH NO
SIGNS OF INFECTION?
Remarks on recommendation: For wounds with appropriate/
deficient effusion, the use of hydrocolloid, hydrogel or polyur-
ethane foam is recommended as an option. For wounds with
excessive effusion or marked edema, the use of alginate or
Hydrofiber is recommended as an option.
Recommendation level: C1 for hydrocolloid, hydrogel, poly-
urethane foam, alginate and Hydrofiber.
Comments:
 Concerning occlusive dressing of diabetic ulcer, there is one
RCT using hydrocolloid,143 and the evidence level is II. How-
ever, the recommendation level was set at C1 because of the
deficiency of the number of cases. As for hydrogel, there are
three RCT,144–146 and the evidence level is II. Because the
conclusions as to the efficacy of hydrogel are not in agree-
ment among these reports, the recommendation level was
set at C1. Regarding polyurethane foam, also, there are two
RCT,147,148 and the evidence level is II. However, as the con-
clusions regarding its efficacy are not in agreement, the rec-
ommendation level was set at C1. Regarding alginate
dressing, there is one RCT and one analytical epidemiological
607
T. Isei et al.
study. In the RCT, the calcium alginate dressing material was
reportedly inferior to silver-containing Hydrofiber in the
improvement in the depth of ulcer. In the analytical epidemio-
logical study, no significant difference was noted in the time
until cure compared with conventional gauze dressing,149,150
so the recommendation level was set at C1. Concerning
Hydrofiber, there is also one RCT,149 and the evidence level
is II. However, the recommendation level was set at C1 due
to the deficiency of the number of cases.
 The recommendation level of chitin and hydropolymer for
the treatment of pressure ulcer is C1, but reports on their
use for the treatment of diabetic ulcers are few. Therefore,
their use for diabetic ulcers is not recommended but is not
excluded.
 For diabetic ulcers, the dressing materials used and the time
of their use must be selected in consideration of the condi-
tion of the wound and skin around it, the patient’s general
condition and characteristics of the dressing materials151,152
with sufficient caution for local infection as a prerequisite.
Dressing materials are very useful as they are expected to
relieve the burden and protect the wound as well as main-
tain a moist environment. Moreover, they reduce the burden
of the co-medical staff.
 In chronic wounds, exudates obtained from occluded wound
surfaces have been reported to inhibit cell proliferation.153
Wound bed preparation is a treatment of sticking to appro-
priate control of effusion, and it should be applied to dia-
betic ulcers with sufficient knowledge about its theories and
practice. Concerning occlusive dressing, as there are few
reports specific to diabetic ulcers, it is reasonable to basi-
cally apply it similarly to chronic wounds, particularly pres-
sure ulcers.
 Hydrocolloid maintains a moist environment without adher-
ing to the wound. It prevents crust formation due to drying
of the wound, promotes migration of epidermal cells by
maintaining a moist environment and, thus, promotes wound
healing.154 It also occludes the wound and prevents expo-
sure of denuded nerve terminals to air, thereby mitigating
the tingling characteristic of shallow wounds.155
 Hydrogel not only promotes granulation and epithelialization
by maintaining a moist environment but also alleviates
inflammation and relieves pain due to its rapid cooling
effect.156 Also, as it is transparent, it allows observation of
the wound.157
 Polyurethane foam absorbs approximately 10 times its
weight of exudates and promotes granulation and epithelial-
ization by maintaining an appropriate moist environment. It
leaves no residues due to dissolving or detaching. Because
its surface that comes into contact with the wound is made
of non-adhesive polyurethane net, it is unlikely to rub off the
newly formed epithelium even if it is displaced from the
wound.156
 Alginate absorbs 10–20 times its weight of water.156 It pro-
motes wound healing by absorbing and gelatinizing a large
amount of exudates and maintaining a moist environment
around the wound.157 Also, calcium ion in alginate and
sodium ion in blood/body fluid are exchanged across the
608
interface between alginate and the wound, and calcium ion
is diffused in the capillaries due to the concentration gradi-
ent. This produces a hemostatic effect.158
 Hydrofiber absorbs approximately 30 times its weight of
water.156 It retains approximately two times more water than
alginate and promotes granulation by maintaining a moist
environment optimal for healing over a long period.156 It pre-
vents maceration of the normal skin around the wound by
blocking horizontal spread of the exudates it has
absorbed.156 Silver-containing Hydrofiber also traps exu-
dates containing bacteria and prevents their reflux to the
wound. Because silver is released in this state, bacteria
contained in the exudates can be rapidly and efficiently
eradicated.159–161
REFERENCES
143 Apelqvist J, Larsson J, Stenstro€ m A. Topical treatment of necro-
tic foot ulcers in diabetic patients: a comparative trial of Duo-
Derm and MeZinc. Br J Dermatol 1990; 123: 787–792 (Evidence
level II).
144 d’Hemecourt PA, Smiell JM, Karim MR. Sodium carboxymethyl
cellulose aqueous-based gel vs becaplermin gel in patients with
nonhealing lower extremity diabetic ulcers. Wounds. Compend Clin
Res Pract 1998; 10: 69–75 (Evidence level II).
145 Jensen JL, Seeley J, Gillin B. Diabetic foot ulcerations. A con-
trolled, randomized comparison of two moist wound healing proto-
cols: Carrasyn Hydrogel Wound dressing and wet-to-moist saline
gauze. Adv Wound Care 1998; 11: 1–4 (Evidence level II).
146 Vandeputte J, Gryson L. Clinical trial on the control of diabetic foot
infection by an immunomodulating hydrogel containing 65% glyc-
erine. Proceedings of the 6th European Conference on Advances
in Wound Management, 1997; 50–53 (Evidence level II)
147 Foster AVM, Greenhill MT, Edmonds ME. Comparing two dress-
ings in the treatment of diabetic foot ulcers. J Wound Care 1994;
3: 244–248 (Evidence level II).
148 Blackman JD, Senseng D, Quinn L, Mazzone T. Clinical evaluation
of a semipermeable polymeric membrane dressing for the treat-
ment of chronic diabetic foot ulcers. Diabetes Care 1994; 17: 322–
325 (Evidence level III).
149 Jude EB, Apelqvist J, Spraul M, Martini J, Silver Dressing Study
Group. Prospective randomized controlled study of Hydrofiber
dressing containing ionic silver or calcium alginate dressings in
non-ischemic diabetic foot ulcers. Diabetes Med 2007; 24: 280–
288 (Evidence level III).
150 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. Diabetes Med 2001; 18: 320–324
(Evidence level III).
151 Jeffcoate W, Price P, Phillips C et al. Randomised controlled trial
of the use of three dressing preparations in the management of
chronic ulceration of the foot in diabetes. Health Technol Assess
2009; 13: 1–110.
152 Sasseville D, Tennstedt D, Lachapelle JM. Allergic contact dermati-
tis from hydrocolloid dressings. Am J Contact Dermatol 1997; 8:
236–238.
153 Bucalo B, Eaglstein WH, Falanga V. Inhibition of cell proliferation
by chronic wound fluid. Wound Repair Regen 1993; 1: 181–186.
154 Hinman CD, Maibach H. Effect of air exposure and occlusion on
experimental human skin wound. Nature 1963; 200: 377–378.
155 Friedman SJ, Su WP. Management of leg ulcer with hydrocolloid
occlusive dressing. Arch Dermatol 1984; 120: 1329–1336.
156 Mino Y. Usage instructions of wound dressings. Visual Dermatol
2003; 2: 546–554 (in Japanese).
© 2016 Japanese Dermatological Association

157 Suzuki S. Conservative therapy with wound dressings. Jpn J Plast
Surg 2003; 46: 471–475 (in Japanese).
158 Koyama H, Akamatsu J, Kawai K, Kawada K, Matsushita Y. The
experience of KST-1 (Calcium Alginate Fiber) as the wound dress-
ing on split skin graft donor site. Clin Rep 1992; 26: 667–673 (in
Japanese).
159 Walker M, Hobot JA, Newman GR, Bowler PG. Scanning electron
microscopic examination of bacterial immobilization in a car-
boxymethyl cellulose (AQUACELⓇ) and alginate dressings. Bioma-
terials 2003; 24: 883–890.
160 Bowler PG, Jones SA, Davies BJ, Coyle E. Infection control prop-
erties of some wound dressings. J Wound Care 1999; 8: 499–502.
161 Jones SA, Bowler PG, Walker M, Parsons D. Controlling wound
bioburden with a novel silver-containing HydrofiberⓇ dressing.
Wound Rep Reg 2004; 12: 288–294.
CQ13: IS NEGATIVE-PRESSURE WOUND
THERAPY USEFUL FOR THE TREATMENT OF
DIABETIC ULCER?
Remarks on recommendation: It is recommended to perform
negative-pressure wound therapy for diabetic ulcers with suffi-
cient attention to the presence or absence of infection.
Recommendation level: B.
Comments:
 Negative-pressure wound therapy is recognized as a treat-
ment that is particularly highly effective for the treatment of
pressure ulcer. There are two RCT,162,163 and the evidence
level is II.
 Negative-pressure wound therapy produces its effects by
draining exudates, reducing bacteria and contracting the
space around the wound by the negative pressure.164–166
 In Japan, also, VACâ has been available since 2010, but
some patients are still expected to be treated using custom-
made instruments. With either instrument, the principle of
applying a negative pressure to the wound is the same, and
the same therapeutic effect is expected from negative-pres-
sure wound therapy. However, as there is the problem of
infection, custom-made instruments should be used appro-
priately by an experienced physician.
 Because there is a report that exudates collected from the
wound under occlusive dressing inhibited cell proliferation
when applied to chronic wounds, caution is needed in
occluding a chronic wound over a long period.167
 In some countries, a portable VAC system is used. This very
small instrument is expected to contribute to improvements
in the QOL in outpatients with diabetic ulcers. However, it is
obviously important to examine the presence or absence of
infection or the appearance of necrotic materials, and peri-
odic examination by a physician is indispensable.
REFERENCES
162 Eginton MT, Brown KR, Seabrook GR, Towne JB, Cambria RA. A
prospective randomized evaluation of negative-pressure wound
dressings for diabetic foot wounds. Ann Vasc Surg 2003; 17: 645–
649 (Evidence level II).
163 Armstrong DG, Lavery LA. Negative pressure wound therapy after
partial diabetic foot amputation: a multi-center randomized con-
© 2016 Japanese Dermatological Association
Wound/Burn Guidelines – 3
trolled trial. Diabetic Foot Study Consortium. Lancet 2005; 366:
1704–1710 (Evidence level II).
164 Andros G, Armstrong DG, Attinger CE et al. Tucson Expert Con-
sensus: Conference Consensus statement on negative pressure
wound therapy (V.A.C. Therapy) for the management of diabetic
foot wounds. Ostomy Wound Manage 2006; Jun, Suppl: S1–S32.
165 Eneroth M, van Houtum WH. The value of debridement and
Vacuum-Assisted Closure (V.A.C.) therapy in diabetic foot ulcers.
Diabetes Metab Res Rev 2008; 24: S76–S80.
166 Clare MP, Fitzgibbons TC, McMullen ST, Stice RC, Hayes DF,
Henkel L. Experience with the vacuum assisted closure negative
pressure technique in the treatment of non-healing diabetic and
dysvascular wounds. Foot Ankle Int 2002; 23: 896–901.
167 Bucalo B, Eaglstein WH, Falanga V. Inhibition of cell proliferation
by chronic wound fluid. Wound Repair Regen 1993; 1: 181–186.
CQ14: ARE WEIGHT-RELIEVING ORTHOSES
USEFUL FOR THE TREATMENT AND
PREVENTION OF DIABETIC ULCER?
Remarks on recommendation:
 It is recommended to use weight-relieving orthoses to
resolve ulcer by the pressure-dispersion effect (B).
 Because weight-relieving orthoses are effective for the pre-
vention of compression, their use is recommended as an
option (C1).
Recommendation level: B for treatment C1 for prevention.
Comments:
 Concerning treatments using weight-relieving orthoses, there
is one systematic review,168 and the evidence level is I.
However, as the treatment was performed using order-made
orthoses prepared by specialists, and as such a treatment is
not available at all medical facilities, the recommendation
level was set at B.
 For prevention, medical shoes are useful. However, while
there is one systematic review,169 there is only one non-
randomized comparative study in patients with diabetic
ulcers.170 Although there is one RCT, it reported no signifi-
cant difference in the ulcer recurrence rate between thera-
peutic and usual shoes.171 The evidence level is III, and the
recommendation level was set at C1.
 In patients who have developed foot deformities or sensory
disorders due to neuropathy, ulcers are often caused in the
sole or toes by abnormalities of pressure distribution on the
skin. Therefore, weight relieving, namely, avoiding exertion
of excessive pressure at particular sites, is the basis of
treatments for diabetic ulcers, particularly neuropathic
ulcers. The insole is a simple weight-relieving orthosis, but
orthoses that firmly fix the leg and induce maximum weight-
bearing by the thigh or lower leg are even more effective.
 The total contact cast (TCC), a fixation method using a
plaster cast, is the most standard and effective among
weight-relieving orthoses.172 Indeed, the cure rate was sig-
nificantly higher in a group treated with the TCC than in a
group treated with a conventional dressing material.173
However, as the TCC is not removable and needs re-wind-
ing once it is removed, its use involves technical difficulties,
and more convenient methods are desirable. Therefore, a
609
T. Isei et al.
removable cast walker, which is a removable ready-made
orthosis for the leg, was compared with a non-removable
cast prepared by covering the removable cast walker with
a rapidly drying plastic casting material, and the cure rate
after 12 weeks was reported to be significantly higher by
the latter treatment.174 Also, as there was no significant dif-
ference in the cure rate between a non-removable cast
converted from a removable cast compared with the TCC,
some reports recommend the former, which can be applied
more easily.175,176 In addition, there is a report that the cure
rate of ulcers did not differ when the TCC was compared
with custom-made temporary foot wear.177
REFERENCES
168 Mason J, O’Keeffe C, Hutchinson A, McIntosh A, Young R, Booth
A. A systematic review of foot ulcer in patients with type 2 dia-
betes mellitus. II. Treatment. Diabet Med 1999; 16: 889–909 (Evi-
dence level I).
169 Mason J, O’Keeffe C, Hutchinson A, Hutchinson A, Booth A,
Young RJ. A systematic review of foot ulcer in patients with
type 2 diabetes mellitus. 1 Prevention. Diabet Med 1999; 16:
801–812.
170 Uccioli L, Faglia E, Monticone G et al. Manufactured shoes in the
prevention of diabetic foot ulcers. Diabetes Care 1995; 18: 1376–
1378 (Evidence level III).
171 Reiber GE, Smith DG, Wallace C, Sullivan K, Hayes S, Vath C.
Effect of therapeutic footwear on foot rehabilitation in patients with
diabetes. JAMA 2002; 287: 2552–2558.
172 Armstrong DG, Nguyen HC, Lavery LA, van Schie CHM, Boulton
AJM, Harkless LB. Off- loading the diabetic foot wound: a random-
ized clinical trial. Diabetes Care 2001; 24: 1019–1022.
173 Mueller MJ, Diamond JE, Sinacore DR, Delitto A, Blair VP, Drury
DA. Total contact casting in treatment of diabetic plantar ulcers.
Diabetes Care 1989; 12: 384–388.
174 Armstrong DG, Lavery LA, Wu S, Boulton AJM. Evaluation of
removable and irremovable cast walkers in the healing of diabetic
foot wounds: a randomized controlled trial. Diabetes Care 2005;
28: 551–554.
175 Katz IA, Harlan A, Miranda-Palma B, Prieto-Sanchez L, Armstrong
DG, Bowker JH. A randomized trial of two irremovable off-loading
devices in the management of plantar neuropathic diabetic foot
ulcers. Diabetes Care 2005; 28: 555–559.
176 Piaggesi A, Macchiarini R, Rizzo L et al. An off-the- shelf instant
contact casting device for the management of diabetic ulcers: a
randomized prospective trial versus traditional fiberglass cast. Dia-
betes Care 2007; 30: 586–590.
177 Weg F, van der Windt DAWM, Vahl AC. Wound healing: total con-
tact cast vs. custom-made temporary footwear for patients with
diabetic foot ulceration. Prosthet Orthot Int 2008; 32: 3–11.
CQ15: WHAT DRUGS ARE USEFUL FOR THE
TREATMENT OF DIABETIC ULCERS DUE TO
ARTERIAL DISORDERS?
Remarks on recommendation:
 In drug therapy for diabetic ulcers caused by arterial disor-
ders, dalteparin is highly useful among antithrombotic
agents, and its administration is recommended (B). Among
vasodilators, the administration of PGE1 or Lipo-PEG1 is
recommended (B).
610
 The administration of argatroban, sarpogrelate hydrochlo-
ride, cilostazol or beraprost sodium is recommended as an
option (C1).
Recommendation level: B for dalteparin, PGE1 and Lipo-
PGE1; C1 for argatroban, sarpogrelate hydrochloride, cilostazol
and beraprost sodium.
Comments:
 The evidence level of reports indicating the usefulness of
antithrombotic agents for the treatment of circulatory disor-
der-induced ulcers varies among drugs. Concerning dal-
teparin, there is an RCT,178 and the evidence level is II, but
there are only case–control studies concerning ketanserin
and pentoxifylline,180,181 and the evidence level is IVb. As for
other antithrombotic drugs, although the evidence level is
low, there is a case series study concerning argatroban182
and a report that sarpogrelate hydrochloride was effective
for the treatment of PAD.183 There are also many expert
opinions. Regarding cilostazol, there is no evaluation of its
effectiveness for the treatment of diabetic ulcers, but it is
highly effective for the treatment of PAD,184 which often
complicates diabetes, so it was rated similarly to the above
drugs. The evidence level of vasodilators also varies among
drugs. Concerning iloprost, there are a few RCT,185,186 and
the evidence level is II, but the drug is not approved in
Japan, with only its clinical trials being scheduled. For
PGE1, there is a case report alone,187 but the drug is used
frequently in Japan, and there are many reports indicating
its effectiveness. Therefore, on the basis of consensus of
the committee, the evidence level of PGE1 and Lipo-PGE1
with a similar action mechanism was set at B. There is no
published work with a high evidence level concerning the
use of beraprost sodium for the treatment of diabetic ulcers.
However, in consideration of its frequent oral use and its
effects on ulcers due to PAD complicating diabetes or other
causes, the recommendation level was set at C1.
 Ulcerative lesions observed in diabetic patients can be
divided into those due to neuropathy and those due to cir-
culatory disorders such as PAD. Those due to circulatory
disorders may be relatively shallow lesions due to microan-
giopathy other than ischemic necrosis due to obstruction of
a major artery such as PAD. In some patients, ulcers due to
circulatory disorders are difficult to differentiate from those
due to neuropathy, and ulcers may be caused by both
mechanisms, but the present guidelines propose drug thera-
pies according to the cause.
 Ulcers due to circulatory disorders are treated primarily with
antithrombotic agents and vasodilators. Antithrombotic
drugs have an inhibitory action on platelet aggregation,
antithrombotic action and microcirculation-improving action,
and some of them also have a vasodilating action. Vasodila-
tors include PEG1, Lipo-PGE1, PGI2 and PGI2 derivatives,
but PGE1 and Lipo-PGE1 are often used intra-arterially or
intravenously, and PGI2 derivatives are often used orally in
Japan. In this section, antithrombotic agents and vasodila-
tors are discussed in this order.
© 2016 Japanese Dermatological Association

 There is an RCT only regarding dalteparin, a low-molecular-
weight heparin (LMWH), among antithrombotic agents in
diabetic patients with foot ulcers and PAD. Although the
cure rate and limb salvage rate were significantly higher with
dalteparin compared with placebo, the time until cure was
not shortened.178 Also, while its effects on ulcers is not dis-
cussed, a similar RCT was carried out by the same institu-
tion, and promotion of skin oxygenation and suppression of
the thrombogenic activity were reported in the dalteparin
group.179
 Although the official price ketanserin, a 5-HT2A/2C receptor
blocker, has not been announced in Japan, there is a dou-
ble-blind case–control study in which it was administrated
to patients with diabetic foot ulcers with severe peripheral
vasculopathy. The ulcer size reduction rate after 3 months
was 50% or higher in 58% of the patients treated with
ketanserin and 37% in those treated with placebo, and,
while the difference was not significant, a therapeutic effect
was observed.180
 Pentoxifylline is an activator of brain metabolism and shows
a platelet aggregation inhibitor action by promoting the
release of PGI2. However, in Japan, it was excluded from
the list of official drug prices in 1999. When patients with
ischemic diabetic ulcers were treated as usual with vasodila-
tors and topical agents alone or with oral pentoxifylline at
400 mg 9 3 in addition to usual treatments, the response
rate after 8 weeks was significantly higher in the pentoxi-
fylline group at 80% than in the usual treatment group at
50%.181
 Argatroban was evaluated in 43 patients with skin ulcers
including those with collagen disease, pressure ulcer and
diabetes. The drug was administrated to 14 patients with
diabetic ulcer without distinction between circulatory and
neuropathic ulcers, and a decrease in the ulcer size or a
higher effect was noted in 69% of the patients.182 Also, the
drug is frequently used clinically.
 Concerning sarpogrelate hydrochloride, there are many
expert opinions supporting its effectiveness against diabetic
ulcers despite the lack of good evidence, and it is used fre-
quently. In Japan, a decrease in the ulcer size and improve-
ments in pain and cold feeling were observed in a study in
patients with severe chronic arterial obstruction showing
ischemic ulcers.183
 Cilostazol has been reported to have reduced the size of leg
ulcers in 177 PAD patients in a multicenter double-blind
study in Japan.184 While its effects on diabetic ulcers have
not been evaluated, PAD is often complicated by diabetes,
and many expert opinions suggest that the drug is also
effective for diabetic ulcers.
 Aspirin and ticlopidine are drugs in wide use, but their effec-
tiveness for the treatment of diabetic ulcers has not been
sufficiently evaluated.
 Concerning ethyl icosapentate, there is a report that partial
or greater response was observed in 80% of the patients
with ASO in a clinical study in Japan, but the subjects of this
study were not restricted to those with diabetes as an
underlying disease.
© 2016 Japanese Dermatological Association
Wound/Burn Guidelines – 3
 Regarding vasodilators, there is an RCT of iloprost, a
prostacyclin analog. The condition was improved in 62% of
the patients (n = 31) administrated iloprost compared with
23.5% of those administrated placebo (n = 12) with a signifi-
cant difference.183 In a study comparing the effect of ilo-
prost with placebo in diabetic patients with ischemic skin
lesions including ulcer, a significantly higher therapeutic
effect was observed in the iloprost group.184 However, while
this drug is approved in Western countries, it is not
observed in the list of official drug prices of Japan, and it is
still on a stage of planning clinical trials.
 Concerning beraprost sodium, a PGI2 derivative, it has been
reported to improve the distance of intermittent claudication
and ABI in PAD patients, and improve the peripheral hemo-
dynamics in patients with PAD complicating diabetes. Con-
cerning the effects of beraprost sodium in patients with PAD
complicating diabetes, there is an analytical epidemiological
study188 and a case series study about the skin ulcer size
reducing effect.189 Although there is no published work
demonstrating its efficacy against diabetic ulcers, it is used
frequently, because it is an oral preparation, and many
expert opinions support its effectiveness.
REFERENCES
178 Kalani M, Apelqvist J, Blombӓck M et al. Effect of dalteparin on
healing of chronic foot ulcers in diabetic patients with peripheral
arterial occlusive disease: a prospective, randomized, double-blind,
placebo-controlled study. Diabetes Care 2003; 26: 2575–2580 (Evi-
dence level II).
179 Kalani M, Silveira A, Blombӓck M et al. Beneficial effects of dal-
teparin on haemostatic function and local tissue oxygenation in
patients with diabetes, severe vascular disease and foot ulcers.
Thromb Res 2007; 120: 653–661 (Evidence level II).
180 Apelqvist J, Castenfors J, Larsson J, Stenstro€ m A, Persson G. Ketan-
serin in the treatment of diabetic foot ulcer with severe peripheral
vascular disease. Int Angiol 1990; 9: 120–124 (Evidence level IVb).
181 Ramani A, Kundaje GN, Nayak MN. Hemorheologic approach in
the treatment of diabetic foot ulcers. Angiology 1993; 44: 623–626
(Evidence level IVb).
182 Furukawa H, Takigawa M, Shirahama S et al. Clinical study of
argatroban in patients with cutaneous ulcer. Acta Dermatol, 1995;
90: 415–423 (in Japanese).
183 Furukawa K, Tanabe T, Hoshino S, Mishima Y, Shinomiya K,
Yoshizaki S. Evaluation of the efficacy of sarpogrelate hydrochlo-
ride (MCI-9042) and ticlopidine hydrochloride in the treatment of
arteriosclerosis obliterans: double blind clinical study. J Clin Therap
Med 1991; 7: 1747–1770 (in Japanese).
184 Mishima Y, Tanabe T, Sakaguchi S et al. Assessing the effects of
OPC-13013 on arteriosclerosis obliterans. J Clin Exp Med 1986;
139: 133–158 (in Japanese).
185 Mu €ller B, Krais T, Stu
€rzebecher S, Witt W, Schillinger E, Baldus B.
Potential therapeutic mechanisms of stable prostacyclin (PGI2)-
mimetics in severe peripheral vascular disease. Biomed Biochem
Acta 1988; 47: S40–S44 (Evidence level II).
186 Brock FE, Abri O, Baitsch G et al. Iloprost in the treatment of
ischemic tissue lesions in diabetics. Results of a placebo-con-
trolled multicenter study with a stable prostacyclin derivative. Sch-
weiz Med Wochenschr 1990; 120: 1477–1482 (Evidence level II).
187 Oda K, Kudou M, Nakayama H et al. Assessing the effects of pros-
taglandin E1 (PGE1) on diabetic neurotrophic foot ulcers and gan-
grene. Gendai Iryo 1985; 17: 1090–1095 (in Japanese) (Evidence
level V).
611
T. Isei et al.
188 Toyota T, Oikawa S, Sato T et al. Clinical study of beraprost
sodium (DornerⓇ) in patients with arteriosclerosis obliterans. Endo-
crinol Diabetol 1999; 8: 104–114 (in Japanese).
189 Ishii N, Nakajima H, Kato Y et al. Assessing the effects of ber-
aprost sodium (DornerⓇ) on cutaneous ulcers. Nishinihon J Derm
1997; 59: 103–106 (in Japanese).
CQ16: WHAT DRUGS ARE USEFUL FOR THE
TREATMENT OF DIABETIC ULCERS DUE TO
NEUROPATHY?
Remarks on recommendation:
Dalteparin, an antithrombotic agent, is recommended as an
option for the treatment of diabetic ulcer caused by neu-
ropathy (C1).
The administration of Lipo-PGE1, a vasodilator, is recom-
mended (B). The administration of PGE1 is recommended
as an option (C1).
Recommendation level: B for Lipo-PGE1 C1 for dalteparin
and PGE1.
Comments:
 For the treatment of neuropathic ulcers, there are case
reports that dalteparin and pentoxifylline, which are LMWH,
were effective among antithrombotic drugs,190,191 but pen-
toxifylline is excluded from the list of official drug prices as
mentioned in CQ15. Among vasodilators, Lipo-PGE1 has
high efficacy.192–195
 In one case report, dalteparin (2500 units) was administrated
to 10 patients with diabetic ulcers complicated by peripheral
neuropathy or peripheral arterial obstructive diseases for
8 weeks, and the ulcerated area was reduced in eight, with
cure being observed in four of them. However, lesions due
to peripheral neuropathy and those due to peripheral arterial
obstruction were not clearly distinguished, and the number
of patients was small.190 In the other, pentoxifylline was
administrated p.o. at 400 mg 9 3 to 12 patients with neuro-
genic diabetic ulcers being treated with insulin, and the
treatment was effective in eight of the nine patients who
could be evaluated after 6 months.191
 Concerning vasodilators, many evaluations using Lipo-PGE1
have been performed, and there is a double-blind RCT com-
paring it with placebo and PGE1. In this trial, patients with
diabetic neuropathy or diabetic ulcer were selected, Lipo-
PGE1 at 10 lg/day, placebo or PGE1 at 40 lg/day was
administrated for 4 weeks, and significant decreases in the
ulcer size were observed in the Lipo-PGE1 group compared
with the placebo group after 1 week and compared with the
PGE1 group after 2 and 3 weeks.192 There is also a multicen-
ter RCT in which Lipo-PGE1 or PGE1 was administrated for
4 weeks to inpatients with symptoms such as spontaneous
pain and sensory abnormality due to diabetic neuropathy or
skin ulcer or necrosis secondary to diabetic neuropathy.
Ulcers and gangrene were observed in 27 and 24 patients,
respectively, and it was reported that the degree of final
improvement in spontaneous pain/sensory abnormality and
skin ulcer/gangrene was significantly higher in the Lipo-PGE1
612
group than in the PGE1 group and that the ulcer size reduc-
tion rate was greater in the Lipo-PGE1 group.193 Moreover,
there is one multicenter non-randomized placebo-controlled
comparative study in patients with diabetic neuropathy and
skin ulcer, and the improvement rate of skin ulcer was signifi-
cantly higher in the Lipo-PGE1 group at 69% compared with
the placebo group at 32%.194 There are also a large number
of case reports including one in which Lipo-PGE1 was effec-
tive in four patients with diabetic ulcer accompanied by neu-
ropathy,195 indicating its high efficacy.
 Concerning PGE1, there is a case series study in which the
drug was administrated by i.v. drip infusion at 20–80 lg/day
to 11 patients with ulcers associated with diabetic neuropa-
thy, resulting in a response rate (effective or very effective)
of 73%.196 There is also a report that PGE1 and Lipo-PGE1
were administrated to five and four, respectively, of nine
patients with diabetic foot (one with gangrene, eight with
ulcers) caused by diabetic neuropathy, that cure was
observed in 77.8%, but that the treatments were ineffective
in the patients with ischemic necrosis.197
REFERENCES
190 Jo€ rneskog G, Brismar K, Fagrell B. Low molecular weight heparin
seems to improve local capillary circulation and healing of chronic
foot ulcers in diabetic patients. Vasa 1993; 22: 137–142 (Evidence
level V).
191 Adler PF. Assessing the effects of pentoxifylline (Trental) on dia-
betic neurotrophic foot ulcers. J Foot Surg 1991; 30: 300–303 (Evi-
dence level V).
192 Toyama T, Hirata Y, Ikeda Y, Matsuoka K, Sakuma A, Mizushima
Y. Lipo-PGE1, a new lipid-encapsulated preparation of prostaglan-
din E1: placebo- and prostaglandin E1- controlled multicenter trials
in patients with diabetic neuropathy and leg ulcers. Prostaglandins
1993; 46: 453–468 (Evidence level II).
193 Hirata Y, Ikeda Y, Matsuoka K, Tanaka T. Clinical study of lipo-
PGE1 and prostaglandin E1- controlled multicenter trials in patients
with diabetic neuropathy and leg ulcers. J Adult Dis 1987; 17: 161–
181 (in Japanese) (Evidence level II).
194 Toyota T, Ikeda Y, Matsuoka K, Sakuma A. Assessing the effects
of lipo-PGE1 on diabetic neuropathy and leg ulcers: controlled
multicenter, placebo-controlled, double-blind study. J Clini Exp
Med 1990; 155: 749–769 (in Japanese) (Evidence level III).
195 Nishimura Y, Inoue Y, Sasaki T et al. Experience of lipo-PGE1 in
patients with diabetic gangrene and leg ulcers. J New Remedies
Clinics 1997; 46: 357–363 (in Japanese) (Evidence level V).
196 Oda K, Kudou M, Nakayama H et al. Assessing the effects of pros-
taglandin E1 (PGE1) on diabetic neurotrophic foot ulcers. Gendai
Iryo 1985; 17: 1090–1095 (in Japanese) (Evidence level V).
197 Nakamura Y, Kobayashi I. Retrospective clinical trail over the
7 years in diabetic foot patients- efficacy and prognosis of prosta-
glandin E1. Kitakanto Med J 1992; 42: 379–385 (in Japanese) (Evi-
dence level V).
CQ17: ARE ALDOSE REDUCTASE INHIBITORS
(ARI) USEFUL FOR THE TREATMENT OF
DIABETIC NEUROPATHY?
Remarks on recommendation: While the published work indi-
cating the effectiveness of ARI in general is deficient, many
papers suggest the effectiveness of epalrestat, so the use of
an ARI is recommended as an option.
© 2016 Japanese Dermatological Association
 Wound/Burn Guidelines – 3

Recommendation level: C1.  Concerning zenarestat, there is an RCT reporting dose-

Comments: dependent responses.209
 For fidarestat, there is one non-randomized comparative
 Concerning the effectiveness of ARI for the treatment of dia-
study reporting alleviation of diabetic neuropathy.210
betic neuropathy, there are two systematic reviews,198,199
 Regarding ponalrestat, there are three RCT, in which no signifi-
and the evidence level is I. However, no significant differ-
cant difference was observed compared with placebo,211–213
ence compared with placebo was noted, and there is a
and a report that some parameters suggested the effective-
meta-analysis indicating that the efficacy evaluation varies
ness.214
with the parameter examined.200 Therefore, the recommen-
 Regarding ranirestat, also, there is an RCT showing that the
dation level was set at C1.
drug was effective for the treatment of mild to moderate
 Diabetic neuropathy along with retinopathy and nephropathy
motor neuropathy but that its effects did not differ signifi-
is a member of the diabetic triopathies caused by prolonged
cantly compared with those of placebo for the treatment of
hyperglycemic state. It is classified into polyneuropathy,
sensory neuropathy215 and an RCT reporting improvements
autonomic neuropathy and mononeuropathy.
in sensory and motor nerve functions.216
 In a hyperglycemic state, aldose reductase is activated,
 Concerning sorbinil, there are two RCT reporting no
polyol metabolism is enhanced, and sorbitol and fructose
effect217,218 and a non-randomized comparative trial report-
accumulate in cells. This causes elevation of the osmotic
ing no effect. Thus, the effectiveness of ARI for the manage-
pressure, depression of the Na+/K+-ATPase activity in the
ment of neuropathy varies among drugs. Also, the results of
neuronal cell membrane, and slowing of the conduction of
efficacy evaluation may differ depending on the parameters
electric stimuli, resulting in neuropathy. ARI attracted atten-
used, and the establishment of standardized evaluation cri-
tion as a treatment for these conditions, and many drugs
teria is desired.
were developed in the 1980s, but clinical trials of various
 Many other drugs have been tentatively used for the treat-
drugs were discontinued due to strong adverse reactions
ment of diabetic neuropathy, and there have been a number
such as rash. Epalrestat is the only ARI covered by Japa-
of reports on antioxidants including a-lipoic acid and L-car-
nese national health insurance, but a number of evaluations
nitine. The published work concerning C-peptide, PKCb inhi-
concerning other ARI have been carried out. In the present
bitors, the lipophilic vitamin B1 derivative benfotiamine,
guidelines, reports evaluating only painful diabetic neuropa-
angiotensin-converting enzyme inhibitor trandolapril and
thy or autonomic neuropathy alone were excluded to avoid
Lipo-PGE1 is also relatively rich. There are also reports of
complexity.
the administration of sarpogrelate hydrochloride, c-linolenic
 As for overall evaluation of ARI, there are two systematic
acid, clomipramine, desipramine, zinc, vitamin B12, PGE1,
reviews concluding that there was no significant difference
cyclandelate and ganglioside.
in the therapeutic effect between ARI and placebo when
 (Supplemental) Among drugs other than ARI, “pain associ-
they were administrated to patients with polyneuropa-
ated with peripheral neuropathy” was approved as an indi-
thy.198,199 There is also a meta-analysis acknowledging an
cation of pregabalin, a c-aminobutyric acid derivative, in
improvement in the nerve conduction velocity of the median
Japan in October 2010.
nerve compared with the control group but concluding that
the efficacy evaluation is difficult by short-term observation
as no significant difference was noted in other parame-
REFERENCES
ters.200
 Epalrestat is approved and marketed in Japan, and there 198 Chalk C, Benstead TJ, Moore F. Aldose reductase inhibitors for
are the largest number of reports about it among ARI. In the treatment of diabetic polyneuropathy. Cochrane Database Syst
Rev 2007; 17: CD004572 (Evidence level I).
addition to RCT reporting that it was effective for the con-
199 Airey M, Bennett C, Nicolucci A, Williams R. Aldose reductase inhibi-
trol of autonomic neuropathy if administrated early after its tors for the prevention and treatment of diabetic peripheral neuropa-
onset but ineffective for the control of motor or sensory thy. Cochrane Database Syst Rev 1996: CD002182 (Evidence level I).
neuropathy,201 and that it delays the progression of neu- 200 Nicolucci A, Carinci F, Cavaliere D et al. A meta-analysis of trials
ropathy and alleviates symptoms in patients with adequate on aldose reductase inhibitors in diabetic peripheral neuropathy.
The Italian Study Group. The St. Vincent Declaration. Diabet Med
control of the blood sugar level and mild microangiopa- 1996; 13: 1007–1008 (Evidence level I).
thy,202 there are three others.203 Moreover, it has also been 201 Nakayama M, Nakamura J, Hamada Y et al. Aldose reductase inhi-
reported to have significantly alleviated numbness, dyses- bition ameliorates papillary light reflex and F-wave latency in
thesia and cold feeling of the leg, suppressed symptoms patients with mild diabetic neuropathy. Diabetes Care 2001; 24:
1093–1098 (Evidence level II).
and improved the nerve function.204,205 There are also a
202 Hotta N, Akanuma Y, Kawamori R et al. Long-term clinical effects
large number of molecular epidemiological studies and of epalrestat, an aldose reductase inhibitor, on diabetic peripheral
descriptive studies both in Japan and abroad, and the drug neuropathy: the 3-year, multicenter, comparative Aldose Reduc-
is highly useful. tase Inhibitor-Diabetes Complications Trial. Diabetes Care 2006;
29: 1538–1544 (Evidence level II).
 As for other ARI, there is a meta-analysis206 and two
203 Goto Y, Shigeta Y, Sakamoto N et al. Clinical efficacy of an aldose
RCT207,208 reporting that tolrestat reduces the risk of neu- reductase inhibitor for the treatment of diabetic neuropathy -clinical
ropathy and suggesting its usefulness. utility and inidication of epalrestat: a double-blind study. Diabetic

© 2016 Japanese Dermatological Association 613

T. Isei et al.
Neuropathy Study Group in Japan. Gendai Iryo, 1994; 26: 1383–
1391 (in Japanese) (Evidence level II).
204 Nakajima T, Fukui M, Deguchi M et al. Clinical efficacy of epal-
restat, an aldose reductase inhibitor, for diabetic neuropathy: cross
over trial. Tonyo byo 2005; 48: 601–606 (in Japanese) (Evidence
level III).
205 Matsuoka T, Aoyama M, Himei T. Subjective and objective efficacy
of an aldose reductase inhibitor for the treatment of diabetic neu-
ropathy. Diabetic Complications 2000; 15: 48–54 (in Japanese)
(Evidence level III).
206 Nicolucci A, Carinci F, Graepel JG et al. The efficacy of tolrestat in
the treatment of diabetic peripheral neuropathy. A meta-analysis of
individual patient data. Diabetes Care 1996; 19: 1091–1096 (Evi-
dence level I).
207 Giugliano D, Marfella R, Quatraro A et al. Tolrestat for mild diabetic
neuropathy. A 52-week, randomized, placebo-controlled trial. Ann
Intern Med 1993; 118: 7–11 (Evidence level II).
208 Boulton AJ, Levin S, Comstock J. A multicentre trial of the aldose-
reductase inhibitor, tolrestat, in patients with symptomatic diabetic
neuropathy. Diabetologia 1990; 33: 431–437 (Evidence level II).
209 Greene DA, Arezzo JC, Brown MB. Effect of aldose reductase inhi-
bition on nerve condition and morphometry in diabetic neuropathy.
Zenarestat Study Group. Neurology 1999; 53: 580–591 (Evidence
level II).
210 Hotta N, Toyama T, Matsuoka K, Shigeta Y, Kikkawa R, Kaneko T.
Clinical efficacy of fidarestat, a novel aldose reductase inhibitor,
for diabetic peripheral neuropathy: a 52-week multicenter placebo
controlled double-blind parallel group study. Diabetes Care 2001;
24: 1776–1782 (Evidence level III).
211 Krentz AJ, Honigsberger L, Ellis SH, Hardman M, Nattrass M. A
12-month randomized controlled study of the aldose reductase
inhibitor ponalrestat in patients with chronic symptomatic diabetic
neuropathy. Diabet Med 1992; 9: 463–468 (Evidence level II).
212 Ziegler D, Mayer P, Rathmann W, Gries FA. One-year treatment
with the aldose reductase inhibitor, ponalrestat, in diabetic neu-
ropathy. Diabetes Res Clin Pract 1991; 14: 63–73 (Evidence level II).
213 Florkowski CM, Rowe BR, Nightingale S, Harvey TC, Barnett AH.
Clinical and neurophysiological studies of aldose reductase inhibi-
tor ponalrestat in chronic symptomatic diabetic peripheral neu-
ropathy. Diabetes 1991; 40: 129–133 (Evidence level II).
214 Gill JS, Williams G, Ghatei MA, Mather HM, Bloom SR. Effect of
the aldose reductase inhibitor, panalrestat, on diabetic neuropathy.
Diabete Metab 1990; 16: 296–302 (Evidence level II).
215 Bril V, Hirose T, Tomioka S, Buchanan R. Ranirestat for the man-
agement of diabetic sensorimotor polyneuropathy. Diabetes Care
2009; 32: 1256–1260 (Evidence level II).
216 Bril V, Buchanan RA. Long-term effects of ranirestat (AS-3201) on
peripheral nerve function in patients with diabetic sensorimotor
polyneuropathy. Diabetes Care 2006; 29: 68–72 (Evidence level II).
217 O’Hare JP, Morgan MH, Alden P, Chissel S, O’Brien IAD, Corrall
JM. Aldose reductase inhibition in diabetic neuropathy: clinical and
neurophysiological studies of one year’s treatment with sorbinil.
Diabet Med 1988; 5: 537–542 (Evidence level II).
218 Christensen JE, Varneck L, Gregersen G. The effect of an aldose
reductase inhibitor (Sorbinil) on diabetic neuropathy and neural
function of the retina: a double-blind study. Acta Neurol Scand
1985; 71: 164–167 (Evidence level II).
CQ18: IS CONTROL OF SERUM GLUCOSE
LEVEL USEFUL FOR IMPROVING THE CURE
RATE OF DIABETIC ULCER?
Remarks on recommendation: Blood sugar control is recom-
mended as it reduces local factors inhibiting wound healing and
leads to improvements in the mechanism of wound healing.
Recommendation level: B.
Comments:
614
 There are five case reports concerning the effectiveness of
blood sugar control for improving the cure rate of diabetic
ulcers,219–223 and their evidence levels are V and VI. How-
ever, as it is clear that controlling symptoms of the primary
disease contributes to a decrease in local factors inhibiting
wound healing from the findings of basic research and the
pathology, the recommendation level was set at B.
 Case reports and expert opinions comprise a majority of the
published work concerning the evaluation of the effects of
blood sugar control on wound healing in patients with dia-
betic ulcers, and the approach is recommended by foreign
guidelines. Various inhibitory factors of wound healing are
involved in the establishment of diabetic ulcers, and blood
sugar control contributes to improvements in the mecha-
nism of wound healing by reducing such factors.224–231
REFERENCES
219 Rai NK, Suryabhan, Ansari M, Schukla K, Tripathi K. Effect of gly-
caemic control on apoptosis in diabetic wounds. J Wound Care
2005; 14: 277–281 (Evidence level V).
220 Glasser J, Barth A. Diabetic wound healing and the case for sup-
plemental treatment with topical insulin. J Foot Surg 1982; 21:
117–121 (Evidence level V).
221 Duckworth WC, Fawcett J, Reddy S, Page JC. Insulin- degrading
activity in wound fluid. J Clin Endocrinol Metab 2004; 89: 847–851
(Evidence level V).
222 Vuorisalo S, Venermo M, Lepa €ntalo M. Treatment of diabetic foot
ulcers. J Cardiovasc Surg (Torino) 2009; 50: 275–291 (Evidence
level VI).
223 Edmonds M. Diabetic foot ulcers: practical treatment recommen-
dations. Drugs 2006; 66: 913–929 (Evidence level VI).
224 Brem H, Sheehan P, Boulton AJ. Protocol for treatment of diabetic
foot ulcers. Am J Sug 2004; 187: S1–S10.
225 Brem H, Sheehan P, Rosenberg HJ, Schneider JS, Boulton AJ.
Evidence-based protocol for diabetic foot ulcers. Plast Reconstr
Surg 2006; 117: S193–S209.
226 Steed DL, Attinger C, Brem H, Colaizzi T, Crossland RN, Franz M.
Guidelines for the prevention of diabetic ulcers. Wound Repair
Regen 2008; 16: 169–174.
227 Steed DL, Attinger C, Colaizzi T et al. Guidelines for the treatment
of diabetic ulcers. Wound Repair Regen 2006; 14: 680–692.
228 Beam HA, Parsons JR, Lin SS. The effects of blood glucose con-
trol upon fracture healing in the BB Wistar rat with diabetes melli-
tus. J Orthop Res 2002; 20: 1210–1216.
229 Gandhi A, Beam HA, O’Connor JP, Parsons JR, Lin SS. The
effects of local insulin delivery on diabetic fracture healing. Bone
2005; 37: 482–490.
230 Greenhalgh DG. Tissue repair in models of diabetes mellitus. Meth-
ods Mol Med 2003; 78: 181–189.
231 Greenhalgh DG. Wound healing and diabetes mellitus. Clin Plast
Surg 2003; 30: 37–45.
CQ19: DOES IMPROVING THE NUTRITIONAL
CONDITION OF DIABETIC PATIENTS
PROMOTE THE HEALING OF DIABETIC
ULCERS?
Remarks on recommendation: Improving the nutritional condi-
tion under the guidance of a specialist in nutrition is recom-
mended as an option.
Recommendation level: C1.
© 2016 Japanese Dermatological Association

Comments:
 Regarding the relationship between improvements in the
nutritional state and promotion of healing of diabetic ulcers,
there is one good non-randomized comparative trial,232 and
the evidence level is III. However, the recommendation level
was set at C1, because some facilities lack specialists in
nutrition.
 Generally, intervention by the NST in the treatment of
ulcers is important, but there are not many reports con-
cerning nutritional intervention specific to patients with dia-
betic ulcer and wound healing. The level of activities of
daily living in patients with a diabetic ulcer is not so low
compared with patients with other skin ulcers, and the
necessity to improve the nutritional state is small. In addi-
tion, as the energy intake is restricted in many patients for
the treatment of diabetes, excessive nutritional supply for
the treatment of ulcers alone should be avoided. However,
some patients are in a poor nutritional condition, and it
must be improved. In such patients, nutritional guidance
by the NST including a nutritionist should be attempted by
monitoring daily changes in the patient’s blood glucose
level.233–235
REFERENCES
232 Bourdel-Marchasson I, Barateau M, Rondeau V, Dequae-Mercha-
dou L, Salles-Montaudon N, Emeriau JP. A multi-center trial of the
effects of oral nutritional supplementation in critically ill older inpa-
tients. GAGE Group. Groupe Aquitain Geriatrique d’Evaluation.
Nutrition 2000; 16: 1–5 (Evidence level III).
233 Lansdown AB. Nutrition 1: a vital consideration in the management
of skin wounds. Br J Nurs 2004; 13: S22–S28 (Evidence level V).
234 Lansdown AB. Nutrition 2: a vital consideration in the management
of skin wounds. Br J Nurs 2004; 13: 1199–1210 (Evidence level V).
235 Himes D. Protein-calorie malnutrition and involuntary weight loss:
the role of aggressive nutritional intervention in wound healing.
Ostomy Wound Manage 1999; 45: 46–51, 54–55.
CQ20: IS ATTENTION TO HEMODIALYSIS
NECESSARY AS A FACTOR OF THE
DEVELOPMENT OF DIABETIC ULCER AND
DELAY OF ITS HEALING?
Remarks on recommendation: It is recommended to manage
diabetic patients undergoing dialysis therapy with attention to
the possibility that dialysis is a factor in the development of
skin ulcers and delay of its healing.
Recommendation level: B.
Comments:
 There are five retrospective cohort studies evaluating the
effects of dialysis on diabetic ulcers,236–240 and the evidence
levels are all IVb. However, dialysis is indispensable to main-
tain life in patients with marked diabetic nephropathy.
Because dialysis is inevitable in such renal failure patients,
an RCT comparing the outcome with and without dialysis is
impossible. Therefore, the management of patients undergo-
ing dialysis, who have many complications, as high-risk
© 2016 Japanese Dermatological Association
Wound/Burn Guidelines – 3
patients is useful, and the recommendation level was set at
B.
 Vascular calcification is frequently observed in dialysis
patients, and dialysis is known to promote the progression
of calcification. Therefore, dialysis as a medical action
affects diabetic skin ulcer indirectly by “promoting the pro-
gression of arteriosclerosis”. Therefore, it is desirable to
manage diabetic patients undergoing dialysis by remember-
ing that they have an extra risk factor of the development
and exacerbation of skin ulcers.
 There are reports that dialysis in a diabetic patient is a risk
factor of ischemic ulcers (odds ratio: 21.58),236 that dialysis
is a risk factor of major amputation in patients with a dia-
betic ulcer (hazard ratio: 2.14),237 that diabetes was
observed as a risk factor in dialysis patients who under-
went major amputation (hazard ratio: 7.4),238 that dialysis
was a risk factor of amputation and death in patients with
CLI (odds ratio: 8,93),239 and that the incidences of ulcer
and amputation increase with the severity of diabetic
nephropathy.240 While the viewpoint of analysis varies
among reports, dialysis in diabetic patients has been sug-
gested to be related to the development or exacerbation of
ischemic ulcers. However, there is also a report that, in
dialysis patients who required major amputation, no differ-
ence was noted in the site of amputation (above or below
the knee) or survival state between those with and without
diabetes.241
 The number of dialysis patients in Japan has continued to
increase, and dialysis is introduced newly due to diabetic
nephropathy in more than half the patients. In Japan,
hemodialysis accounts for 95% of dialysis, with peritoneal
dialysis constituting only 5%, but the proportion overseas is
reported to be two in three for hemodialysis and one in
three for peritoneal dialysis. It should be noted that there
are three types of reports evaluating the relationship
between dialysis and diabetic ulcers: those dealing with
hemodialysis alone, peritoneal dialysis alone, and both.
REFERENCES
236 Yasuhara H, Naka S, Yanagie H, Nagawa H. Influence of diabetes
on persistant non healing ischemic foot ulcer in end-stage renal
disease. World J Surg 2002; 26: 1360–1364 (Evidence level IV).
237 Miyajima S, Shirai A, Yamamoto S et al. Risk factors for major limb
amputations in diabetic foot gangrene patients. Diabet Res Clin
Pract 2006; 71: 272–279 (Evidence level IV).
238 Speckman RA, Bedinger MR, Frankenfield DL et al. Diabetes is the
strongest risk factor for lower-extremitiy amputation in new
hemodyalysis patients. Diabetes Care, 2004; 27: 2198–2203 (Evi-
dence level IV).
239 Volaco A, Chantelau E, Richter B, Luther B. Outcome of critical
foot ischemia in longstanding diabetic patients : a retrospective
cohort study in a specialized tertiary care centre. Vasa 2004; 33:
36–41 (Evidence level IV).
240 Schleiffer T, Holken H, Brass H. Morbidity in 565 type 2 diabetic
patients according to stage of nephropathy. J Diabetes Complica-
tions 1998; 12: 103–109 (Evidence level IV).
241 Korzets A, Ori Y, Rathaus M et al. Lower extremity amputation in
chronically dialysed patients: a 10 year study. Isr Med Assoc
J 2003; 5: 501–505.
615
T. Isei et al.
CQ21: IS HYPERBARIC OXYGEN THERAPY
USEFUL FOR THE TREATMENT OF DIABETIC
ULCERS?
Remarks on recommendation: Hyperbaric oxygen therapy is
recommended as an option for the treatment of diabetic ulcers.
However, not many facilities are equipped for this treatment.
Recommendation level: C1.
Comments:
 There are five systematic reviews concerning the usefulness
of hyperbaric oxygen therapy for the treatment of diabetic
ulcers,242–246 and the evidence level is I. While the treatment
is useful according to four of them,242,243,245,246 its usefulness
has not been established according to one.244 Moreover, not
many medical facilities are equipped for this treatment, and
3 h or longer is needed for one application of the treatment.
Therefore, the recommendation level was set at C1.
 By increasing the partial pressure of oxygen in blood and
tissues, hyperbaric oxygen therapy not only resolves a
hypoxic state but also produces a wide range of effects
such as alleviation of edema due to the pressure and sup-
pression of bacterial growth due to the toxicity of oxygen.
However, this therapy has defects such as that it can be
performed only at the few medical facilities equipped for it
and that a long time (≥3 h) is needed for a single applica-
tion.
 Of the five systematic reviews, four242,243,245,246 conclude
that the therapy is effective. In the RCT reviewed, the
decreases in the amputation rate,247,248,250 increases in the
percutaneous oxygen partial pressure247,250 and decreases
in the ulcer area249,250 were evaluated, and the treatment
was reported to be effective.
REFERENCES
242 Goldman RJ. Hyperbaric oxygen therapy for wound healing and
limb salvage: a systematic review. Am Acad Phys Med Rehab
2009; 1: 471–489 (Evidence level I).
243 Gray M, Ratliff CR. Is hyperbaric oxygen therapy effective for the
management of chronic wounds? J Wound Ostomy Continence
Nurs 2006; 33: 21–25 (Evidence level I).
244 Wang C, Schwaitzberg S, Berliner E, Zarin DA, Lau J Hyperbaric
oxygen for treating wounds: a systematic review of the literature.
Arch Surg 2003; 138: 272–279 (Evidence level I).
245 Roeckl-Wiedmann I, Bennett M, Kranke P. Systematic review of
hyperbaric oxygen in the management of chronic wounds. Br J
Surg 2005; 92: 24–32 (Evidence level I).
246 Kranke P, Bennett M, Roeckl-Wiedmann I et al. Hyperbaric oxygen
therapy for chronic wounds. Cochrane Database Syst Rev 2004:
CD004123 (Evidence level I).
247 Doctor N, Pandya S, Supe A. Hyperbaricoxygen therapy in diabetic
foot. J Postgrad Med 1992; 38: 112–114 (Evidence level II).
248 Faglia E, Favales F, Aldeghi A et al. Adjunctive systemic hyperbaric
oxygen therapy in treatment of severe prevalenty ischemic diabetic
foot ulcer. Diabetes Care 1986; 19: 1338–1343 (Evidence level II).
249 Kessler L, Bilbault P, Ortega F et al. Hyperbaric oxygeneration
accerlates the healing rate of nonischemic chronic diabetic foot
ulcers. Diabetes Care 2003; 26: 2378–2382 (Evidence level II).
250 Abidia A, Laden G, Kuhan G et al. The role of hyperbaric oxygen
therapy in ischemic diabetic lower extremity ulcers: a double-blind
616
randomized-controlled trial. Eur J Vasc Endovasc Surg 2003; 25:
513–518 (Evidence level II).
CQ22: IS LOW-DENSITY LIPOPROTEIN (LDL)
APHERESIS USEFUL FOR THE TREATMENT
OF DIABETIC ULCERS?
Remarks on recommendation: LDL apheresis is recommended
as an option, because its therapeutic effects are expected in
diabetic ulcers complicated by major vascular disease.
Recommendation level: C1.
Comments:
 Concerning the effects of LDL apheresis on diabetic ulcers,
there are two case series studies251,252 and four case
reports,253–256 and the evidence level is V.
 LDL apheresis as a treatment for ASO of the leg is covered
by health insurance in Japan and has been reported to be
effective. However, it is not mentioned as a treatment for
diabetic or non-diabetic PAD in the TASCII, which is an
international guideline for the diagnosis and treatment of
ASO of the leg. Concerning its effectiveness in clinical situa-
tions, there are only sporadic case series studies251,252 and
case reports.253–256
 The principle of this treatment is to adsorb and eliminate
lipoproteins such as LDL and very low-density lipoprotein,
which are arteriosclerogenic factors, using dextran sulfate
given a strong negative electrical charge as an adsorption
ligand. However, the mechanisms of its effects on PAD are
considered to be an decrease in the blood viscosity due to
elimination of lipids and clotting factors, improvements in
the oxygen and nutrient transport due to an increase in the
erythrocyte deformability, and vasodilation caused by brady-
kinin generated during the treatment rather than a decrease
in LDL cholesterol. The clarification of the mechanisms of its
effects have been advanced recently by a series of the
reports of increases in vasodilator materials such as nitric
oxide (NO), vascular endothelial growth factor and insulin-
like growth factor (IGF), decreases in inflammogenic materi-
als such as oxidized LDL, intercellular adhesion molecule-1,
high-sensitivity CRP and P-selectin, and decreases in fac-
tors that delay wound healing such as MMP-9, tissue inhibi-
tor of metalloproteinase-1, vascular cell adhesion molecule-
1 and endothelin-1. However, as the necessity of large
equipment, and problems with blood access have hampered
its spread, it is currently implanted at very limited facilities
(primarily dialysis facilities).
REFERENCES
251 Rietzsch H, Panzner I, Selisko T et al. Heparin-induced extracorpo-
real LDL precipitation (H.E.L.P) in diabetic foot syndrome-preven-
tive and regenerative potential? Horm Metab Res 2008; 40: 487–
490 (Evidence level V).
252 Richter WO, Jahn P, Jung N, Nielebock E, Tachezy H. Fibrinogen
adsorption in the diabetic foot syndrome and peripheral arterial
occlusive disease: first clinical experience. Ther Apher Dial 2001;
5: 335–339 (Evidence level V).
© 2016 Japanese Dermatological Association

253 Iizuka T, Takeda H, Inoue H et al. Clinical trial of low density
lipoprotein-apheresis for treatment of diabetic gangrene. Intern
Med 1997; 36: 898–902 (Evidence level V).
254 Kamimura M, Matsuo M, Miyahara T et al. Improvement in artery
occlusion by low-density lipoprotein apheresis in a patient with
peripheral arterial disease. Ther Apher Dial 2002; 6: 467–470 (Evi-
dence level V).
255 Nakamura A, Kawagoe Y, Kuga Y. A successful case of LDL
apheresis to skin ulcer from arteriosclerosis obliterans in diabetic
neuropathy. J Saiseikai Suita 2003; 9: 75–79 (in Japanese) (Evi-
dence level V).
256 Inoue H, Takeda H, Miyamoto T et al. Effect of LDL apheresis for
diabetic gangrene. Ther Res 1997; 18: 205–206 (in Japanese) (Evi-
dence level V).
CQ23: CAN EXACERBATION OF DIABETIC
ULCERS BE PREVENTED BY TREATING TINEA
PEDIS OR TOENAIL TINEA UNGUIUM?
Remarks on recommendation: Treatment for tinea pedis or toe-
nail tinea unguium is recommended to prevent exacerbation of
diabetic ulcers.
Recommendation level: B.
Comments:
 Concerning whether treatment of tinea pedis is effective for
the prevention of diabetic ulcers, there is one RCT, and the
evidence level is II, but no significant difference was noted
in the incidence of ulcers whether tinea pedis was treated or
not.257 However, there are reports that patients with tinea
pedis are more likely to develop cellulitis258 and that infec-
tion is frequently observed in patients with a high hemoglo-
bin A1c level, indicating poor control of diabetes.259
Although many such reports are expert opinions, the recom-
mendation level was set at B on the basis of consensus of
the committee in consideration of the seriousness of the
results of complicating infections.
 There is no report with a high evidence level that tinea pedis
promotes diabetic ulcers. A study evaluating risk factors of
the occurrence of ulcerative lesions in 1285 diabetic patients
concluded that factors include concurrent visual impairment,
history of foot ulcer and history of foot amputation as well
as tinea unguium.260
 As to whether or not treatment of tinea pedis contributes to
the prevention of diabetic ulcers, an RCT showed that exter-
nal application of nail lacquer containing an antifungal agent
(ciclopirox 8%) reduced the incidence of ulcers in diabetic
patients with fungal infection, but the difference in the inci-
dence of ulcer with and without the treatment was not sig-
nificant.257
 In tinea unguium, inappropriate nail clipping may cause
acronyx in healthy as well as infected nails. Also, as
infected nails are often thickened, nail clipping may be diffi-
cult with a nail clipper. Because of the possibility of dam-
age to the surrounding skin and the high risk of secondary
infection, it is desirable for diabetic patients with difficulty
to clip nails due to reduced vision or muscle strength to
visit the dermatology or foot care outpatient clinic every
1–2 months.
© 2016 Japanese Dermatological Association
Wound/Burn Guidelines – 3
REFERENCES
257 Armstrong DG, Holtz K, Wu S. Can the use of a topical antifungal
nail lacquer reduce risk for diabetic foot ulceration? Results from a
randomized controlled pilot study. Int Wound J 2005; 2: 166–170
(Evidence level II).
258 Bristow IR, Spruce MC. Fungal foot infection, cellulitis and dia-
betes: a review. Diabet Med 2009; 25: 548–551.
259 Eckhard M, Lengler A, Liersch J, Bretzel G, Mayser P. Fungal foot
infection in patients with diabetes mellitus – results of two indepen-
dent investigations. Mycosis 2007; 50: 14–19.
260 Bokyo EJ, Ahroni JH, Cohen V, Nelson KM, Heagerty PJ. Predic-
tion of diabetic foot ulcer occurrence using available clinical infor-
mation: Seattle Diabetic Study. Diabetes Care 2006; 29: 1202–
1207 (Evidence level IVa).
CQ24: IS APPROPRIATE TREATMENT FOR
CALLUSES OR FOOT CORNS NECESSARY IN
DIABETIC PATIENTS?
Remarks on recommendation: Because, in diabetic patients,
calluses and foot corns, which increase the pressure on partic-
ular sites of the sole, are factors of ulcer formation and exacer-
bation, it is recommended to carefully examine the toes and
take measures to prevent them. However, as treatments such
as scraping may induce ulcer formation or exacerbation of
symptoms of bacterial infection, they should be performed
appropriately as medical actions.
Recommendation level: B.
Comments:
 There is one systematic review on the relationship
between plantar calluses or foot corns and foot ulcer for-
mation,261 and the risk of ulcer is not reduced by treat-
ment for foot corns. However, as there are two analytical
epidemiological studies recommending treatment for cal-
luses262,263 and a case–control study encouraging it,264 the
recommendation level was set at B on the basis of con-
sensus of the committee. However, as there is a report
that infection was caused by treatment,265 treatment
should be performed appropriately under a physician’s
supervision.
 Concentration of the weight load at particular sites of the
sole is known to be a major factor of the formation of
diabetic ulcers, and calluses and foot corns contribute to
it. Also, as weight loads are increased by joint deforma-
tion, differentiation from neuropathic ulcer is often neces-
sary. In a prospective evaluation of 63 diabetic patients,
a history of ulcer and the presence of calluses were
shown to increase the relative risk of ulcer formation.261
 When diabetic and non-diabetic patients with calluses were
compared, marked symptoms of calluses were observed
only in diabetic patients, suggesting that calluses are a
pathogenic factor of diabetic ulcers.262
 Concerning treatments, there is a report evaluating weight
loads on the sole and the advisability of treatment in 33
patients with type 2 diabetes divided into a group with cal-
luses, group with no calluses, and group in which calluses
were removed. The plantar pressure was significantly
617
T. Isei et al.
increased in the group having calluses, and as the pressure
was reduced significantly by removing calluses, the
treatment is recommended.263,265 However, while there is a
report that calluses should be treated, because the weight
loads on the sole were reduced by the treatment,266 there
is also a systematic review that the risk of ulcer formation
is not reduced by treatment of calluses.261 One report rec-
ommends a careful attitude to treating foot corns, because
severe foot ulcers and sepsis occurred after treatment for
foot corns in seven diabetic patients.266 In consideration of
these reports, and because treatments for calluses or foot
corns such as scraping are medical actions, they should be
performed carefully by, or under the supervision of, a
physician.
REFERENCES
261 Spencer S. Pressure relieving interventions for preventing and
treating diabetic foot ulcers. Cochrane Database of Systematic
Reviews 2000; 3 (Evidence level I).
262 Murray HJ, Young MJ, Hollis S, Boulton AJ. The association
between callus formation, high pressures and neuropathy in dia-
betic foot ulceration. Diabet Med 1996; 13: 979–982 (Evidence
level IVa).
263 Nishide K, Nagase T, Oba M et al. Ultrasonographic and thermo-
graphic screening for latent inflammation in diabetic foot callus.
Diabetes Res Clin Pract 2009; 85: 304–309.
264 Pataky Z, Golay A, Faravel L et al. The impact of callosities on the
magnitude and duration of planter pressure in patients with dia-
betes mellitus. A callus may cause 18,600 kilograms of excess
planter pressure per day. Diabet Metab 2002; 28: 356–361 (Evi-
dence level IVb).
265 Young MJ, Cavanagh PR, Thomas G, Johnson MM, Murray H,
Boulton AJ. The effect of callus removal dynamic plantar foot pres-
sures in diabetic patients. Diabet Med 1992; 9: 55–57.
266 Foster A, Edmonds ME, Das AK, Watkins PJ. Corn cures can dam-
age your feet: an important lesson for diabetic patients. Diabet
Med 1989; 6: 818–819.
CQ25: IS BATHING EDUCATION (INCLUDING
WHOLE-BODY AND FOOT BATHING) IN
DERMATOLOGICAL CARE USEFUL FOR THE
TREATMENT OF DIABETIC ULCER PATIENTS?
Remarks on recommendation: Patient education (self-learning)
through diabetes classes is useful as part of the treatment and
is recommended.
Recommendation level: B.
Comments:
 Concerning the usefulness of patient education about mat-
ters including physical therapy in dermatological care, there
is one systematic review,267 and the evidence level is I.
Patient education is particularly important in the high-risk
group. However, there has been an additional report based
on an RCT that education of patients with diabetic ulcers
did not affect the treatment for ulcers.268 Thus, no consen-
sus has been reached concerning education of patients with
diabetic ulcers, and there is no published work with statisti-
618
cal grounds in Japan. However, the recommendation level
was set at B on the basis of consensus of the committee
that appropriate guidance in bathing and skin care is indis-
pensable for the treatment.
 While there are reports that patient education does not
affect symptoms of diabetic ulcer,269,270 there are reports
that it has a suppressive effect on ulcer formation.271–274 It
has also been reported to reduce the risk of leg amputa-
tion.275
 In Japan, various grass-roots opportunities have been taken
to promote understanding in diabetic patients of the dis-
ease, and there have been some accomplishments. For the
management of diabetes, patient education is performed
enthusiastically at each medical organization under the title
of “diabetes class”. Restriction of diet and appropriate
exercise in daily living are important for the control of dia-
betes, and patient education provides opportunities for
patients to learn about matters important in the prevention
of ulcer formation and promotion of its cure such as weight
relieving and keeping the body clean by improving the
washing method.
 Education about the foot as well as blood sugar control is
necessary for diabetic patients.276 Particularly, guidance to
have the patient or caregiver examine the foot daily is
important.277
 Climate therapy such as bathing in a hot spring is widely per-
formed among diabetic patients. In pressure ulcer patients,
the bacterial mass has been shown to decrease with
increases in the regional blood flow by bathing, and bathing
is defined by textbooks as a skin care technique and is rec-
ommended as part of the treatment. In diabetic skin ulcers,
inappropriate foot bathing may induce infection, and a dia-
betic ulcer is considered by some to be a contraindication to
foot bathing, but the evidence is unclear. Bathing in a hot
spring is widely accepted as a folk therapy for diabetes. How-
ever, diabetic patients are more active than pressure ulcer
patients, and they may have more opportunities to bathe not
under the supervision of medical professionals. On such
occasions, there is the possibility of sustaining burn injuries
due to hypesthesia caused by diabetic peripheral neuropathy
as well as the risk of infection.278–280 Therefore, bathing is
recommended on condition that appropriate guidance in
bathing and skin care is provided.
 There are not many studies on the effects of warm or
cold water bathing on patients with diabetic ulcer. There
is a report that repeated alternate stimulation by warm
and cold water bathing did not significantly increase the
blood flow in diabetic patients compared with healthy
individuals.281
 There is a report that bathing promoted the healing of
burn injuries in diabetic patients. As for the mechanism
of this promotion, bathing in a hot spring is reported to
have a peripheral vasodilating effect but not to be
expected to reduce the blood glucose level in diabetic
patients.282,283
© 2016 Japanese Dermatological Association

REFERENCES
267 Valk GD, Kriegsman DM, Assendelft WJ. Patient education for pre-
venting diabetic foot ulceration. A systematic review. Endocrinol
Metab Clin North Am 2002; 31: 633–658 (Evidence level I).
268 Lincoln NB, Radford KA, Game FL, Jeffcoate WJ. PatieEducation
for secondary prevention of foot ulcers in people with diabetes: a
randomised controlled trial. Diabetologia 2008; 51: 1954–1961 (Evi-
dence level II).
269 Dorresteijn JA, Kriegsman DM, Assendelft WJ, Valk GD. Patient
education for preventing diabetic foot ulceration. Cochrane Data-
base Syst Rev 2010; 5: CD001488.
270 Jbour AS, Jarrah NS, Radaideh AM et al. Prevalence and predic-
tors of diabetic foot syndrome in type 2 diabetes mellitus in Jor-
dan. Saudi Med J 2003; 24: 761–764 (Evidence level V).
271 Pinzur MS, Slovenkai MP, Trepman E, Shields NN, Diabetes Com-
mittee of American Orthopaedic Foot and Ankle Society. Guideli-
nes for diabetic foot care: recommendations endorsed by the
Diabetes Committee of the American Orthopaedic Foot and Ankle
Society. Foot Ankle Int 2005; 26: 113–119.
272 Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in
patients with diabetes. JAMA 2005; 293: 217–228 (Evidence level
V).
273 Del Aguila MA, Reiber GE, Koepsell TD. How does provider and
patient awareness of high-risk status for lower-extremity amputa-
tion influence foot-care practice? Diabetes Care 1994; 17: 1050–
1054 (Evidence level V).
274 Bloomgarden ZT, Karmally W, Metzger MJ et al. Randomized con-
trolled trial of diabetic patient education: improved knowledge
© 2016 Japanese Dermatological Association
Wound/Burn Guidelines – 3
without improved metabolic status. Diabetes Care 1987; 10: 263–
272.
275 Reed L, Revel AO, Carter A, Saadi HF, Dunn EV. A clinical trial of
chronic care diabetic clinics in general practice in the United Arab
Emirates: a preliminary analysis. Arch Physiol Biochem 2001; 109:
272–308.
276 Shinjo T. The diabetic foot. J Jap Med Assoc 2003; 130: S278–
S281 (Evidence level VI).
277 Ueno T, Takezaki S, Miura Y, Kawana S. Clinical analysis of thirty-
eight cases of diabetic foot gangrene. Nishinihon J Derm 2008; 70:
67–70 (Evidence level VI).
278 Putz Z, Nadas J, Jermendy G. Severe but preventable foot burn
injury in diabetic patients with peripheral neuropathy. Med Sci
Monit 2008; 14: CS89–CS91.
279 Balakrishnan C, Pak TP, Meiniger MS. Burns of the neuropathic
foot following use of therapeutic footbaths. Burns 1995; 21: 622–
623.
280 O’Neal LW. Surgical pathology of the foot and clinicopathologic
correlations. In: Bowker JH, Pfeifer MA, eds. The Diabetic Foot,
6th edn. St. Louis: Mosby Inc., 2001; 483–512.
281 Petrofsky J, Lohman E 3rd, Lee S et al. Effects of contrast baths
on skin blood flow on the dorsal and plantar foot in people with
type 2 diabetes and age-matched controls. Physiother Theory
Pract 2007; 23: 189–197.
282 Kubota K (eds). Hot-Spring Therapy, Tokyo: Kinpodo, 2006; 4–56
(in Japanese).
283 Yamaoka K, Komoto Y. Experimental study of alleviation of hyper-
tension, diabetes and pain by radon inhalation. Physol Chem Phys
Med NMR 1996; 28: 1–5.
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