- Email: [email protected]
Incidence and Risk Factors Associated With Ulcer Recurrence Among Patients With Diabetic Foot Ulcers Treated in a Multidisciplinary Setting
j o u r n a l o f s u r g i c a l r e s e a r c h f e b r u a r y 2 0 2 0 ( 2 4 6 ) 2 4 3 e2 5 0
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Incidence and Risk Factors Associated With Ulcer Recurrence Among Patients With Diabetic Foot Ulcers Treated in a Multidisciplinary Setting Caitlin W. Hicks, MD, MS,a,b Joseph K. Canner, MHS,c Nestoras Mathioudakis, MD, MHS,a,d Christopher Lippincott, MD,a,e Ronald L. Sherman, DPM,a,b and Christopher J. Abularrage, MDa,b,* a
Diabetic Foot and Wound Service, The Johns Hopkins Hospital, Baltimore, Maryland Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, The Johns Hopkins Hospital, Baltimore, Maryland c Department of Surgery, Center for Surgical Trials and Outcomes Research, The Johns Hopkins Hospital, Baltimore, Maryland d Division of Endocrinology and Metabolism, Department of Medicine, The Johns Hopkins Hospital, Baltimore, Maryland e Division of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, Maryland b
article info
abstract
Article history:
Background: Recent studies demonstrate favorable diabetic foot ulcer (DFU) healing out-
Received 3 May 2019
comes with the implementation of a multidisciplinary team. We aimed to describe the
Received in revised form
incidence of and risk factors associated with ulcer recurrence after initial complete healing
24 July 2019
among a cohort of patients with DFU treated in a multidisciplinary setting.
Accepted 13 September 2019
Methods: All patients presenting to our multidisciplinary diabetic limb preservation service
Available online xxx
from 6/2012-04/2018 were enrolled in a prospective database. The incidence of ulcer recurrence after complete wound healing was assessed per limb using the Kaplan-Meier
Keywords:
method, and a stepwise multivariable Cox proportional hazards model was created to
Diabetic foot ulcer
identify independent predictors of ulcer recurrence.
Diabetic foot wound
Results: A total of 244 patients with 304 affected limbs were included. Ulcer recurrence rates
Ulcer recurrence
at one and 3 y after healing were 30.6 3.0% and 64.4 5.2%, respectively. Recurrent ulcers
Wound healing
were smaller (4.4 1.1 cm2 versus 8.2 1.2 cm2; P ¼ 0.04) and had a lower Wound, Ischemia,
Multidisciplinary team
and foot Infection stage (stage 4: 7.7% versus 22.4%; P < 0.001) than initial ulcers, and wound healing time was significantly reduced (95.0 9.8 versus 131.8 7.0 d; P ¼ 0.004). Independent predictors of ulcer recurrence included abnormal proprioception (HR, 1.57 [95% CI 1.02-4.43]) and younger age (HR 1.02 per year [95% CI 1.01-1.04]). Conclusions: In this prospective cohort of patients with DFU, time to diagnosis and healing was significantly lower for recurrent ulcers, and downstaging was common. These data suggest that engaging patients with DFU in a multidisciplinary care model with frequent follow-up and focused patient education may serve to decrease DFU morbidity. ª 2019 Elsevier Inc. All rights reserved.
* Corresponding author. 600 North Wolfe Street, Halsted 671, Baltimore, MD 21287. Tel.: þ(410) 955 5165; fax: þ(410)-614-2079. E-mail address: [email protected] (C.J. Abularrage). 0022-4804/$ e see front matter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jss.2019.09.025
244
j o u r n a l o f s u r g i c a l r e s e a r c h f e b r u a r y 2 0 2 0 ( 2 4 6 ) 2 4 3 e2 5 0
Introduction
Wound definitions
Diabetic foot ulcers (DFUs) are a significant cause of morbidity and mortality among adults with diabetes. In the United States alone, it is estimated that between 1 million and 3.5 million adults have a history of DFU.1 Approximately 25% of adults with diabetes will be affected by a DFU during their lifetime,2 of which 20% will require either minor or major amputation to achieve healing.3,4 Among patients with DFU who ultimately achieve wound healing, ulcer recurrence occurs in as many as 40% by 1 y.1 Adults with a DFU also have a 2.5 times increased risk of death at 5 y compared to adults with diabetes but no DFU,5 and the 5-year mortality for a DFUrelated amputation is more than 70%.6 Given the prevalence and morbidity of DFU, the health care burden associated with the disease is substantial. The risk of emergency department visits and hospital admissions related to DFU is higher than that of congestive heart failure, renal disease, and most cancers.7 The estimate inpatient costs for DFU care in the United States are $1.38 billion per year8 and are increasing significantly with time.9 Most of these costs are related to the treatment of infected foot ulcers, which highlights the need for early diagnosis and treatment strategies in the outpatient setting as a means to preventing further increases in what is already a substantial economic burden.8 The development of multidisciplinary limb preservation teams for the treatment and prevention of DFU is one strategy that has been described as a means of improving care and containing health care costs in the long term.10 Recent studies demonstrate favorable DFU healing outcomes with implementation of a multidisciplinary team approach compared with traditional treatment strategies.11-14 However, the long-term outcomes of this approach to DFU care are unknown. Specifically, it is unclear whether use of a multidisciplinary team can achieve favorable ulcer recurrence rates compared with those previously reported in the literature.1 We aimed to describe the incidence of and risk factors associated with ulcer recurrence after initial complete healing among a cohort of patients with DFU treated in a multidisciplinary setting.
On initial presentation, all wounds were graded according to the Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification system15 based on provider consensus. Patients with WIfI stage 5 wounds were excluded from the analysis as affected limbs are considered unsalvageable.15 Patients who underwent major amputation for their initial wound were also excluded because they could not contract a recurrent ulcer on an amputated limb. Wound healing was defined as complete epithelialization with the restoration of sustained functional and anatomic continuity for 6 wk after complete healing.16,17 Recurrent ulcers were defined as ulcers that formed on the same foot after complete wound healing was achieved.
Methods Study cohort All patients presenting to our multidisciplinary diabetic limb preservation service between June 1, 2012 and April 30, 2018 were enrolled in a prospective database. Patients are referred via both inpatient consult and outpatient referral to our service. Because we are responsible for the assessment and management of all DFU in our hospital system, the scope of our practice includes a wide range of minor to extensive wounds. The Johns Hopkins Institutional Review Board approved the study, and all patients signed informed consent, allowing for the longitudinal collection of their sociodemographic, comorbidity, and surgical intervention data.
Multidisciplinary limb preservation service Our multidisciplinary limb preservation service has been previously described in detail.18 Briefly, our team consists of vascular surgeons, surgical podiatrists, endocrinologists, wound care nurse, physician assistant, and prosthetist. All patients are assessed by all members of the team at each visit in an integrated fashion. Consultation from infectious disease, plastic surgery, and orthopedic foot and ankle physicians is obtained on a case-by-case basis as needed. All patients are followed up closely on an outpatient basis to assess wound healing, medication compliance, and glycemic control. On initial presentation, all patients undergo noninvasive vascular lab testing to assess perfusion. Patients with evidence of chronic limb-threatening ischemia are scheduled for an angiogram with endovascular revascularization whenever possible. In patients with atherosclerotic disease that is not amenable to endovascular intervention, open bypass is performed. All wounds are assessed via X-ray imaging, followed by magnetic resonance imaging when indicated. After lower extremity revascularization, any radiographic evidence of osteomyelitis is surgically excised, and wounds are debrided to clear margins. All patients are treated with culture-targeted antibiotics after debridement; wounds limited to the toes are treated with 2 wk of oral antibiotics, whereas wounds involving the metatarsophalangeal joint or more proximally are typically treated with 6 wk of intravenous antibiotics with Infectious Diseases guidance. After revascularization and debridement, all wounds are offloaded to maximize wound healing. Patients are educated on foot care, lifestyle habits, and medication compliance to ensure close adherence to our treatment paradigm. Specifically, patients are given educational handout outlining how to care for their diabetes, how to check and wash their feet, how to trim their toenails, and how to protect their feet with appropriate footwear. During healing, patients are followed up on a biweekly basis. Once complete wound healing is achieved, patients continue to follow up on an outpatient basis for regular noninvasive testing and to assess for new ulcer development, in accordance with the Comprehensive Foot Examination and Risk Assessment Guidelines.19
245
hicks et al risk factors for diabetic foot ulcer recurrence
Outcomes Our primary outcome was recurrent ulcer rate at 1 and 3 y after initial healing. Secondary outcomes included recurrent ulcer WIfI staging, size, and wound healing time.
Statistical analysis
Table 1 e Demographics and baseline characteristics of patients with diabetic foot ulcer treated by the Multidisciplinary Limb Preservation Team. Variable
Overall (n ¼ 244)
Age (y)
59.2 3.8
Male sex
153 (62.7)
Race
All baseline characteristics were described for each patient using mean standard error of the mean or count (percent) as appropriate. Patient characteristics were reported on a perpatient basis, whereas wound characteristics and outcomes were reported on a per-limb basis. Univariable analyses were performed to assess differences in wound characteristics and outcomes for initial wounds versus recurrent wounds using student’s t-tests for continuous variables and chi-squared test for categorical variables. One- and 3-year ulcer recurrence rates were assessed per limb using the Kaplan-Meier method with log-rank tests. Univariable Cox proportional hazards models were used to assess the association of various patient- and wound-related covariates with ulcer recurrence. A stepwise multivariable Cox proportional hazards model was then created to identify independent predictors of recurrent ulcers. The covariates chosen for inclusion in the multivariable model were chosen using a forward stepwise multivariable model with P (enter) ¼ 0.20. All patient-level covariates were included in the model after clustering by patient to account for the fact that some patients had wounds on both limbs. All analyses were performed using Stata version 14.0 (StataCorp, College Station, TX). A significance level of P < 0.05 was used for all comparisons.
Results
White
86 (35.3)
Black
151 (61.9)
Other/unknown
Medicare
125 (51.2)
Medicaid
58 (23.8)
Private
55 (22.5)
Self-pay
3 (1.2)
Other
3 (1.2)
Type of diabetes DM-I
12 (4.9)
DM-II
232 (95.1)
Baseline hemoglobin A1c (%)
8.6 0.2
Body mass index (kg/m2)
31.6 5.1
Comorbidities HTN
209 (85.7)
Dyslipidemia
141 (57.8)
CAD
76 (31.2)
CHF
39 (16.0)
CVD
33 (13.5)
PAD
107 (43.9)
CKD
49 (20.1)
Dialysis
29 (11.9)
Retinopathy LOPS
Study cohort A total of 244 patients with 304 affected limbs were included. The mean patient age was 59.2 3.8 y, 62.7% (n ¼ 153) were male, and 61.9% (n ¼ 151) were black. More than half of patients had Medicare insurance (51.2%, n ¼ 125), followed by Medicaid (23.8%, n ¼ 58), private insurance (22.5%, n ¼ 55), and self-pay/other (2.5%, n ¼ 6). Most patients (95.1%, n ¼ 232) had type 2 diabetes mellitus, and baseline hemoglobin A1c was 8.6 0.2%. Medical comorbidities were common and are summarized in Table 1. The mean area of initial ulcers was 8.2 1.2 cm2. The mean time from ulcer onset to initial assessment was 2.4 0.2 mo. Most initial ulcers were located on the toe (53.3%, n ¼ 162), followed by the forefoot (24.1%, n ¼ 73), midfoot (9.2%, n ¼ 28), heel (7.6%, n ¼ 23), and leg/ankle (5.9%, n ¼ 18). There was a relatively equal distribution of WIfI stage 1 through 4 wounds on initial presentation (Table 2). Nearly all (95.1%, n ¼ 232) patients had loss of protective sensation, and abnormal proprioception was present in 24.0% (n ¼ 73) of affected limbs. Chronic limb-threatening ischemia affected 27.0% (n ¼ 82) of limbs. Forty-four percent of wounds (n ¼ 135) achieved healing after podiatric surgery alone, whereas 12.5% (n ¼ 38) required a
7 (2.9)
Insurance status
Gastroparesis
71 (29.1) 232 (95.1) 9 (3.7)
COPD
16 (6.6)
Renal transplant
25 (10.3)
Other transplant
11 (4.5)
Smoking status Current
56 (23.0)
Former
79 (32.4)
Never
109 (44.7)
DM ¼ diabetes mellitus; HTN ¼ hypertension; CAD ¼ coronary artery disease; CHF ¼ congestive heart failure; CVD ¼ cerebrovascular disease; PAD ¼ peripheral arterial disease; CKD ¼ chronic kidney disease; LOPS ¼ loss of protective sensation; COPD ¼ chronic obstructive pulmonary disease.
combination of vascular and podiatric surgery, and 11.8% (n ¼ 36) required an isolated vascular intervention. Thirty-one percent of initial wounds (n ¼ 31.3%) achieved healing with dedicated wound care only. Hyperbaric oxygen therapy was used in only a small proportion of cases for lower extremity ischemia that was not amenable to revascularization or severe microvascular disease in the foot (n ¼ 17, 5.6%). The mean time to initial wound healing was 131.8 7.0 d.
246
j o u r n a l o f s u r g i c a l r e s e a r c h f e b r u a r y 2 0 2 0 ( 2 4 6 ) 2 4 3 e2 5 0
Table 2 e Initial and recurrent ulcer characteristics and treatment. Variable
Initial ulcer (n ¼ 304)
Recurrent ulcer (n ¼ 117)
Table 2 e (continued ) Variable
Initial ulcer (n ¼ 304)
Recurrent ulcer (n ¼ 117)
4
68 (22.4)
9 (7.7)
5
0 (0)
3 (2.6)
P-value
Wound characteristics Mean area (cm2)
8.2 1.2
4.4 1.1
0.04
Interventions performed
Mean depth (cm)
0.7 0.1
0.5 0.1
0.02
Podiatric surgery only
135 (44.4)
0.50
Vascular surgery only
36 (11.8)
9 (8.1)
38 (12.5)
5 (4.5)
Wound location
<0.001 42 (37.8)
Leg/ankle
18 (5.9)
Heel
23 (7.6)
9 (7.7)
Midfoot
28 (9.2)
11 (9.4)
Vascular surgery þ podiatric surgery
Forefoot
73 (24.1)
37 (31.6)
Wound care only
95 (31.3)
49 (44.1)
56 (47.9)
Major amputation
0 (0)
6 (5.4)
2.4 0.2
0.9 0.3
<0.001
131.8 7.0
95.0 9.8
0.004
Toe
162 (53.3)
4 (3.4)
P-value
Vibratory sense (Vib 1st MTP) Normal
0.76
Time from onset to assessment (mo)
4 (1.3)
1 (0.9)
299 (98.4)
116 (99.2)
1 (0.3)
0 (0)
225 (74.0)
88 (75.2)
73 (24.0)
28 (23.9)
Not assessed
6 (2.0)
1 (0.9)
Previous podiatric surgery
75 (24.7)
81 (69.2)
<0.001
Chronic limbthreatening ischemia
82 (27.0)
15 (13.2)
0.003
Abnormal/decreased Not assessed Proprioception Normal Abnormal/decreased
None Femoral-popliteal
Time to wound healing (d) 0.86
Level of atherosclerotic disease 87 (74.4)
3 (1.0)
0 (0)
Tibial
34 (11.2)
15 (12.8)
Multilevel
53 (17.4)
15 (12.8)
0
2 (0.7)
0 (0)
1
156 (51.3)
66 (57.4)
2
111 (36.5)
35 (30.4)
3
35 (11.5)
14 (12.2)
0
221 (72.7)
100 (87.0)
1
42 (13.8)
12 (10.4)
2
15 (4.9)
1 (0.9)
3
26 (8.6)
2 (1.7)
WIfI wound grade
0.52
WIfI ischemia grade
MTP ¼ metatarsophalangeal joint.
Recurrent ulcers
0.45 214 (70.4)
Wound healing outcomes
0.006
Recurrent ulcers occurred in 38.5% (n ¼ 117) of limbs at a mean time of 310.0 29.6 d. Only 12.8% (n ¼ 15) of recurrent ulcers occurred at the same site as the initial wound. Recurrent ulcer rates at 1 and 3 y after healing were 30.6 3.0% and 64.4 5.2%, respectively (Figure). Recurrent ulcers were smaller (area 4.4 1.1 cm2 versus 8.2 1.2 cm2; P ¼ 0.04) and had a lower WIfI stage on presentation (stage 4: 7.7% versus 22.4%; P < 0.001) than initial ulcers (Table 2). Specifically, WIfI ischemia and infection grades were lower in recurrent versus initial ulcers (both, P 0.006; Table 2). A higher proportion of recurrent ulcers ultimately achieved healing with wound care alone compared with initial ulcers (44.1% versus 31.3%; P < 0.001). Time from ulcer onset to assessment was lower for recurrent ulcers (0.9 0.3 versus 2.4 0.2 mo; P < 0.001), and wound healing time was significantly reduced (95.0 9.8 versus 131.8 7.0 d; P ¼ 0.004). Six of the 177 limbs (5.4%) presenting with a recurrent ulcer ultimately required major amputation, three of which were due to the presence of advanced (WIfI stage 5) wounds on representation and three of which were due to an ultimate failure to achieve wound healing.
Covariates associated with secondary ulcers <0.001
WIfI foot infection grade 0
127 (41.8)
63 (54.8)
1
27 (8.9)
21 (18.3)
2
119 (39.1)
29 (25.2)
3
31 (10.2)
2 (1.7)
1
89 (29.3)
45 (38.5)
2
68 (22.4)
42 (35.9)
3
79 (26.0)
18 (15.4)
<0.001
WIfI clinical stage
(continued)
Based on univariable Cox proportional hazards models, only younger patient age (HR 1.02 per year [95% CI 1.01-1.04]) was associated with a higher risk of recurrent ulcers. Chronic limbthreatening ischemia was associated with a slightly lower risk of recurrent ulcers (HR 0.65 [95% CI 0.42-1.02]), although this was not statistically significant (P ¼ 0.06). Patient sex, race, BMI, comorbidities, proprioception, hemoglobin A1c, initial WIfI stage, and wound location were not significantly associated with ulcer recurrence based on crude (unadjusted) analysis (all, P 0.11; Table 3).
hicks et al risk factors for diabetic foot ulcer recurrence
Fig e KaplaneMeier curve demonstrating recurrent ulcer incidence over time after initial complete wound healing. The standard error of the curve is <10% for all reported values. (Color version of figure is available online.)
A multivariable stepwise Cox proportional hazards model was then constructed to assess the risk-adjusted association of patient and wound-related factors with ulcer recurrence (Table 3). Independent predictors of ulcer recurrence included abnormal proprioception (HR 1.57 [95% CI 1.02-4.43]) and younger age (HR 1.02 per year [95% CI 1.01-1.04]). There was also a slight but nonsignificant association of female sex (HR 1.50 [95% CI 1.00-2.26]) and type 2 (versus type 1) diabetes (HR 4.0 [95% CI 0.96-16.7]) with ulcer recurrence, whereas chronic limb-threatening ischemia was somewhat protective (HR 0.60 [95% CI 0.35-1.03]).
Discussion Multiple multidisciplinary groups have shown favorable wound healing outcomes and reduced major amputation rates among patients with DFU.11,18,20-22 In the present study, we sought to describe the long-term outcomes of a multidisciplinary approach to DFU care. We found that ulcer recurrence was common, occurring in nearly two-thirds of patients by 3 y after healing. However, recurrent ulcers were diagnosed earlier, frequently downstaged, and healed more quickly than initial ulcers. Our data suggest that dedicated multidisciplinary limb preservation teams may not reduce overall ulcer recurrence risk among patients with diabetes but can potentially reduce the morbidity traditionally associated with DFU. The ulcer recurrence rates that we report are similar to those reported by previous studies. Based on a 2017 review article by Armstrong et al. that examined data from 19 clinical studies,1 the estimate incidence of DFU recurrence is 40% within 1 y of wound healing, 60% within 3 y, and 65% within 5 y. The risk of recurrence is highest within the first 3 y after healing and then somewhat level thereafter.1 In our study, the one- and 3-year rates of ulcer recurrence were 30% and 64%, respectively, which are not substantially different than those reported by Armstrong et al. We also observed a steady rise in
247
the risk of ulcer recurrence over our 3 y of follow-up, suggesting that patients are at risk for recurrence in the long term and not just immediately after initial wound healing. Despite the high ulcer recurrence rates in our study, we saw significant improvements in the clinical characteristics and outcomes of recurrent versus initial ulcers. Recurrent ulcers were diagnosed within a month of their appearance, whereas initial ulcers averaged 2.4 mo from onset to diagnosis. In addition, recurrent ulcers had lower WIfI ischemia and foot infection grades, and the majority (74%) of recurrent ulcers were WIfI stage 1 or 2, whereas 48% of initial ulcers were WIfI stage 3 or 4. Furthermore, mean wound healing time for recurrent ulcers was 95 d, compared with 132 d for initial ulcers. Therefore, although we did not observe a reduction in ulcer recurrence rates compared with the general population, the severity of recurrent DFUs was less severe in our experience. We attribute these benefits to our use of a multidisciplinary limb preservation team. All patients with DFU are treated comprehensively by a team composed of vascular surgeons, surgical podiatrists, endocrinologists, a wound care nurse, and dedicated physician assistant. The same team sees the patients both in the hospital and in the outpatient clinic in a single location. This arrangement has mitigated the challenges with loss to follow-up, patient compliance, and care coordination teams that can occur with a more traditional treatment approach.23 It also ensures regular follow-up for patients who have achieved wound healing, thereby providing them with regular foot examinations, blood sugar control, and preventative foot care more frequently than the annual examination currently prescribed by the American Diabetes Association.24 We also spend time explaining that although the ulcers have healed, they are in remission rather than cured. We specifically point out to patients not to call their primary care physician or local podiatrist when they develop any injury to the foot, and that our multidisciplinary team should be point of first contact if any new wounds develop. Notably, the major amputation rate in our study was only 5.4% over 3 y, which is substantially lower than the 5%-15% amputation risk for patients with DFU reported previously.25,26 We found that impaired proprioception and younger age were independent variables associated with ulcer recurrence after risk adjustment. The association of proprioception with ulcer recurrence was not surprising. Diabetes-related neuropathy, including motor, sensory, and autonomic neuropathy, is a major factor in the development of DFU.1 The prevalence of diabetic peripheral neuropathy ranges from 19% to 28% depending on the population studied,27-30 which is consistent with the 24% prevalence that we report. Monami et al. previously showed that impaired vibration perception threshold was associated with a 12-fold increased risk of ulcer recurrence in an observational cohort study of type 2 diabetes patients aged 60 y and older.31 In a randomized controlled trial designed to assess the efficacy of therapeutic shoes and inserts for reducing ulcer recurrence among 400 patients with diabetes, Reiber et al. demonstrated that foot insensitivity was associated with 3.7 relative risk for recurrent foot ulceration compared to full foot sensation.32 In our study, we found a 1.6time increase in the risk of ulcer recurrence for patients with impaired proprioception compared to those with normal
248
j o u r n a l o f s u r g i c a l r e s e a r c h f e b r u a r y 2 0 2 0 ( 2 4 6 ) 2 4 3 e2 5 0
Table 3 e Univariable and multivariable analysis of factors associated with ulcer recurrence. Variable
Ulcer recurrence HR (95% CI) Univariable
P-value
Multivariable
P-value
Age (per year)
0.98 (0.96-0.99)
0.008
0.98 (0.96-0.99)
0.02
Female sex
1.25 (0.86-1.82)
0.25
1.50 (1.00-2.26)
0.051
Race White
Ref
Black
0.98 (0.66-1.45)
0.93
Other
0.36 (0.05-2.64)
0.32
1.00 (0.97-1.02)
0.82
0.98 (0.95-1.01)
0.12
DM-I
0.45 (0.14-1.43)
0.18
0.25 (0.06-1.04)
0.06
DM-II
Ref
BMI (kg/m2) Diabetes type
Insulin-dependent diabetes
0.97 (0.67-1.41)
Ref 0.88
Proprioception Normal Abnormal/decreased
Ref
Ref
1.14 (0.74-1.75)
0.54
1.57 (1.02-4.43)
0.04
Chronic limb-threatening ischemia
0.65 (0.42-1.02)
0.06
0.60 (0.35-1.03)
0.07
Chronic kidney disease
0.98 (0.62-1.54)
0.93
Dialysis
0.95 (0.55-1.64)
0.86
Kidney transplant
0.94 (0.49-1.81)
0.86
Smoking Never
Ref
Former
0.70 (0.45-1.09)
0.11
Current
0.95 (0.61-1.48)
0.82
1.27 (0.86-1.88)
0.23
Hemoglobin A1C Initial wound WIfI stage 1
Ref
2
1.43 (0.87-2.35)
0.16
3
1.17 (0.71-1.92)
0.53
4
0.98 (0.56-1.71)
0.95
Leg/ankle
0.48 (0.17-1.31)
0.15
Heel
1.13 (0.56-2.28)
0.73
Midfoot
0.87 (0.45-1.70)
0.69
Forefoot
1.19 (0.76-1.85)
0.45
Wound location
Toe
Ref
DM ¼ diabetes mellitus.
proprioception. Taken together, these data support the notion that diabetic peripheral neuropathy is a significant risk factor for recurrent DFU.1 The association of younger age with ulcer recurrence was less expected but can likely be explained by higher levels of activity in the younger population. The etiology of DFU is thought to be a combination of neuropathy, impaired vascular perfusion, and repetitive trauma.1,33,34 Pressure-point offloading is therefore an important component to ulcer prevention35 and likely one of the primary reasons for ulcer recurrence among adults with diabetes and a known propensity for DFU.36 Younger patients tend to have better ambulatory status than older patients, and thereby may be
more susceptible to repetitive trauma injury because of higher levels of cumulative tissue stress.37 Consistent with this notion, a higher in-shoe plantar pressure has been shown to be a significant risk factor for ulcer recurrences from unrecognized repetitive trauma, suggesting that the use of effective footwear for pressure offloading is important in ulcer prevention.34 In our practice, we have taken this finding seriously. Although we have always worked closely with a prosthetist to ensure appropriate wound offloading during healing, we have subsequently adjusted our focus to include formal gait analysis with orthotics to assist in pressure-point offloading in appropriate patients once wound healing is achieved.
hicks et al risk factors for diabetic foot ulcer recurrence
Other risk factors previously found to be associated with ulcer recurrence have varied substantially depending on the population studied and include the presence of peripheral artery disease, the presence of a preulcerative lesion, presence of a previous ulcer at the plantar hallux, osteomyelitis, high levels of C-reactive protein, and less day-to-day variation in step activity.1 Peters et al. reported a 10-fold increased risk of diabetic ulcer recurrence among patients with peripheral artery disease.38 In our study, we actually found that chronic limb-threatening ischemia, which is an advanced form of peripheral artery disease, was slightly protective against ulcer recurrence. We suggest that this finding is an indication that impaired vascular perfusion was the etiology of the initial ulcer and that, with subsequent revascularization, the risk of ulcer recurrence is actually reduced. As a practice, we are aggressive with lower extremity revascularization, and all patients are evaluated with vascular lab testing on initial presentation to evaluate for a potentially treatable perfusion etiology to their ulcer. As a result, patients with primarily ischemic ulcers are treated early and aggressively and therefore probably less likely to recur than patients with primarily neuropathic or trauma-induced ulcers. The limitations of our study include its applicability to the general population and our failure to capture data on all variables that have previously been described in association with DFU recurrence. As described previously, we have implemented a multidisciplinary limb preservation team that treats all patients presenting to our institution with a DFU. Such a team can be costly to set up and maintain.23,39 However, the potential cost savings associated with the use of a multidisciplinary approach to limb preservation is encouraging in the long-term, assuming that ulcer recurrences can be reduced or downstaged.10,40 It is our opinion that the positive ulcer recurrence outcomes we have reported here support this notion, as we have shown significantly lower costs associated with WIfI stage 1 or 2 compared with WIfI stage 3 or 4 wound episodes.41
Conclusion In this prospective cohort of patients with DFU, ulcer recurrence occurred in nearly two-thirds of limbs within 3 y. Importantly, time to diagnosis and healing was significantly lower for recurrent ulcers, and downstaging was common. Although engaging patients with DFU in a multidisciplinary care model with frequent follow-up and focused patient education does not decrease the overall risk of ulcer recurrence, it may serve to decrease DFU morbidity.
Acknowledgment Authors’ contributions: C.W.H., R.L.S., and C.J.A. were responsible for study conception and design. C.W.H., N.M., C.L., R.L.S., and C.J.A. were responsible for data collection. C.W.H., J.K.C., and C.J.A. were responsible for analysis and interpretation. C.W.H. and C.J.A. were responsible for writing the manuscript, and J.K.C., N.M., C.L., and R.L.S. were
249
responsible for critical revision of the manuscript. All authors give approval of the final manuscript, and all authors agree to be accountable for the manuscript content.
Disclosure No competing interests were declared. This work was completed without financial support.
references
1. Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med. 2017;376:2367e2375. 2. Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA. 2005;293:217e228. 3. Lipsky BA, Berendt AR, Cornia PB, et al. 2012 infectious diseases society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2012;54:e132ee173. 4. Lavery LA, Armstrong DG, Wunderlich RP, et al. Diabetic foot syndrome: evaluating the prevalence and incidence of foot pathology in mexican americans and non-hispanic whites from a diabetes disease management cohort. Diabetes Care. 2003;26:1435e1438. 5. Walsh JW, Hoffstad OJ, Sullivan MO, Margolis DJ. Association of diabetic foot ulcer and death in a population-based cohort from the United Kingdom. Diabet Med. 2016;33:1493e1498. 6. Lavery LA, Hunt NA, Ndip A, et al. Impact of chronic kidney disease on survival after amputation in individuals with diabetes. Diabetes Care. 2010;33:2365e2369. 7. Skrepnek GH, Mills JLS, Lavery LA, Armstrong DG. Health care service and outcomes among an estimated 6.7 million ambulatory care diabetic foot cases in the U.S. Diabetes Care. 2017;40:936e942. 8. Hicks CW, Selvarajah S, Mathioudakis N, et al. Burden of infected diabetic foot ulcers on hospital admissions and costs. Ann Vasc Surg. 2016;33:149e158. 9. Hicks CW, Selvarajah S, Mathioudakis N, et al. Trends and determinants of costs associated with the inpatient care of diabetic foot ulcers. J Vasc Surg. 2014;60:1247e1254.e2. 10. Ollendorf DA, Kotsanos JG, Wishner WJ, et al. Potential economic benefits of lower-extremity amputation prevention strategies in diabetes. Diabetes Care. 1998;21:1240e1245. 11. Vartanian SM, Robinson KD, Ofili K, et al. Outcomes of neuroischemic wounds treated by a multidisciplinary amputation prevention service. Ann Vasc Surg. 2015;29:534e542. 12. Alexandrescu V, Hubermont G, Coessens V, et al. Why a multidisciplinary team may represent a key factor for lowering the inferior limb loss rate in diabetic neuroischaemic wounds: application in a departmental institution. Acta Chir Belg. 2009;109:694e700. 13. Armstrong DG, Bharara M, White M, et al. The impact and outcomes of establishing an integrated interdisciplinary surgical team to care for the diabetic foot. Diabetes Metab Res Rev. 2012;28:514e518. 14. Rogers LC, Andros G, Caporusso J, et al. Toe and flow: essential components and structure of the amputation prevention team. J Vasc Surg. 2010;52(3 Suppl l):23Se27S. 15. Mills JLS, Conte MS, Armstrong DG, et al. The society for vascular surgery lower extremity threatened limb classification system: risk stratification based on wound, ischemia, and foot infection (WIfI). J Vasc Surg. 2014;59:220e234.
250
j o u r n a l o f s u r g i c a l r e s e a r c h f e b r u a r y 2 0 2 0 ( 2 4 6 ) 2 4 3 e2 5 0
16. Margolis DJ, Berlin JA, Strom BL. Interobserver agreement, sensitivity, and specificity of a "healed" chronic wound. Wound Repair Regen. 1996;4:335e338. 17. Lazarus GS, Cooper DM, Knighton DR, et al. Definitions and guidelines for assessment of wounds and evaluation of healing. Wound Repair Regen. 1994;2:165e170. 18. Mathioudakis N, Hicks CW, Canner JK, et al. The society for vascular surgery wound, ischemia, and foot infection (WIfI) classification system predicts wound healing but not major amputation in patients with diabetic foot ulcers treated in a multidisciplinary setting. J Vasc Surg. 2017;65:1698e1705. 19. Boulton AJ, Armstrong DG, Albert SF, et al. Comprehensive foot examination and risk assessment: a report of the task force of the foot care interest group of the american diabetes association, with endorsement by the american association of clinical endocrinologists. Diabetes Care. 2008;31:1679e1685. 20. Roth-Albin I, Mai SH, Ahmed Z, et al. Outcomes following advanced wound care for diabetic foot ulcers: a canadian study. Can J Diabetes. 2017;41:26e32. 21. Causey MW, Ahmed A, Wu B, et al. Society for vascular surgery limb stage and patient risk correlate with outcomes in an amputation prevention program. J Vasc Surg. 2016;63:1563e1573.e2. 22. Wang C, Mai L, Yang C, et al. Reducing major lower extremity amputations after the introduction of a multidisciplinary team in patient with diabetes foot ulcer. BMC Endocr Disord. 2016;16:38. 23. Driver VR, Fabbi M, Lavery LA, Gibbons G. The costs of diabetic foot: the economic case for the limb salvage team. J Vasc Surg. 2010;52(3 Suppl l):17Se22S. 24. American Diabetes Association. 11. Microvascular complications and foot care: standards of medical care in diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S124eS138. 25. Ndosi M, Wright-Hughes A, Brown S, et al. Prognosis of the infected diabetic foot ulcer: a 12-month prospective observational study. Diabet Med. 2018;35:78e88. 26. Incidence of diabetic foot ulcer and lower extremity amputation among Medicare beneficiaries, 2006 to 2008: data points #2. 2011. Available at: https://www.ncbi.nlm.nih.gov/ books/NBK65149/. Accessed January 22, 2019. 27. Tesfaye S, Stevens LK, Stephenson JM, et al. Prevalence of diabetic peripheral neuropathy and its relation to glycaemic control and potential risk factors: the EURODIAB IDDM complications study. Diabetologia. 1996;39:1377e1384. 28. Abbott CA, Malik RA, van Ross ER, et al. Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the U.K. Diabetes Care. 2011;34:2220e2224.
29. Cabezas-Cerrato J. The prevalence of clinical diabetic polyneuropathy in Spain: a study in primary care and hospital clinic groups. neuropathy Spanish study group of the Spanish diabetes society (SDS). Diabetologia. 1998;41:1263e1269. 30. Gregg EW, Gu Q, Williams D, et al. Prevalence of lower extremity diseases associated with normal glucose levels, impaired fasting glucose, and diabetes among U.S. adults aged 40 or older. Diabetes Res Clin Pract. 2007;77:485e488. 31. Monami M, Longo R, Desideri CM, et al. The diabetic person beyond a foot ulcer: healing, recurrence, and depressive symptoms. J Am Podiatr Med Assoc. 2008;98:130e136. 32. Reiber GE, Smith DG, Wallace C, et al. Effect of therapeutic footwear on foot reulceration in patients with diabetes: a randomized controlled trial. JAMA. 2002;287:2552e2558. 33. Telfer S, Bigham JJ. The influence of population characteristics and measurement system on barefoot plantar pressures: a systematic review and meta-regression analysis. Gait Posture. 2019;67:269e276. 34. Waaijman R, de Haart M, Arts ML, et al. Risk factors for plantar foot ulcer recurrence in neuropathic diabetic patients. Diabetes Care. 2014;37:1697e1705. 35. Edmonds ME, Blundell MP, Morris ME, et al. Improved survival of the diabetic foot: the role of a specialized foot clinic. Q J Med. 1986;60:763e771. 36. Sacco IC, Bacarin TA, Canettieri MG, Hennig EM. Plantar pressures during shod gait in diabetic neuropathic patients with and without a history of plantar ulceration. J Am Podiatr Med Assoc. 2009;99:285e294. 37. Maluf KS, Mueller MJ. Novel award 2002. Comparison of physical activity and cumulative plantar tissue stress among subjects with and without diabetes mellitus and a history of recurrent plantar ulcers. Clin Biomech (Bristol, Avon). 2003;18:567e575. 38. Peters EJ, Armstrong DG, Lavery LA. Risk factors for recurrent diabetic foot ulcers: site matters. Diabetes Care. 2007;30:2077e2079. 39. Hicks CW, Canner JK, Karagozlu H, et al. Quantifying the costs and profitability of care for diabetic foot ulcers treated in a multidisciplinary setting. J Vasc Surg. 2019;70:233e240. 40. Horswell RL, Birke JA, Patout Jr CA. A staged management diabetes foot program versus standard care: a 1-year cost and utilization comparison in a state public hospital system. Arch Phys Med Rehabil. 2003;84:1743e1746. 41. Hicks CW, Canner JK, Karagozlu H, et al. The society for vascular surgery wound, ischemia, and foot infection (WIfI) classification system correlates with cost of care for diabetic foot ulcers treated in a multidisciplinary setting. J Vasc Surg. 2018;67:1455e1462.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Incidence and Risk Factors Associated With Ulcer Recurrence Among Patients With Diabetic Foot Ulcers Treated in a Multidisciplinary Setting Caitlin W. Hicks, MD, MS,a,b Joseph K. Canner, MHS,c Nestoras Mathioudakis, MD, MHS,a,d Christopher Lippincott, MD,a,e Ronald L. Sherman, DPM,a,b and Christopher J. Abularrage, MDa,b,* a
Diabetic Foot and Wound Service, The Johns Hopkins Hospital, Baltimore, Maryland Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, The Johns Hopkins Hospital, Baltimore, Maryland c Department of Surgery, Center for Surgical Trials and Outcomes Research, The Johns Hopkins Hospital, Baltimore, Maryland d Division of Endocrinology and Metabolism, Department of Medicine, The Johns Hopkins Hospital, Baltimore, Maryland e Division of Infectious Diseases, Department of Medicine, The Johns Hopkins Hospital, Baltimore, Maryland b
article info
abstract
Article history:
Background: Recent studies demonstrate favorable diabetic foot ulcer (DFU) healing out-
Received 3 May 2019
comes with the implementation of a multidisciplinary team. We aimed to describe the
Received in revised form
incidence of and risk factors associated with ulcer recurrence after initial complete healing
24 July 2019
among a cohort of patients with DFU treated in a multidisciplinary setting.
Accepted 13 September 2019
Methods: All patients presenting to our multidisciplinary diabetic limb preservation service
Available online xxx
from 6/2012-04/2018 were enrolled in a prospective database. The incidence of ulcer recurrence after complete wound healing was assessed per limb using the Kaplan-Meier
Keywords:
method, and a stepwise multivariable Cox proportional hazards model was created to
Diabetic foot ulcer
identify independent predictors of ulcer recurrence.
Diabetic foot wound
Results: A total of 244 patients with 304 affected limbs were included. Ulcer recurrence rates
Ulcer recurrence
at one and 3 y after healing were 30.6 3.0% and 64.4 5.2%, respectively. Recurrent ulcers
Wound healing
were smaller (4.4 1.1 cm2 versus 8.2 1.2 cm2; P ¼ 0.04) and had a lower Wound, Ischemia,
Multidisciplinary team
and foot Infection stage (stage 4: 7.7% versus 22.4%; P < 0.001) than initial ulcers, and wound healing time was significantly reduced (95.0 9.8 versus 131.8 7.0 d; P ¼ 0.004). Independent predictors of ulcer recurrence included abnormal proprioception (HR, 1.57 [95% CI 1.02-4.43]) and younger age (HR 1.02 per year [95% CI 1.01-1.04]). Conclusions: In this prospective cohort of patients with DFU, time to diagnosis and healing was significantly lower for recurrent ulcers, and downstaging was common. These data suggest that engaging patients with DFU in a multidisciplinary care model with frequent follow-up and focused patient education may serve to decrease DFU morbidity. ª 2019 Elsevier Inc. All rights reserved.
* Corresponding author. 600 North Wolfe Street, Halsted 671, Baltimore, MD 21287. Tel.: þ(410) 955 5165; fax: þ(410)-614-2079. E-mail address: [email protected] (C.J. Abularrage). 0022-4804/$ e see front matter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jss.2019.09.025
244
j o u r n a l o f s u r g i c a l r e s e a r c h f e b r u a r y 2 0 2 0 ( 2 4 6 ) 2 4 3 e2 5 0
Introduction
Wound definitions
Diabetic foot ulcers (DFUs) are a significant cause of morbidity and mortality among adults with diabetes. In the United States alone, it is estimated that between 1 million and 3.5 million adults have a history of DFU.1 Approximately 25% of adults with diabetes will be affected by a DFU during their lifetime,2 of which 20% will require either minor or major amputation to achieve healing.3,4 Among patients with DFU who ultimately achieve wound healing, ulcer recurrence occurs in as many as 40% by 1 y.1 Adults with a DFU also have a 2.5 times increased risk of death at 5 y compared to adults with diabetes but no DFU,5 and the 5-year mortality for a DFUrelated amputation is more than 70%.6 Given the prevalence and morbidity of DFU, the health care burden associated with the disease is substantial. The risk of emergency department visits and hospital admissions related to DFU is higher than that of congestive heart failure, renal disease, and most cancers.7 The estimate inpatient costs for DFU care in the United States are $1.38 billion per year8 and are increasing significantly with time.9 Most of these costs are related to the treatment of infected foot ulcers, which highlights the need for early diagnosis and treatment strategies in the outpatient setting as a means to preventing further increases in what is already a substantial economic burden.8 The development of multidisciplinary limb preservation teams for the treatment and prevention of DFU is one strategy that has been described as a means of improving care and containing health care costs in the long term.10 Recent studies demonstrate favorable DFU healing outcomes with implementation of a multidisciplinary team approach compared with traditional treatment strategies.11-14 However, the long-term outcomes of this approach to DFU care are unknown. Specifically, it is unclear whether use of a multidisciplinary team can achieve favorable ulcer recurrence rates compared with those previously reported in the literature.1 We aimed to describe the incidence of and risk factors associated with ulcer recurrence after initial complete healing among a cohort of patients with DFU treated in a multidisciplinary setting.
On initial presentation, all wounds were graded according to the Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification system15 based on provider consensus. Patients with WIfI stage 5 wounds were excluded from the analysis as affected limbs are considered unsalvageable.15 Patients who underwent major amputation for their initial wound were also excluded because they could not contract a recurrent ulcer on an amputated limb. Wound healing was defined as complete epithelialization with the restoration of sustained functional and anatomic continuity for 6 wk after complete healing.16,17 Recurrent ulcers were defined as ulcers that formed on the same foot after complete wound healing was achieved.
Methods Study cohort All patients presenting to our multidisciplinary diabetic limb preservation service between June 1, 2012 and April 30, 2018 were enrolled in a prospective database. Patients are referred via both inpatient consult and outpatient referral to our service. Because we are responsible for the assessment and management of all DFU in our hospital system, the scope of our practice includes a wide range of minor to extensive wounds. The Johns Hopkins Institutional Review Board approved the study, and all patients signed informed consent, allowing for the longitudinal collection of their sociodemographic, comorbidity, and surgical intervention data.
Multidisciplinary limb preservation service Our multidisciplinary limb preservation service has been previously described in detail.18 Briefly, our team consists of vascular surgeons, surgical podiatrists, endocrinologists, wound care nurse, physician assistant, and prosthetist. All patients are assessed by all members of the team at each visit in an integrated fashion. Consultation from infectious disease, plastic surgery, and orthopedic foot and ankle physicians is obtained on a case-by-case basis as needed. All patients are followed up closely on an outpatient basis to assess wound healing, medication compliance, and glycemic control. On initial presentation, all patients undergo noninvasive vascular lab testing to assess perfusion. Patients with evidence of chronic limb-threatening ischemia are scheduled for an angiogram with endovascular revascularization whenever possible. In patients with atherosclerotic disease that is not amenable to endovascular intervention, open bypass is performed. All wounds are assessed via X-ray imaging, followed by magnetic resonance imaging when indicated. After lower extremity revascularization, any radiographic evidence of osteomyelitis is surgically excised, and wounds are debrided to clear margins. All patients are treated with culture-targeted antibiotics after debridement; wounds limited to the toes are treated with 2 wk of oral antibiotics, whereas wounds involving the metatarsophalangeal joint or more proximally are typically treated with 6 wk of intravenous antibiotics with Infectious Diseases guidance. After revascularization and debridement, all wounds are offloaded to maximize wound healing. Patients are educated on foot care, lifestyle habits, and medication compliance to ensure close adherence to our treatment paradigm. Specifically, patients are given educational handout outlining how to care for their diabetes, how to check and wash their feet, how to trim their toenails, and how to protect their feet with appropriate footwear. During healing, patients are followed up on a biweekly basis. Once complete wound healing is achieved, patients continue to follow up on an outpatient basis for regular noninvasive testing and to assess for new ulcer development, in accordance with the Comprehensive Foot Examination and Risk Assessment Guidelines.19
245
hicks et al risk factors for diabetic foot ulcer recurrence
Outcomes Our primary outcome was recurrent ulcer rate at 1 and 3 y after initial healing. Secondary outcomes included recurrent ulcer WIfI staging, size, and wound healing time.
Statistical analysis
Table 1 e Demographics and baseline characteristics of patients with diabetic foot ulcer treated by the Multidisciplinary Limb Preservation Team. Variable
Overall (n ¼ 244)
Age (y)
59.2 3.8
Male sex
153 (62.7)
Race
All baseline characteristics were described for each patient using mean standard error of the mean or count (percent) as appropriate. Patient characteristics were reported on a perpatient basis, whereas wound characteristics and outcomes were reported on a per-limb basis. Univariable analyses were performed to assess differences in wound characteristics and outcomes for initial wounds versus recurrent wounds using student’s t-tests for continuous variables and chi-squared test for categorical variables. One- and 3-year ulcer recurrence rates were assessed per limb using the Kaplan-Meier method with log-rank tests. Univariable Cox proportional hazards models were used to assess the association of various patient- and wound-related covariates with ulcer recurrence. A stepwise multivariable Cox proportional hazards model was then created to identify independent predictors of recurrent ulcers. The covariates chosen for inclusion in the multivariable model were chosen using a forward stepwise multivariable model with P (enter) ¼ 0.20. All patient-level covariates were included in the model after clustering by patient to account for the fact that some patients had wounds on both limbs. All analyses were performed using Stata version 14.0 (StataCorp, College Station, TX). A significance level of P < 0.05 was used for all comparisons.
Results
White
86 (35.3)
Black
151 (61.9)
Other/unknown
Medicare
125 (51.2)
Medicaid
58 (23.8)
Private
55 (22.5)
Self-pay
3 (1.2)
Other
3 (1.2)
Type of diabetes DM-I
12 (4.9)
DM-II
232 (95.1)
Baseline hemoglobin A1c (%)
8.6 0.2
Body mass index (kg/m2)
31.6 5.1
Comorbidities HTN
209 (85.7)
Dyslipidemia
141 (57.8)
CAD
76 (31.2)
CHF
39 (16.0)
CVD
33 (13.5)
PAD
107 (43.9)
CKD
49 (20.1)
Dialysis
29 (11.9)
Retinopathy LOPS
Study cohort A total of 244 patients with 304 affected limbs were included. The mean patient age was 59.2 3.8 y, 62.7% (n ¼ 153) were male, and 61.9% (n ¼ 151) were black. More than half of patients had Medicare insurance (51.2%, n ¼ 125), followed by Medicaid (23.8%, n ¼ 58), private insurance (22.5%, n ¼ 55), and self-pay/other (2.5%, n ¼ 6). Most patients (95.1%, n ¼ 232) had type 2 diabetes mellitus, and baseline hemoglobin A1c was 8.6 0.2%. Medical comorbidities were common and are summarized in Table 1. The mean area of initial ulcers was 8.2 1.2 cm2. The mean time from ulcer onset to initial assessment was 2.4 0.2 mo. Most initial ulcers were located on the toe (53.3%, n ¼ 162), followed by the forefoot (24.1%, n ¼ 73), midfoot (9.2%, n ¼ 28), heel (7.6%, n ¼ 23), and leg/ankle (5.9%, n ¼ 18). There was a relatively equal distribution of WIfI stage 1 through 4 wounds on initial presentation (Table 2). Nearly all (95.1%, n ¼ 232) patients had loss of protective sensation, and abnormal proprioception was present in 24.0% (n ¼ 73) of affected limbs. Chronic limb-threatening ischemia affected 27.0% (n ¼ 82) of limbs. Forty-four percent of wounds (n ¼ 135) achieved healing after podiatric surgery alone, whereas 12.5% (n ¼ 38) required a
7 (2.9)
Insurance status
Gastroparesis
71 (29.1) 232 (95.1) 9 (3.7)
COPD
16 (6.6)
Renal transplant
25 (10.3)
Other transplant
11 (4.5)
Smoking status Current
56 (23.0)
Former
79 (32.4)
Never
109 (44.7)
DM ¼ diabetes mellitus; HTN ¼ hypertension; CAD ¼ coronary artery disease; CHF ¼ congestive heart failure; CVD ¼ cerebrovascular disease; PAD ¼ peripheral arterial disease; CKD ¼ chronic kidney disease; LOPS ¼ loss of protective sensation; COPD ¼ chronic obstructive pulmonary disease.
combination of vascular and podiatric surgery, and 11.8% (n ¼ 36) required an isolated vascular intervention. Thirty-one percent of initial wounds (n ¼ 31.3%) achieved healing with dedicated wound care only. Hyperbaric oxygen therapy was used in only a small proportion of cases for lower extremity ischemia that was not amenable to revascularization or severe microvascular disease in the foot (n ¼ 17, 5.6%). The mean time to initial wound healing was 131.8 7.0 d.
246
j o u r n a l o f s u r g i c a l r e s e a r c h f e b r u a r y 2 0 2 0 ( 2 4 6 ) 2 4 3 e2 5 0
Table 2 e Initial and recurrent ulcer characteristics and treatment. Variable
Initial ulcer (n ¼ 304)
Recurrent ulcer (n ¼ 117)
Table 2 e (continued ) Variable
Initial ulcer (n ¼ 304)
Recurrent ulcer (n ¼ 117)
4
68 (22.4)
9 (7.7)
5
0 (0)
3 (2.6)
P-value
Wound characteristics Mean area (cm2)
8.2 1.2
4.4 1.1
0.04
Interventions performed
Mean depth (cm)
0.7 0.1
0.5 0.1
0.02
Podiatric surgery only
135 (44.4)
0.50
Vascular surgery only
36 (11.8)
9 (8.1)
38 (12.5)
5 (4.5)
Wound location
<0.001 42 (37.8)
Leg/ankle
18 (5.9)
Heel
23 (7.6)
9 (7.7)
Midfoot
28 (9.2)
11 (9.4)
Vascular surgery þ podiatric surgery
Forefoot
73 (24.1)
37 (31.6)
Wound care only
95 (31.3)
49 (44.1)
56 (47.9)
Major amputation
0 (0)
6 (5.4)
2.4 0.2
0.9 0.3
<0.001
131.8 7.0
95.0 9.8
0.004
Toe
162 (53.3)
4 (3.4)
P-value
Vibratory sense (Vib 1st MTP) Normal
0.76
Time from onset to assessment (mo)
4 (1.3)
1 (0.9)
299 (98.4)
116 (99.2)
1 (0.3)
0 (0)
225 (74.0)
88 (75.2)
73 (24.0)
28 (23.9)
Not assessed
6 (2.0)
1 (0.9)
Previous podiatric surgery
75 (24.7)
81 (69.2)
<0.001
Chronic limbthreatening ischemia
82 (27.0)
15 (13.2)
0.003
Abnormal/decreased Not assessed Proprioception Normal Abnormal/decreased
None Femoral-popliteal
Time to wound healing (d) 0.86
Level of atherosclerotic disease 87 (74.4)
3 (1.0)
0 (0)
Tibial
34 (11.2)
15 (12.8)
Multilevel
53 (17.4)
15 (12.8)
0
2 (0.7)
0 (0)
1
156 (51.3)
66 (57.4)
2
111 (36.5)
35 (30.4)
3
35 (11.5)
14 (12.2)
0
221 (72.7)
100 (87.0)
1
42 (13.8)
12 (10.4)
2
15 (4.9)
1 (0.9)
3
26 (8.6)
2 (1.7)
WIfI wound grade
0.52
WIfI ischemia grade
MTP ¼ metatarsophalangeal joint.
Recurrent ulcers
0.45 214 (70.4)
Wound healing outcomes
0.006
Recurrent ulcers occurred in 38.5% (n ¼ 117) of limbs at a mean time of 310.0 29.6 d. Only 12.8% (n ¼ 15) of recurrent ulcers occurred at the same site as the initial wound. Recurrent ulcer rates at 1 and 3 y after healing were 30.6 3.0% and 64.4 5.2%, respectively (Figure). Recurrent ulcers were smaller (area 4.4 1.1 cm2 versus 8.2 1.2 cm2; P ¼ 0.04) and had a lower WIfI stage on presentation (stage 4: 7.7% versus 22.4%; P < 0.001) than initial ulcers (Table 2). Specifically, WIfI ischemia and infection grades were lower in recurrent versus initial ulcers (both, P 0.006; Table 2). A higher proportion of recurrent ulcers ultimately achieved healing with wound care alone compared with initial ulcers (44.1% versus 31.3%; P < 0.001). Time from ulcer onset to assessment was lower for recurrent ulcers (0.9 0.3 versus 2.4 0.2 mo; P < 0.001), and wound healing time was significantly reduced (95.0 9.8 versus 131.8 7.0 d; P ¼ 0.004). Six of the 177 limbs (5.4%) presenting with a recurrent ulcer ultimately required major amputation, three of which were due to the presence of advanced (WIfI stage 5) wounds on representation and three of which were due to an ultimate failure to achieve wound healing.
Covariates associated with secondary ulcers <0.001
WIfI foot infection grade 0
127 (41.8)
63 (54.8)
1
27 (8.9)
21 (18.3)
2
119 (39.1)
29 (25.2)
3
31 (10.2)
2 (1.7)
1
89 (29.3)
45 (38.5)
2
68 (22.4)
42 (35.9)
3
79 (26.0)
18 (15.4)
<0.001
WIfI clinical stage
(continued)
Based on univariable Cox proportional hazards models, only younger patient age (HR 1.02 per year [95% CI 1.01-1.04]) was associated with a higher risk of recurrent ulcers. Chronic limbthreatening ischemia was associated with a slightly lower risk of recurrent ulcers (HR 0.65 [95% CI 0.42-1.02]), although this was not statistically significant (P ¼ 0.06). Patient sex, race, BMI, comorbidities, proprioception, hemoglobin A1c, initial WIfI stage, and wound location were not significantly associated with ulcer recurrence based on crude (unadjusted) analysis (all, P 0.11; Table 3).
hicks et al risk factors for diabetic foot ulcer recurrence
Fig e KaplaneMeier curve demonstrating recurrent ulcer incidence over time after initial complete wound healing. The standard error of the curve is <10% for all reported values. (Color version of figure is available online.)
A multivariable stepwise Cox proportional hazards model was then constructed to assess the risk-adjusted association of patient and wound-related factors with ulcer recurrence (Table 3). Independent predictors of ulcer recurrence included abnormal proprioception (HR 1.57 [95% CI 1.02-4.43]) and younger age (HR 1.02 per year [95% CI 1.01-1.04]). There was also a slight but nonsignificant association of female sex (HR 1.50 [95% CI 1.00-2.26]) and type 2 (versus type 1) diabetes (HR 4.0 [95% CI 0.96-16.7]) with ulcer recurrence, whereas chronic limb-threatening ischemia was somewhat protective (HR 0.60 [95% CI 0.35-1.03]).
Discussion Multiple multidisciplinary groups have shown favorable wound healing outcomes and reduced major amputation rates among patients with DFU.11,18,20-22 In the present study, we sought to describe the long-term outcomes of a multidisciplinary approach to DFU care. We found that ulcer recurrence was common, occurring in nearly two-thirds of patients by 3 y after healing. However, recurrent ulcers were diagnosed earlier, frequently downstaged, and healed more quickly than initial ulcers. Our data suggest that dedicated multidisciplinary limb preservation teams may not reduce overall ulcer recurrence risk among patients with diabetes but can potentially reduce the morbidity traditionally associated with DFU. The ulcer recurrence rates that we report are similar to those reported by previous studies. Based on a 2017 review article by Armstrong et al. that examined data from 19 clinical studies,1 the estimate incidence of DFU recurrence is 40% within 1 y of wound healing, 60% within 3 y, and 65% within 5 y. The risk of recurrence is highest within the first 3 y after healing and then somewhat level thereafter.1 In our study, the one- and 3-year rates of ulcer recurrence were 30% and 64%, respectively, which are not substantially different than those reported by Armstrong et al. We also observed a steady rise in
247
the risk of ulcer recurrence over our 3 y of follow-up, suggesting that patients are at risk for recurrence in the long term and not just immediately after initial wound healing. Despite the high ulcer recurrence rates in our study, we saw significant improvements in the clinical characteristics and outcomes of recurrent versus initial ulcers. Recurrent ulcers were diagnosed within a month of their appearance, whereas initial ulcers averaged 2.4 mo from onset to diagnosis. In addition, recurrent ulcers had lower WIfI ischemia and foot infection grades, and the majority (74%) of recurrent ulcers were WIfI stage 1 or 2, whereas 48% of initial ulcers were WIfI stage 3 or 4. Furthermore, mean wound healing time for recurrent ulcers was 95 d, compared with 132 d for initial ulcers. Therefore, although we did not observe a reduction in ulcer recurrence rates compared with the general population, the severity of recurrent DFUs was less severe in our experience. We attribute these benefits to our use of a multidisciplinary limb preservation team. All patients with DFU are treated comprehensively by a team composed of vascular surgeons, surgical podiatrists, endocrinologists, a wound care nurse, and dedicated physician assistant. The same team sees the patients both in the hospital and in the outpatient clinic in a single location. This arrangement has mitigated the challenges with loss to follow-up, patient compliance, and care coordination teams that can occur with a more traditional treatment approach.23 It also ensures regular follow-up for patients who have achieved wound healing, thereby providing them with regular foot examinations, blood sugar control, and preventative foot care more frequently than the annual examination currently prescribed by the American Diabetes Association.24 We also spend time explaining that although the ulcers have healed, they are in remission rather than cured. We specifically point out to patients not to call their primary care physician or local podiatrist when they develop any injury to the foot, and that our multidisciplinary team should be point of first contact if any new wounds develop. Notably, the major amputation rate in our study was only 5.4% over 3 y, which is substantially lower than the 5%-15% amputation risk for patients with DFU reported previously.25,26 We found that impaired proprioception and younger age were independent variables associated with ulcer recurrence after risk adjustment. The association of proprioception with ulcer recurrence was not surprising. Diabetes-related neuropathy, including motor, sensory, and autonomic neuropathy, is a major factor in the development of DFU.1 The prevalence of diabetic peripheral neuropathy ranges from 19% to 28% depending on the population studied,27-30 which is consistent with the 24% prevalence that we report. Monami et al. previously showed that impaired vibration perception threshold was associated with a 12-fold increased risk of ulcer recurrence in an observational cohort study of type 2 diabetes patients aged 60 y and older.31 In a randomized controlled trial designed to assess the efficacy of therapeutic shoes and inserts for reducing ulcer recurrence among 400 patients with diabetes, Reiber et al. demonstrated that foot insensitivity was associated with 3.7 relative risk for recurrent foot ulceration compared to full foot sensation.32 In our study, we found a 1.6time increase in the risk of ulcer recurrence for patients with impaired proprioception compared to those with normal
248
j o u r n a l o f s u r g i c a l r e s e a r c h f e b r u a r y 2 0 2 0 ( 2 4 6 ) 2 4 3 e2 5 0
Table 3 e Univariable and multivariable analysis of factors associated with ulcer recurrence. Variable
Ulcer recurrence HR (95% CI) Univariable
P-value
Multivariable
P-value
Age (per year)
0.98 (0.96-0.99)
0.008
0.98 (0.96-0.99)
0.02
Female sex
1.25 (0.86-1.82)
0.25
1.50 (1.00-2.26)
0.051
Race White
Ref
Black
0.98 (0.66-1.45)
0.93
Other
0.36 (0.05-2.64)
0.32
1.00 (0.97-1.02)
0.82
0.98 (0.95-1.01)
0.12
DM-I
0.45 (0.14-1.43)
0.18
0.25 (0.06-1.04)
0.06
DM-II
Ref
BMI (kg/m2) Diabetes type
Insulin-dependent diabetes
0.97 (0.67-1.41)
Ref 0.88
Proprioception Normal Abnormal/decreased
Ref
Ref
1.14 (0.74-1.75)
0.54
1.57 (1.02-4.43)
0.04
Chronic limb-threatening ischemia
0.65 (0.42-1.02)
0.06
0.60 (0.35-1.03)
0.07
Chronic kidney disease
0.98 (0.62-1.54)
0.93
Dialysis
0.95 (0.55-1.64)
0.86
Kidney transplant
0.94 (0.49-1.81)
0.86
Smoking Never
Ref
Former
0.70 (0.45-1.09)
0.11
Current
0.95 (0.61-1.48)
0.82
1.27 (0.86-1.88)
0.23
Hemoglobin A1C Initial wound WIfI stage 1
Ref
2
1.43 (0.87-2.35)
0.16
3
1.17 (0.71-1.92)
0.53
4
0.98 (0.56-1.71)
0.95
Leg/ankle
0.48 (0.17-1.31)
0.15
Heel
1.13 (0.56-2.28)
0.73
Midfoot
0.87 (0.45-1.70)
0.69
Forefoot
1.19 (0.76-1.85)
0.45
Wound location
Toe
Ref
DM ¼ diabetes mellitus.
proprioception. Taken together, these data support the notion that diabetic peripheral neuropathy is a significant risk factor for recurrent DFU.1 The association of younger age with ulcer recurrence was less expected but can likely be explained by higher levels of activity in the younger population. The etiology of DFU is thought to be a combination of neuropathy, impaired vascular perfusion, and repetitive trauma.1,33,34 Pressure-point offloading is therefore an important component to ulcer prevention35 and likely one of the primary reasons for ulcer recurrence among adults with diabetes and a known propensity for DFU.36 Younger patients tend to have better ambulatory status than older patients, and thereby may be
more susceptible to repetitive trauma injury because of higher levels of cumulative tissue stress.37 Consistent with this notion, a higher in-shoe plantar pressure has been shown to be a significant risk factor for ulcer recurrences from unrecognized repetitive trauma, suggesting that the use of effective footwear for pressure offloading is important in ulcer prevention.34 In our practice, we have taken this finding seriously. Although we have always worked closely with a prosthetist to ensure appropriate wound offloading during healing, we have subsequently adjusted our focus to include formal gait analysis with orthotics to assist in pressure-point offloading in appropriate patients once wound healing is achieved.
hicks et al risk factors for diabetic foot ulcer recurrence
Other risk factors previously found to be associated with ulcer recurrence have varied substantially depending on the population studied and include the presence of peripheral artery disease, the presence of a preulcerative lesion, presence of a previous ulcer at the plantar hallux, osteomyelitis, high levels of C-reactive protein, and less day-to-day variation in step activity.1 Peters et al. reported a 10-fold increased risk of diabetic ulcer recurrence among patients with peripheral artery disease.38 In our study, we actually found that chronic limb-threatening ischemia, which is an advanced form of peripheral artery disease, was slightly protective against ulcer recurrence. We suggest that this finding is an indication that impaired vascular perfusion was the etiology of the initial ulcer and that, with subsequent revascularization, the risk of ulcer recurrence is actually reduced. As a practice, we are aggressive with lower extremity revascularization, and all patients are evaluated with vascular lab testing on initial presentation to evaluate for a potentially treatable perfusion etiology to their ulcer. As a result, patients with primarily ischemic ulcers are treated early and aggressively and therefore probably less likely to recur than patients with primarily neuropathic or trauma-induced ulcers. The limitations of our study include its applicability to the general population and our failure to capture data on all variables that have previously been described in association with DFU recurrence. As described previously, we have implemented a multidisciplinary limb preservation team that treats all patients presenting to our institution with a DFU. Such a team can be costly to set up and maintain.23,39 However, the potential cost savings associated with the use of a multidisciplinary approach to limb preservation is encouraging in the long-term, assuming that ulcer recurrences can be reduced or downstaged.10,40 It is our opinion that the positive ulcer recurrence outcomes we have reported here support this notion, as we have shown significantly lower costs associated with WIfI stage 1 or 2 compared with WIfI stage 3 or 4 wound episodes.41
Conclusion In this prospective cohort of patients with DFU, ulcer recurrence occurred in nearly two-thirds of limbs within 3 y. Importantly, time to diagnosis and healing was significantly lower for recurrent ulcers, and downstaging was common. Although engaging patients with DFU in a multidisciplinary care model with frequent follow-up and focused patient education does not decrease the overall risk of ulcer recurrence, it may serve to decrease DFU morbidity.
Acknowledgment Authors’ contributions: C.W.H., R.L.S., and C.J.A. were responsible for study conception and design. C.W.H., N.M., C.L., R.L.S., and C.J.A. were responsible for data collection. C.W.H., J.K.C., and C.J.A. were responsible for analysis and interpretation. C.W.H. and C.J.A. were responsible for writing the manuscript, and J.K.C., N.M., C.L., and R.L.S. were
249
responsible for critical revision of the manuscript. All authors give approval of the final manuscript, and all authors agree to be accountable for the manuscript content.
Disclosure No competing interests were declared. This work was completed without financial support.
references
1. Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med. 2017;376:2367e2375. 2. Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA. 2005;293:217e228. 3. Lipsky BA, Berendt AR, Cornia PB, et al. 2012 infectious diseases society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2012;54:e132ee173. 4. Lavery LA, Armstrong DG, Wunderlich RP, et al. Diabetic foot syndrome: evaluating the prevalence and incidence of foot pathology in mexican americans and non-hispanic whites from a diabetes disease management cohort. Diabetes Care. 2003;26:1435e1438. 5. Walsh JW, Hoffstad OJ, Sullivan MO, Margolis DJ. Association of diabetic foot ulcer and death in a population-based cohort from the United Kingdom. Diabet Med. 2016;33:1493e1498. 6. Lavery LA, Hunt NA, Ndip A, et al. Impact of chronic kidney disease on survival after amputation in individuals with diabetes. Diabetes Care. 2010;33:2365e2369. 7. Skrepnek GH, Mills JLS, Lavery LA, Armstrong DG. Health care service and outcomes among an estimated 6.7 million ambulatory care diabetic foot cases in the U.S. Diabetes Care. 2017;40:936e942. 8. Hicks CW, Selvarajah S, Mathioudakis N, et al. Burden of infected diabetic foot ulcers on hospital admissions and costs. Ann Vasc Surg. 2016;33:149e158. 9. Hicks CW, Selvarajah S, Mathioudakis N, et al. Trends and determinants of costs associated with the inpatient care of diabetic foot ulcers. J Vasc Surg. 2014;60:1247e1254.e2. 10. Ollendorf DA, Kotsanos JG, Wishner WJ, et al. Potential economic benefits of lower-extremity amputation prevention strategies in diabetes. Diabetes Care. 1998;21:1240e1245. 11. Vartanian SM, Robinson KD, Ofili K, et al. Outcomes of neuroischemic wounds treated by a multidisciplinary amputation prevention service. Ann Vasc Surg. 2015;29:534e542. 12. Alexandrescu V, Hubermont G, Coessens V, et al. Why a multidisciplinary team may represent a key factor for lowering the inferior limb loss rate in diabetic neuroischaemic wounds: application in a departmental institution. Acta Chir Belg. 2009;109:694e700. 13. Armstrong DG, Bharara M, White M, et al. The impact and outcomes of establishing an integrated interdisciplinary surgical team to care for the diabetic foot. Diabetes Metab Res Rev. 2012;28:514e518. 14. Rogers LC, Andros G, Caporusso J, et al. Toe and flow: essential components and structure of the amputation prevention team. J Vasc Surg. 2010;52(3 Suppl l):23Se27S. 15. Mills JLS, Conte MS, Armstrong DG, et al. The society for vascular surgery lower extremity threatened limb classification system: risk stratification based on wound, ischemia, and foot infection (WIfI). J Vasc Surg. 2014;59:220e234.
250
j o u r n a l o f s u r g i c a l r e s e a r c h f e b r u a r y 2 0 2 0 ( 2 4 6 ) 2 4 3 e2 5 0
16. Margolis DJ, Berlin JA, Strom BL. Interobserver agreement, sensitivity, and specificity of a "healed" chronic wound. Wound Repair Regen. 1996;4:335e338. 17. Lazarus GS, Cooper DM, Knighton DR, et al. Definitions and guidelines for assessment of wounds and evaluation of healing. Wound Repair Regen. 1994;2:165e170. 18. Mathioudakis N, Hicks CW, Canner JK, et al. The society for vascular surgery wound, ischemia, and foot infection (WIfI) classification system predicts wound healing but not major amputation in patients with diabetic foot ulcers treated in a multidisciplinary setting. J Vasc Surg. 2017;65:1698e1705. 19. Boulton AJ, Armstrong DG, Albert SF, et al. Comprehensive foot examination and risk assessment: a report of the task force of the foot care interest group of the american diabetes association, with endorsement by the american association of clinical endocrinologists. Diabetes Care. 2008;31:1679e1685. 20. Roth-Albin I, Mai SH, Ahmed Z, et al. Outcomes following advanced wound care for diabetic foot ulcers: a canadian study. Can J Diabetes. 2017;41:26e32. 21. Causey MW, Ahmed A, Wu B, et al. Society for vascular surgery limb stage and patient risk correlate with outcomes in an amputation prevention program. J Vasc Surg. 2016;63:1563e1573.e2. 22. Wang C, Mai L, Yang C, et al. Reducing major lower extremity amputations after the introduction of a multidisciplinary team in patient with diabetes foot ulcer. BMC Endocr Disord. 2016;16:38. 23. Driver VR, Fabbi M, Lavery LA, Gibbons G. The costs of diabetic foot: the economic case for the limb salvage team. J Vasc Surg. 2010;52(3 Suppl l):17Se22S. 24. American Diabetes Association. 11. Microvascular complications and foot care: standards of medical care in diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S124eS138. 25. Ndosi M, Wright-Hughes A, Brown S, et al. Prognosis of the infected diabetic foot ulcer: a 12-month prospective observational study. Diabet Med. 2018;35:78e88. 26. Incidence of diabetic foot ulcer and lower extremity amputation among Medicare beneficiaries, 2006 to 2008: data points #2. 2011. Available at: https://www.ncbi.nlm.nih.gov/ books/NBK65149/. Accessed January 22, 2019. 27. Tesfaye S, Stevens LK, Stephenson JM, et al. Prevalence of diabetic peripheral neuropathy and its relation to glycaemic control and potential risk factors: the EURODIAB IDDM complications study. Diabetologia. 1996;39:1377e1384. 28. Abbott CA, Malik RA, van Ross ER, et al. Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the U.K. Diabetes Care. 2011;34:2220e2224.
29. Cabezas-Cerrato J. The prevalence of clinical diabetic polyneuropathy in Spain: a study in primary care and hospital clinic groups. neuropathy Spanish study group of the Spanish diabetes society (SDS). Diabetologia. 1998;41:1263e1269. 30. Gregg EW, Gu Q, Williams D, et al. Prevalence of lower extremity diseases associated with normal glucose levels, impaired fasting glucose, and diabetes among U.S. adults aged 40 or older. Diabetes Res Clin Pract. 2007;77:485e488. 31. Monami M, Longo R, Desideri CM, et al. The diabetic person beyond a foot ulcer: healing, recurrence, and depressive symptoms. J Am Podiatr Med Assoc. 2008;98:130e136. 32. Reiber GE, Smith DG, Wallace C, et al. Effect of therapeutic footwear on foot reulceration in patients with diabetes: a randomized controlled trial. JAMA. 2002;287:2552e2558. 33. Telfer S, Bigham JJ. The influence of population characteristics and measurement system on barefoot plantar pressures: a systematic review and meta-regression analysis. Gait Posture. 2019;67:269e276. 34. Waaijman R, de Haart M, Arts ML, et al. Risk factors for plantar foot ulcer recurrence in neuropathic diabetic patients. Diabetes Care. 2014;37:1697e1705. 35. Edmonds ME, Blundell MP, Morris ME, et al. Improved survival of the diabetic foot: the role of a specialized foot clinic. Q J Med. 1986;60:763e771. 36. Sacco IC, Bacarin TA, Canettieri MG, Hennig EM. Plantar pressures during shod gait in diabetic neuropathic patients with and without a history of plantar ulceration. J Am Podiatr Med Assoc. 2009;99:285e294. 37. Maluf KS, Mueller MJ. Novel award 2002. Comparison of physical activity and cumulative plantar tissue stress among subjects with and without diabetes mellitus and a history of recurrent plantar ulcers. Clin Biomech (Bristol, Avon). 2003;18:567e575. 38. Peters EJ, Armstrong DG, Lavery LA. Risk factors for recurrent diabetic foot ulcers: site matters. Diabetes Care. 2007;30:2077e2079. 39. Hicks CW, Canner JK, Karagozlu H, et al. Quantifying the costs and profitability of care for diabetic foot ulcers treated in a multidisciplinary setting. J Vasc Surg. 2019;70:233e240. 40. Horswell RL, Birke JA, Patout Jr CA. A staged management diabetes foot program versus standard care: a 1-year cost and utilization comparison in a state public hospital system. Arch Phys Med Rehabil. 2003;84:1743e1746. 41. Hicks CW, Canner JK, Karagozlu H, et al. The society for vascular surgery wound, ischemia, and foot infection (WIfI) classification system correlates with cost of care for diabetic foot ulcers treated in a multidisciplinary setting. J Vasc Surg. 2018;67:1455e1462.