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Journal of Diabetes and Its Complications xxx (2014) xxx–xxx

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Journal of Diabetes and Its Complications


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Original Article

Comparison of characteristics and healing course of diabetic foot ulcers by


etiological classification: Neuropathic, ischemic, and neuro-ischemic type
Rie Roselyne Yotsu a,⁎, Ngoc Minh Pham b, Makoto Oe c, Takeshi Nagase c, Hiromi Sanada c, Hisao Hara d,
Shoji Fukuda e, Junko Fujitani f, Ritsuko Yamamoto-Honda g, Hiroshi Kajio g, Mitsuhiko Noda g, Takeshi Tamaki a
a
Department of Dermatology, National Center for Global Health and Medicine, Tokyo, Japan
b
Department of Epidemiology and Prevention, Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan
c
Department of Gerontological Nursing/Wound Care Management, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
d
Division of Cardiovascular Medicine, National Center for Global Health and Medicine, Tokyo, Japan
e
Department of Cardiovascular Surgery, National Center for Global Health and Medicine, Tokyo, Japan
f
Department of Rehabilitation, National Center for Global Health and Medicine, Tokyo, Japan
g
Department of Diabetes and Metabolic Medicine, National Center for Global Health and Medicine, Tokyo, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Aims: To identify differences in the characteristics of patients with diabetic foot ulcers (DFUs) according to
Received 2 January 2014 their etiological classification and to compare their healing time.
Received in revised form 7 March 2014 Methods: Over a 4.5-year period, 73 patients with DFUs were recruited. DFUs were etiologically classified as
Accepted 24 March 2014 being of neuropathic, ischemic, or neuro-ischemic origin. Descriptive analyses were performed to
Available online xxxx
characterize study subjects, foot-related factors, and healing outcome and time. Duration of healing was
assessed using the Kaplan–Meier method. Healing time among the three types was compared using the log
Keywords:
Age
rank test.
Diabetic foot ulcer Results: The number of patients manifesting neuropathic, ischemic, and neuro-ischemic ulcers was 30, 20, and
Healing time 14, respectively. Differences were identified for age, diabetes duration, body mass index, hypertension, and
Outcome estimated glomerular filtration rate. Patients with neuro-ischemic ulcers had better ankle–brachial index,
Risk factor skin perfusion pressure (SPP), and transcutaneous oxygen pressure values compared to those with ischemic
Skin perfusion pressure ulcers. The average time in which 50% of patients had healed wounds was 70, 113, and 233 days for
neuropathic, neuro-ischemic, and ischemic ulcers, respectively. Main factors associated with healing were age
and SPP values.
Conclusions: Based on the etiological ulcer type, DFU healing course and several patient factors differed.
Failure to consider the differences in DFU etiology may have led to heterogeneity of results in previous studies
on DFUs.
© 2014 Elsevier Inc. All rights reserved.

1. Introduction hospital care, and impose a major burden not only on patients, but
also on society with considerable medical cost (Prompers et al., 2008;
Diabetic foot ulcers (DFUs) are one of the most serious and Stockl, Vanderplas, Tafesse, & Chang, 2004). Given these various
disabling complications of diabetes. Prevalence of DFUs among negative impacts, determination of the factors related to ulcerations
diabetic patients is reported to be between 4% and 10%, with an and wound healing delay is of major importance.
estimated lifetime incidence of almost 25% (Singh, Armstrong, & Previous studies have reported multiple risk factors associated
Lipsky, 2005). Due to delayed wound healing, DFUs may lead to lower with DFU development (Crawford, Inkster, Kleijnen, & Fahey, 2007;
limb amputations, which deteriorate patients’ quality of life and Monteiro-Soares, Boyko, Ribeiro, Ribeiro, & Dinis-Ribeiro, 2012).
increase morbidity (Nabuurs-Franssen, Huijberts, Nieuwenhuijzen These include, but are not limited to: age, gender, duration of
Kruseman, Willems, & Schaper, 2005). DFUs often require prolonged diabetes, body mass index (BMI), co-morbidities including retinop-
athy and nephropathy, glycated hemoglobin level, macro-vascular
complications, foot deformity, edema, and foot self-care habits.
Conflict of interest: The authors declare that there are no known conflicts of interest. However, there is inconsistent evidence regarding the association
⁎ Corresponding author at: Department of Dermatology, National Center for Global
Health and Medicine, 1-21-1, Toyama, Shinjuku-ku, Tokyo 162-8655 Japan. Tel.: + 81
between these factors and DFUs (Monteiro-Soares et al., 2012). Some
3 3202 7181; fax: + 81 3 3207 1038. studies have demonstrated that younger patients were at higher risk
E-mail address: yotsurie@hotmail.com (R.R. Yotsu). for DFU development than older counterparts (Armstrong et al.,

http://dx.doi.org/10.1016/j.jdiacomp.2014.03.013
1056-8727/© 2014 Elsevier Inc. All rights reserved.

Please cite this article as: Yotsu, R.R., et al., Comparison of characteristics and healing course of diabetic foot ulcers by etiological
classification: Neuropathic, ischemic..., Journal of Diabetes and Its Complications (2014), http://dx.doi.org/10.1016/j.jdiacomp.2014.03.013
2 R.R. Yotsu et al. / Journal of Diabetes and Its Complications xxx (2014) xxx–xxx

2007), while other studies observed opposite results (Abbott et al., 2.3. Peripheral arterial disease
2002; Monami et al., 2009). Only a few studies have shown an
association between BMI and DFUs (Carrington et al., 2002; McNeely To assess the severity of PAD, we performed ankle–brachial index
et al., 1995; Tentolouris et al., 2009), or between hypertension and (ABI) (BP-203RPEIII, OMRON Corporation, Kyoto, Japan), skin perfu-
DFUs (Guerrero-Romero & Rodriguez-Moran, 1998; Margolis, Hof- sion pressure (SPP) (SensiLase™ PAD3000, Vasamed Inc., Minnesota,
stad, & Feldman, 2008). USA), and transcutaneous oxygen pressure (tcpO2) (TCM400, Radi-
To unfold the complexity of DFUs, they can be classified by their ometer Medical, Bronshoj, Denmark) on all patients. We obtained
underlying etiology — by the presence of peripheral neuropathy, and/ multiple measurements from two sites on each foot. The lowest values
or peripheral arterial disease (PAD), i.e., neuropathic, ischemic, and we obtained were recorded in the data set for these examinations. For
neuro-ischemic type (Caputo, Cavanagh, Ulbrecht, Gibbons, & patients whose measurements were difficult to obtain due to
Karchmer, 1994; Frykberg et al., 2000; McNeely et al., 1995). condition of the lesion(s), we took measurements from the opposite
Peripheral neuropathy is one form of micro-vascular complications foot. Patients who were suspected with PAD due to these measure-
of diabetes, together with nephropathy and retinopathy. On the other ments (either one of the three: ABI below 0.9 or above 1.4; SPP below
hand, PAD is one form of macro-vascular complications and is known 40 mmHg; tcpO2 below 40 mmHg Norgren et al., 2000) underwent
to be positively associated with age and other forms of macro-vascular enhanced computed tomography (CT) scan for diagnostic confirma-
complications, including hypertension and myocardial infarction tion (n = 37). For those who met the criteria but also had severe
(Savji et al., 2013). Therefore, there may be differences in patient nephropathy as a complication, we assessed measurements of ABI,
characteristics when DFUs are grouped using this etiological classi- SPP, and tcpO2 comprehensively for diagnosis of PAD (n = 8). We
fication. Previously, Zimny et al. categorized individuals with DFUs excluded ABI values above 1.4, with suspected mediasclerosis, from
into these three ulcer types, and observed discrepancies in diabetes our analyses (n = 2).
duration, peripheral circulation measurements, and ulcer size in
relation to healing (Zimny, Schatz, & Pfohl, 2002). Thus, it is important 2.4. Other clinical parameters
to compare these three ulcer types and understand the differences in
their characteristics and healing process. This may aid development of We measured basic demographic data for these patients, including
effective screening and management tools for DFUs. Notably, the age, sex, duration of diabetes, body mass index (BMI), family history
study by Zimny et al. was limited by its small sample size and of diabetes, marital status, mobility, previous periodical follow-up of
associated factors. Furthermore, to our knowledge no study has diabetes, smoking history, and alcohol intake, using an interview-
compared the healing time of these three ulcer types. administered questionnaire and electronic medical records. We
The aim of this study was to identify differences in characteristics recorded family history of diabetes (i.e., having a first-degree relative
of DFU patients according to etiological classification, namely (parent, sibling, or child) with diabetes) to determine whether there
neuropathic, ischemic, and neuro-ischemic ulcer type, and to compare are any possible hereditary or habitual associations to DFU
the DFU healing time. The findings of this study may serve as a guide development in patients with a positive family history (Potisat,
to clinical decision-making in both prevention and management Krairittichai, Jongsareejit, Sattaputh, & Arunratanachote, 2013;
of DFUs. Scollan-Koliopoulos, Walker, & Bleich, 2010). We defined smoking
as current smoking of at least one cigarette per week or past smoking
within three years prior to recruitment (Ghanassia et al., 2008).
2. Subjects and method
Alcohol intake was defined as drinking more than 23 g ethanol per
day within the last three years (Nakanishi, Suzuki, & Tatara, 2003). We
2.1. Patients
measured glycated hemoglobin (HbA1c), fasting glucose, total
cholesterol, LDL-cholesterol, HDL-cholesterol, triglyceride, hemoglobin,
Between October 2009 and March 2013, we prospectively
and serum albumin at recruitment. We calculated estimated glomerular
recruited a total of 84 type 2 diabetic patients with DFUs, aged
filtration rate (eGFR) with the formula: eGFR (ml/min/1.73 m 2) =
between 35 and 87 years (average age 65.2 ± 12.1 years), who were
194 × serum creatinine−0.094 × age−0.287 × 0.739 (if female) (Matsuo et
treated in a tertiary hospital in Japan. All patients received
al., 2009). Dyslipidemia, retinopathy (both non-proliferative and
standardized treatment. The end-points of follow-up were healing,
proliferative diabetic retinopathy), renal dialysis, hypertension, history
lower limb amputation, or death, or the end of the study period. We
of myocardial infarction, and history of amputation were recorded.
defined DFUs as ulcers located below the ankle that needed more than
14 days to heal, and we defined healing as complete epithelialization
2.5. Foot characteristics
without amputation and without recurrence for more than 6 months
(Apelqvist & Agardh, 1992). We excluded patients with secondary
We recorded diagnosis of plantar callus, tinea pedis, onychomy-
diabetes, autoimmune disease, or malignancies (n = 11), which left
cosis, edema, and deep fissure (defined as fissures that penetrate into
73 patients for our analyses. The study protocol was approved by the
the dermis). Foot deformity was noted when patients presented with
Ethical Committee of the National Center for Global Health and
claw toe, hammer toe, crowed toes, hallux valgus (bunion), digitus
Medicine, Japan.
quintus varus (bunionette), prominent metatarsal heads, high arch,
flat feet, and Charcot neuroarthropathy.
2.2. Peripheral neuropathy In addition, we characterized DFUs by the number of lesion(s)
(single or multiple), size, site, presence of gangrene, infection, and
We evaluated peripheral neuropathy using Semmes-Weinstein osteomyelitis. Size was measured by the longest diameter
5.07/10 g monofilament, 128-Hz tuning fork, Achilles tendon reflexes, multiplied by the intersecting diameter at 90° (cm 2). We defined
and coefficient of variation for the R–R intervals (CVRR). Sixty patients infection as the presence of warm skin, redness, swelling
underwent nerve conduction velocity (NCV) exams. The remaining 13 surrounding the wound, elevated values in white blood cells
patients were unable to undergo NCV exams due to pain and other (N8000/μL) and C-reactive protein (N0.3 mg/dL). We diagnosed
medical conditions. We recorded neuropathic symptoms such as pain, osteomyelitis with images of bone destruction from X-ray exam
paresthesia, tingling, discomfort, and numbness. Assessments of and/or decreased signal on T1 weighted images and increased
peripheral neuropathy were performed based on these findings, as signal on T2 weighted images of MRI. When both exam results
previously described (Tesfaye et al., 2010). were negative or not available but the ulcer depth reached the

Please cite this article as: Yotsu, R.R., et al., Comparison of characteristics and healing course of diabetic foot ulcers by etiological
classification: Neuropathic, ischemic..., Journal of Diabetes and Its Complications (2014), http://dx.doi.org/10.1016/j.jdiacomp.2014.03.013
R.R. Yotsu et al. / Journal of Diabetes and Its Complications xxx (2014) xxx–xxx 3

Table 1
Characteristics of patients with diabetic foot ulcers according to etiological classification.⁎

Variables Neuropathic (n = 39) Ischemic (n = 20) Neuro-ischemic (n = 14) p value†

Demographic factors
Age (years) 58.7 ± 10.1 75.6 ± 7.2 (1c)† 68.3 ± 11.7(3b)† b0.001
Male 30 (76.9) 16 (80.0) 11 (78.6) 0.999
Duration of diabetes (years) 15.6 ± 11.8 24.2 ± 14.1(1b)† 18.2 ± 7.2 0.039
BMI (kg/m2) 24.9 ± 5.3 20.3 ± 2.8(1b)† 22.5 ± 3.3 0.001
Family history of diabetes 23 (59.0) 12 (60.0) 8 (57.1) 0.986
Unmarried or living alone 23 (59.0) 4 (20.0) 6 (42.9) 0.016
Poor mobility 9 (23.1) 17 (85.0) 8 (57.1) b0.001
No follow-up of diabetes 15 (38.5) 7 (35.0) 6 (42.9) 0.898
Smoking 25 (64.1) 15 (75.0) 11 (78.6) 0.617
Alcohol 10 (25.6) 6 (30.0) 5 (35.7) 0.767
Diabetes-related factors
DM oral medication 20 (51.3) 6 (42.9) 11 (55.0) 0.780
Insulin 22 (56.4) 9 (45.0) 10 (71.4) 0.322
HbA1c (%) 7.53 ± 2.25 6.95 ± 1.36 7.42 ± 1.27 0.527
Fasting glucose (mg/dL) 168.2 ± 79.1 148.0 ± 59.3 201.7 ± 79.5 0.123
Dyslipidemia 17 (43.6) 11 (55.0) 7 (50.0) 0.698
Triglyceride (mg/dL) 116.5 ± 47.0 150.7 ± 83.0 142.4 ± 71.8 0.118
Total cholesterol (mg/dL) 164.7 ± 29.7 183.3 ± 37.4 186.2 ± 34.3 0.042
LDL cholesterol (mg/dL) 94.7 ± 27.4 103.7 ± 28.5 103.7 ± 23.9 0.374
HDL cholesterol (mg/dL) 45.8 ± 15.3 46.6 ± 16.0 49.2 ± 16.4 0.783
Comorbidities
Achilles tendon 30 (77.0) 13 (65.0) 14 (100.0) 0.038
Monofilament 21 (53.9) 5 (25.0) 10 (71.4) 0.020
Vibration 29 (74.4) 10 (50.0) 11 (78.6) 0.122
Neuropathic symptoms 27 (69.2) 6 (30.0) 13 (92.9) b0.001
Retinopathy 29 (74.4) 12 (60.0) 12 (85.7) 0.260
Renal dialysis 4 (10.3) 4 (20.0) 4 (28.6) 0.248
ABI 1.15 ± 0.12 0.67 ± 0.14 (1c)† 0.81 ± 0.1 (2c, 3a)† b0.001
SPP (mmHg) 65.0 ± 13.6 27.0 ± 14.1 (1c)† 34.6 ± 23.2 (2c)† b0.001
tcpO2 (mmHg) 48.0 ± 11.6 27.9 ± 18.3(1c)† 34.6 ± 15.4 (2a)† b0.001
Hypertension 25 (64.1) 19 (95.0) 14 (100.0) 0.002
History of myocardial infarction 8 (20.5) 8 (40.0) 3 (21.4) 0.266
Hemoglobin (g/dL) 12.0 ± 1.8 11.2 ± 1.7 11.6 ± 2.0 0.308
Serum albumin (g/dL) 3.70 ± 0.67 3.41 ± 0.54 3.45 ± 0.81 0.220
eGFR (mL/min/1.73 m2) 62.8 ± 34.5 40.5 ± 27.0 (1a)† 46.1 ± 30.7 0.030
Diabetic foot problems
Callus 15 (38.5) 5 (25.0) 8 (57.1) 0.165
Tinea pedis 24 (61.5) 8 (40.0) 9 (64.3) 0.228
Onychomycosis 21 (53.9) 7 (35.0) 10 (71.4) 0.121
Foot deformity 17 (43.6) 3 (15.0) 5 (35.7) 0.086
Edema 8 (20.5) 7 (35.0) 6 (42.9) 0.220
Deep fissure 8 (20.5) 5 (25.0) 1 (7.1) 0.447
History of ulcer 28 (71.8) 15 (75.0) 11 (78.6) 0.938
History of amputation 5 (12.8) 4 (20.0) 1 (7.1) 0.599
Local wound factors
Multiple ulcers 4 (10.3) 10 (50.0) 6 (42.9) 0.001
Gangrene 7 (18.0) 8 (40.0) 6 (42.9) 0.090
Infection 19 (48.7) 9 (45.0) 9 (64.3) 0.508
Osteomyelitis 4 (10.3) 8 (40.0) 4 (28.6) 0.025
Size N1 cm2 23 (59.0) 11 (55.0) 9 (64.3) 0.864
Size N5 cm2 12 (30.8) 7 (35.0) 6 (42.9) 0.713
Wagner Grade N = 3 11 (28.2) 9 (45.9) 9 (64.3) 0.052
External precipitating factor 32 (82.1) 4 (20.0) 7 (50.0) b0.001
Pain 4 (10.3) 17 (85.0) 6 (42.9) b0.001

Abbreviation: BMI, body mass index; HbA1c, glycated hemoglobin; ABI, ankle brachial index; SPP, skin perfusion pressure; tcpO2, transcutaneous oxygen pressure; eGFR, estimated
glomerular filtration rate.
Data are shown as mean ± SD and n (%) for continuous and categorical variables, respectively.
⁎ Based on t-test or ANOVA for continuous variables, or χ2 test and Fisher’s exact test for categorical variables.

Notes in parenthesis and p-values are from the Bonferroni’s multiple comparisons: 1, between neuropathic and ischemic; 2, between neuropathic and neuro-ischemic;
3, between ischemic and neuro-ischemic; a, p b 0.05, b, p b 0.01, c, p b 0.001.

bone, we regarded the patient as having osteomyelitis. We graded neuropathy and PAD. We used either χ 2 test or Fisher’s exact
each DFU according to the Wagner classification, as described test for categorical variables, and used a t-test or ANOVA for
previously (Wagner, 1979). continuous variables. Post hoc analysis with Bonferroni’s adjust-
ment was performed to compare mean values between the three
2.6. Statistical analysis DFU groups. We analyzed outcomes of the lesions using χ 2 test or
Fisher’s exact test. Analysis for time needed for healing was
We categorized patients into the neuropathic, ischemic, or performed using the Kaplan–Meier method. We compared
neuro-ischemic group based on the diagnosis of peripheral healing time of the three DFU types using the log rank test. We

Please cite this article as: Yotsu, R.R., et al., Comparison of characteristics and healing course of diabetic foot ulcers by etiological
classification: Neuropathic, ischemic..., Journal of Diabetes and Its Complications (2014), http://dx.doi.org/10.1016/j.jdiacomp.2014.03.013
4 R.R. Yotsu et al. / Journal of Diabetes and Its Complications xxx (2014) xxx–xxx

1-Toe *
N: 18 (46%)
I: 15 (75%)
NI: 11 (79%) 1 6-Dorsal
N: 4 (10%)
2-Metatarsal head I: 1 (5%)
N: 6 (15%)
NI: 7 (7%)
I: 1 (5%) 7 7
NI: 2 (14%)
3 2 3 7-Malleolus
3-Lateral N: 1 (3%)
N: 6 (15%) I: 2 (10%)
I: 3 (15%) NI: 1 (7%)
4
NI: 1 (7%)

4-Plantar medial 8-Achilles tendon


6
N: 2 (5%) N: 2 (5%)
I: 0 (0%) I: 0 (0%)
5
NI: 0 (0%) NI: 0 (0%)

5-Heel
N: 5 (13%)
8
I: 3 (15%)
High-pressure
NI: 2 (14%) areas
Weight movement
*p<0.01 on walking

Fig. 1. Sites of ulcers and high-pressure areas.

considered two-sided p-values b 0.05 as statistically significant. in the neuropathic and neuro-ischemic groups than in the ischemic
All analyses were performed using Stata version 12.1 (Statacorp, group. Over 70% of patients had a history of ulcers in all three groups.
College Station, TX, USA). With regards to local wound characteristics, multiple ulcers
occurred more often in the ischemic and neuro-ishemic groups
compared to the neuropathic group, as did pain (Table 1). Gangrene
3. Results appeared more prevalent in the ischemic and neuro-ischemic ulcers
than in the neuropathic ulcer. An external precipitating factor was
In this study, there were 39 patients (30 males, 9 females) with most common in the neuropathic group (82.1%). Infection was noted
neuropathic ulcers, 20 patients (16 males, 4 females) with ischemic ulcers, across all three groups. More patients progressed to osteomyelitis in
and 14 patients (11 males, 3 females) with neuro-ischemic ulcers. the ischemic group (40.0%) than the other two groups. There was no
Table 1 summarizes the characteristics of patients with DFUs difference in ulcer size between the three groups. When the Wagner
according to ulcer types. Regarding mean patient age, patients with classification was applied, the number of patients graded as level 3 or
neuropathic ulcers were the youngest, with 10 years’ age difference higher was greater in the neuro-ischemic group (64.3%) than in the
between neuropathic and neuro-ischemic groups, and 20 years’ remaining two groups.
difference between neuropathic and ischemic groups. Patients with Eight ulcer sites were specified from the descriptive data on sites
ischemic ulcers had diabetes for the longest duration, had the lowest (Fig. 1), and one patient in the ischemic group suffered from total foot
BMI values, and the highest tendency to be of poor mobility. involvement. A figure by Morton (Morton, 1935) is included in Fig. 1 and
Neuropathic symptoms were most frequent in patients with neuro- details the high pressure areas and weight distribution placed on the
ischemic ulcers. The measurements to determine the severity of PAD, foot during a single step. We observed that 84.1% of patients with
i.e. ABI, SPP, and tcpO2, decreased in the order of neuropathic, neuro- neuropathic ulcers developed ulcers in the high-pressure areas (toe,
ischemic, and ischemic. Hypertension was more common in the metatarsal head, plantar medial, and heel). The dorsal, malleolus, and
ischemic and neuro-ischemic groups than in the neuropathic group. Achilles tendon were other sites for wound formation in neuropathic
Retinopathy complications were high in all three groups. Lower eGFR ulcers, and all patients with ulcers in these areas had a history of external
values were observed among patients in the ischemic and neuro- precipitating factors (e.g., two patients with ulcers in their Achilles
ischemic groups compared to the neuropathic group. Plantar callus, tendon complained of ill-fitting shoes). Over 70% of patients in both the
tinea pedis, onychomycosis, and foot deformity were more prevalent ischemic and neuro-ischemic groups had wounds in their toes.
In our study cohort, healing occurred in 34 patients (87.2%) with
Table 2
neuropathic ulcers, 9 patients (45.0%) with ischemic ulcers and 9
Outcomes of diabetic foot ulcers by etiological ulcer type. patients (64.3%) with neuro-ischemic ulcers (Table 2). Fig. 2 presents
the time (in days) until patients achieved healing according to ulcer
Outcome Neuropathic Ischemic Neuro-ischemic p value⁎
types. The average time in which 50% of patients had healed wounds
(n = 39) (n = 20) (n = 14)
was 70, 113, and 233 days for neuropathic, neuro-ischemic, and
Healed 34 (87.2) 9 (45.0) 9 (64.3) 0.003
ischemic ulcers, respectively. Cumulative healing rates within
Amputation at any level 2 (5.1) 4 (20.0) 2 (14.3) 0.204
Death 0 (0.0) 3 (15.0) 1 (7.1) 0.421 1 month were 32% (95% CI: 19%–49%) for neuropathic ulcers, 0% for
Non-healed 2 (5.1) 4 (20.0) 1 (7.1) 0.172 neuro-ischemic ulcers, and 11% (95% CI: 2.7%–36%) for ischemic ulcers;
Lost for follow-up 1 (2.6) 0 (0.0) 1 (7.1) 0.421 and those within 3 months were 58% (95% CI: 43%–74%), 42% (95% CI:
Data are shown in n (%). 20%–73%), and 16% (95% CI: 5.6%–43%), respectively. 11% (8/73) of
⁎ Obtained from χ2 test or Fisher’s exact test. patients underwent lower limb amputation, of which four resulted from

Please cite this article as: Yotsu, R.R., et al., Comparison of characteristics and healing course of diabetic foot ulcers by etiological
classification: Neuropathic, ischemic..., Journal of Diabetes and Its Complications (2014), http://dx.doi.org/10.1016/j.jdiacomp.2014.03.013
R.R. Yotsu et al. / Journal of Diabetes and Its Complications xxx (2014) xxx–xxx 5

Table 3
Comparison of patient and wound characteristics with healed and non-healed diabetic
foot ulcers by etiological ulcer type.

bNeuropathicN

Healed (n = 34) Non-healed (n = 5) p value⁎

Age (years) 58.6 ± 10.4 59.8 ± 8.7 0.785


Male 25 (73.5) 5 (100.0) 0.318
No follow-up of diabetes 12 (35.3) 3 (60.0) 0.354
Retinopathy 24 (70.6) 5 (100.0) 0.302
Renal dialysis 4 (11.8) 0 (0.0) 0.999
ABI 1.2 (1.1; 1.3) 1.1 (1.1; 1.1) 0.966
SPP (mmHg) 67 (57; 75) 65 (40; 69) 0.192
tcpO2 (mmHg) 48 (40; 56) 44 (43; 50) 0.866
Hemoglobin (g/dL) 12.1 ± 1.9 11.4 ± 1.1 0.264
Serum albumin (g/dL) 3.8 (3.4; 4.2) 3.7 (3.0; 4.1) 0.643
eGFR (mL/min/1.73 m2) 68 (33; 88) 56 (50; 78) 0.950
Multiple 4 (11.8) 0 (0.0) 0.999
Gangrene 6 (17.7) 1 (20.0) 0.999
Infection 15 (44.1) 4 (80.0) 0.182
Osteomyelitis 1 (2.9) 3 (60.0) 0.004
Fig. 2. Healing time of diabetic foot ulcers by etiological ulcer type (Kaplan-Meier Site - plantar 21 (61.8) 4 (80.0) 0.636
healing estimates). Size N5 cm2 8 (23.5) 4 (80.0) 0.025
Size N1 cm2 19 (55.9) 4 (80.0) 0.631
Wagner N = Grade 3 7 (20.6) 4 (80.0) 0.017
ischemic ulcers and two arose from each of neuropathic and neuro-
ischemic ulcers. Four patients, three from ischemic and one from neuro- bIschemicN
ischemic groups, died during the follow-up due to acute myocardial Healed (n = 9) Non-healed (n = 11) p value⁎
infarction, chronic renal failure, brain hemorrhage, or septic shock. Age (years) 77.3 ± 7.9 74.2 ± 6.5 0.352
Table 3 shows the patient and wound characteristics of healed and Male 8 (89.9) 8 (72.7) 0.591
non-healed ulcers according to ulcer type. No differences were No follow-up of diabetes 1 (11.1) 6 (54.6) 0.070
observed regarding age for the neuropathic and ischemic groups, Retinopathy 3 (33.3) 9 (81.8) 0.065
Renal dialysis 0 (0.0) 4 (36.4) 0.094
but younger patients in the neuro-ischemic group tended to have
ABI 0.6 (0.5; 0.8) 0.7 (0.6; 0.9) 0.270
better and faster healing. Diabetes without previous follow-up and SPP (mmHg) 37 (17; 43) 20 (15; 37) 0.341
lower values in hemoglobin, serum albumin, and eGFR were common tcpO2 (mmHg) 38 (12; 40) 30 (3; 45) 0.676
high risk characteristics among all three groups for non-healing. eGFR Hemoglobin (g/dL) 11.7 ± 2.0 10.8 ± 1.3 0.267
Serum albumin (g/dL) 3.6 (3.3; 4.1) 3.3 (2.8; 3.4) 0.039
values were considerably lower in the ischemic group with non-
eGFR (mL/min/1.73 m2) 51 (27; 64) 17 (12; 56) 0.102
healed ulcers. SPP values were lower in the non-healed group Multiple 2 (22.2) 8 (72.7) 0.070
compared to the healed group in ischemic and neuro-ischemic Gangrene 2 (22.2) 6 (54.6) 0.197
groups. In the same two groups, wounds remained unhealed in over Infection 3 (33.3) 6 (54.6) 0.406
50% of patients with multiple ulcers. Infection, osteomyelitis, larger Osteomyelitis 1 (11.1) 7 (63.6) 0.028
Site - plantar 6 (66.7) 9 (81.8) 0.617
ulcer size, and plantar ulcers were common features among all three
Size N5 cm2 0 (0.0) 7 (63.6) 0.005
groups with non-healed ulcers. Size N1 cm2 1 (11.1) 10 (90.9) 0.001
Wagner N = Grade 3 2 (22.2) 7 (63.6) 0.092
4. Discussion
bNeuro-ischemicN

This clinical study identified some differences in factors potentially Healed (n = 9) Non-healed (n = 5) p value⁎
associated with foot ulceration among three types of DFUs classified by Age (years) 66.2 ± 11.7 72.0 ± 11.8 0.400
their etiology (neuropathic, ischemic, and neuro-ischemic type). There Male 8 (88.9) 3 (60.0) 0.505
was significant variation between the three groups regarding patient No follow-up of diabetes 3 (33.3) 3 (60.0) 0.580
Retinopathy 8 (88.9) 4 (80.0) 0.999
age, duration of diabetes, BMI, and hypertension. Notably, previous
Renal dialysis 2 (22.2) 2 (40.0) 0.580
studies have neglected to classify DFUs into the etiological ulcer types ABI 0.8 (0.6; 1.0) 1.0 (0.7; 1.0) 0.546
when investigating these factors, which may have precluded the SPP (mmHg) 38 (22; 51) 17 (16; 32) 0.141
understanding of their associations. Considering peripheral circulation, tcpO2 (mmHg) 38 (31; 49) 39 (27; 41) 0.738
patients with both peripheral neuropathy and PAD were at higher risk of Hemoglobin (g/dL) 12.2 ± 1.9 10.7 ± 2.2 0.221
Serum albumin (g/dL) 3.6 (3.5; 4.0) 3.3 (2.9; 3.4) 0.082
developing ulcers than those with PAD alone, as they had more
eGFR (mL/min/1.73 m2) 55 (33; 62.7) 31 (18; 80) 0.739
favorable ABI, SPP, and tcpO2 measurements. However, patients with Multiple 3 (33.3) 3 (60.0) 0.580
neuro-ischemic ulcers had a better and faster healing compared to those Gangrene 1 (11.1) 5 (100.0) 0.003
with ischemic ulcers. Patient age and severity of ischemia, but not Infection 5 (55.6) 4 (80.0) 0.580
Osteomyelitis 1 (11.1) 3 (60.0) 0.095
peripheral neuropathy, were critical factors for delay in wound healing.
Site – plantar 7 (77.8) 5 (100.0) 0.505
In all three study groups, diabetes without previous follow-up, lower Size N 5 cm2 3 (33.3) 6 (60.0) 0.580
values in hemoglobin/serum albumin/eGFR, infection, osteomyelitis, Size N1 cm2 4 (44.4) 5 (100.0) 0.086
larger ulcer size, and plantar ulcer were common factors for non- Wagner N = Grade 3 4 (44.4) 5 (100.0) 0.086
healing. In addition to these findings, we also described the different Abbreviation: DFU, diabetic foot ulcer; ABI, ankle brachial index; SPP, skin perfusion pressure;
local wound characteristics of the three ulcer types. Recently, attempts tcpO2, transcutaneous oxygen pressure; eGFR, estimated glomerular filtration rate.
have been made to develop an effective system for both prevention and †Based on Student t test for continuous variables, Wilcoxon rank-sum test for
continuous variables with skew distribution, or χ2 test and Fisher’s exact test for
management of DFUs (Armstrong, Lavery, Vela, Quebedeaux, & Fleischli,
categorical variables.
1998; Boyko, Ahroni, Cohen, Nelson, & Heagerty, 2006; Lavery, ⁎ Data are shown as mean ± S.D., median (25% and 75% percentiles), and n (%) for
Armstrong, Vela, Quebedeaux, & Fleischli, 1998; McGill, Molyneaux, & continuous variables, continuous variables with skew distribution, and categorical
Yue, 2005), and our findings may contribute to this process. variables, respectively.

Please cite this article as: Yotsu, R.R., et al., Comparison of characteristics and healing course of diabetic foot ulcers by etiological
classification: Neuropathic, ischemic..., Journal of Diabetes and Its Complications (2014), http://dx.doi.org/10.1016/j.jdiacomp.2014.03.013
6 R.R. Yotsu et al. / Journal of Diabetes and Its Complications xxx (2014) xxx–xxx

Currently, there are several DFU classification systems, including factors including ill-fitting shoes/socks, acute mechanical trauma,
the Wagner classification (Wagner, 1979), the University of Texas stress ulcer, and paronychia (Apelqvist, Larsson, & Agardh, 1990).
classification (Lavery, Armstrong, & Harkless, 1996), and the size Similarly, 82% of patients in our study claimed of having some kind of
(area, depth), sepsis, arteriopathy denervation (S(AD)SAD) systems external precipitating factors in occurrence of their neuropathic
(Jeffcoate, Chipchase, Ince, & Game, 2006). These grading systems ulcers. This presumably accounted for their variety in ulcer sites. On
measure wound severity and are useful in outcome prediction the other hand, over 70% of our patients with ischemic and neuro-
(Apelqvist, Castenfors, Larsson, Stenstrom, & Agardh, 1989; Gul, ischemic ulcers were affected in their toes, where the blood supply is
Basit, Ali, Ahmadani, & Miyan, 2006). However, they focus predom- anatomically limited. Multiple ulcers and gangrene were other
inantly on local wound characteristics, and do not reflect much of the common features of ischemic and neuro-ischemic ulcers in our
DFU etiology. Therefore, they are unsuitable for predicting what kind study. However, it is important to note that neuro-ischemic ulcers
of ulcer a patient may develop or for the management of DFUs. The were also associated with the same characteristics as neuropathic
etiological classification system has been neglected as a DFU ulcers. More patients with neuro-ischemic ulcers gave some kind of
classification system in research studies although it is regularly used external precipitating factors as triggers for their ulcers and were
in clinical practice (Caputo et al., 1994; Frykberg et al., 2000; McNeely without pain compared to those with ischemic ulcers. It is possible
et al., 1995). To predict and manage DFUs, it is essential to assess the that the combined data of site, number of ulcers, gangrene, pain, and
presence and severity of peripheral neuropathy and PAD, by which external precipitating factors may provide clinicians with guidance on
attempts can be made to overcome the limitations of other systems. predicting the origin of the ulcer (i.e., neuropathic, ischemic, or both)
In our study using the etiological classification system, patients during an initial visit without undertaking multiple examinations.
with peripheral neuropathy alone tended to develop DFUs at a In this study, we also compared the healing time of three ulcer
younger age, while the risk of DFUs for those with PAD increased as types, which was the first attempt of its kind with this number of
the severity of PAD increased with age. PAD is known to become more patients. As a result, we found that neuropathic ulcers were most
prevalent, and more severe, as diabetes progresses (Savji et al., 2013), likely to heal if proper management was provided. On the other hand,
and this can be an explanation for this age difference. The same trend ischemic ulcers had the worst healing rate and needed the longest
was observed by (Zimny et al., 2002). Lower BMI is known to co-exist time to heal during follow-up. This was contradictory to our
with PAD (Criqui et al., 2005; Tseng, 2003), but the relationship hypothesis that the neuro-ischemic ulcers would be more inclined
between PAD and BMI is still unclear due to possible confounding to poor healing compared to the other two types, having complica-
factors (Ix et al., 2011). Hypertension is a type of macro-vascular tions of peripheral neuropathy and PAD. In addition to having both of
disease along with PAD, and therefore, showed higher prevalence in these complications, neuro-ischemic ulcers were initially more
patients with ischemic and neuro-ischemic ulcers. Our findings severe, with 64% of them being equal to or above Wagner grade 3
indicate the importance of considering the underlying DFU etiology (Wagner, 1979). This raised the question of why they were able to
when investigating high-risk patients for DFU development for obtain better outcome and faster healing than ischemic ulcers.
certain factors. Given the low statistical power of our study, we were unable to
Furthermore, we found significant differences in peripheral perform multivariate analysis. However, our univariate analysis
circulation measurements between the three ulcer types. Most showed that patients in the neuro-ischemic group with healed ulcers
importantly, we found that the measurements for SPP and tcpO2 were younger than those with unhealed ulcers or those from the
were less severe in the neuro-ischemic group compared to the ischemic group. Previous studies have suggested age as an important
ischemic group. Critical wound healing delay described previously for predictor of wound healing (Prompers et al., 2008). We also found
SPP and tcpO2 is when either is below 30 mmHg (Castronuovo, Adera, that mean measurements for SPP in patients with non-healed ulcers
Smiell, & Price, 1997; Norgren et al., 2000). However, the average in both the ischemic and neuro-ischemic group were notably low,
values of both two exams for our patients in the neuro-ischemic group falling in the range for non-healing status given by previous studies
were above these values. Patients assessed by Zimny et al. also had (Castronuovo et al., 1997; Kalani, Brismar, Fagrell, Ostergren, &
similar values for tcpO2, with an even wider gap than in our study, and Jorneskog, 1999; Tsai et al., 2000). This finding indicated that although
the tcpO2 measurements for neuro-ischemic and ischemic were patients with both peripheral neuropathy and PAD had the tendency
54.0 ± 3.8 mmHg and 21.8 ± 2.3 mmHg, respectively (Zimny et al., to develop ulcers at their earlier stages of the disease (neuro-ischemic
2002). These two studies suggest a need to set a higher threshold for ulcers), they would heal if their PAD status was less severe. On the
SPP and tcpO2 in screening high-risk patients for DFU development in contrary, if their PAD status was as severe as the patients in the
case of complication with peripheral neuropathy. ischemic group, they did not heal.
Retinopathy, reduction in eGFR, and history of ulcer were common Previous studies have found wound factors including plantar ulcer,
factors associated with ulceration among the three ulcer types in our larger ulcer size, infection, osteomyelitis, and higher Wagner grading
study. Prior studies have also observed a positive association between to be independent factors for non-healing of ulcers (Mutluoglu et al.,
the aforementioned factors and DFUs (Abbott et al., 2002; Boyko et al., 2013; Oyibo et al., 2001; Pickwell, Siersma, Kars, Holstein, & Schaper,
2006; Carrington et al., 2002; Margolis et al., 2008; McGill et al., 2005; 2013). The results from our patients with non-healing ulcers were
Monami et al., 2009; Monteiro-Soares & Dinis-Ribeiro, 2010). These consistent with these findings, irrespective of ulcer type. In addition,
factors are objective and relatively easy to obtain, and therefore, ideal lower values in hemoglobin, serum albumin, and eGFR were also
for screening purposes. Hurley et al. examined whether eGFR alone common factors among our patients with non-healing ulcers in the
could be an indicator for screening of high-risk patients for DFUs, but three ulcer groups, which were in line with previous findings for
found no association between the two (Hurley et al., 2013). indication of non-healing (Li et al., 2011; Prompers, Schaper et al.,
Nevertheless, combining several factors may help to increase accuracy 2008; Sun et al., 2012). As these factors did not relate to the etiological
of prediction. For instance, Baber et al. reported that a combination of background, they are potentially good candidates for predictors of
eGFR and microalbuminuria showed a high predictability of PAD healing across all the three ulcer groups.
(Baber et al., 2009). In addition, we found that not previously having follow-up for
We noted eight sites in the foot that were prone to ulceration. We diabetes even before ulcer onset was a common high-risk factor for
found that neuropathic ulcers could be formed in any of these sites, non-healing. This finding presents the importance of preventative
with the plantar surface of the foot in weight-bearing areas being the interventions for diabetic patients. Preventative interventions are not
most prevalent. Apelqvist et al. reported that 84% of patients (n = only important for avoiding DFUs in diabetic patients, but also for
314) with neuropathic ulcers were affected by external precipitating other complications including cardiac autonomic neuropathy

Please cite this article as: Yotsu, R.R., et al., Comparison of characteristics and healing course of diabetic foot ulcers by etiological
classification: Neuropathic, ischemic..., Journal of Diabetes and Its Complications (2014), http://dx.doi.org/10.1016/j.jdiacomp.2014.03.013
R.R. Yotsu et al. / Journal of Diabetes and Its Complications xxx (2014) xxx–xxx 7

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Please cite this article as: Yotsu, R.R., et al., Comparison of characteristics and healing course of diabetic foot ulcers by etiological
classification: Neuropathic, ischemic..., Journal of Diabetes and Its Complications (2014), http://dx.doi.org/10.1016/j.jdiacomp.2014.03.013