What Are Diabetic Foot Ulcers?

This JAMA Patient Page describes diabetic foot ulcers and their evaluation and treatment.

Microenvironment-Based Diabetic Foot Ulcer Nanomedicine.

Diabetic foot ulcers (DFU), one of the most serious complications of diabetes, are essentially chronic, nonhealing wounds caused by diabetic neuropathy, vascular disease, and bacterial infection. Given its pathogenesis, the DFU microenvironment is rather complicated and characterized by hyperglycemia, ischemia, hypoxia, hyperinflammation, and persistent infection. However, the current clinical therapies for DFU are dissatisfactory, which drives researchers to turn attention to advanced nanotechnology to address DFU therapeutic bottlenecks. In the last decade, a large number of multifunctional nanosystems based on the microenvironment of DFU have been developed with positive effects in DFU therapy, forming a novel concept of "DFU nanomedicine". However, a systematic overview of DFU nanomedicine is still unavailable in the literature. This review summarizes the microenvironmental characteristics of DFU, presents the main progress of wound healing, and summaries the state-of-the-art therapeutic strategies for DFU. Furthermore, the main challenges and future perspectives in this field are discussed and prospected, aiming to fuel and foster the development of DFU nanomedicines successfully.

Worldwide Research Trends on Diabetic Foot Ulcers (2004-2020): Suggestions for Researchers.

OBJECTIVES: Diabetic foot ulcer (DFU) is one of the devastating complications of diabetes. It has high mortality and disability rates. The number of research articles on DFUs has increased. This study was designed to explore the global trends and research hotspots of DFUs to benefit researchers in shaping future research directions. METHODS: Literatures relating to DFU from 2004 to 2020 were retrieved from the Science Citation Index Expanded (SCI-expanded) of Web of Science Core Collection (WoSCC). The current status of DFU research (including publications, journals, the performances of relevant countries, institutions, and authors and the research trends and hotspots of DFU) was analyzed with the WoSCC. VOSviewer v1.6.10.0 was utilised for cocitation, coauthorship, cooccurrence analyses, and bibliographic coupling. RESULTS: A total of 5869 publications on DFUs were retrieved. We performed a longitudinal review of publications over 17 years: 4500 articles and 865 review articles on DFUs published from 2004 to 2020 were analyzed. The total citation was 107,296. The USA (n = 1866), England (n = 606), and China (n = 599) were the three largest contributors. The University of Washington had the greatest number of publications within this time period (n = 103), and it had the most cooperative units and was in the core position in all research institutions, followed by the University of Manchester (n = 94) and the University of Miami (n = 92). Armstrong DG (91/1.69%) and Lavery LA (55/1.19%) should be regarded as scholars who have made outstanding contributions. The top journal with the greatest total link strength was Diabetes Care. Analysis showed that the global research hotspots of DFU focused on lower limb amputation, diabetic foot infection, and treatment and management of DFU. Studies on osteomyelitis, wound therapy and management, multidisciplinary integration and mechanism of DFUs, and its related diseases are the research fronts that should be closely watched in the future. CONCLUSIONS: This study revealed the current research status and hotspots in the domain of DFU over the past 17 years, which can help researchers to further pinpoint potential perspectives on hot topics and research frontiers.

Terahertz imaging demonstrates its diagnostic potential and reveals a relationship between cutaneous dehydration and neuropathy for diabetic foot syndrome patients.

Diabetic foot syndrome, a long term consequence of Diabetes Mellitus, is the most common cause of non-traumatic amputations. Around 8% of the world population suffers from diabetes, 15% of diabetic patients present a diabetic foot ulcer which leads to amputation in 2.5% of the cases. There is no objective method for the early diagnosis and prevention of the syndrome and its consequences. We test terahertz imaging, which is capable of mapping the cutaneous hydration, for the evaluation of the diabetic foot deterioration as an early diagnostic test as well as ulcers prevention and tracking tool. Furthermore, the analysis of our terahertz measurements combined with neurological and vascular assessment of the patients indicates that the dehydration is mainly related to the peripheral neuropathy without a significant vascular cause.

Acceptance of illness, quality of life and nutritional status of patients after lower limb amputation due to diabetes mellitus.

INTRODUCTION: Diabetes mellitus is one of the most common chronic diseases with a high number of sufferers worldwide. Diabetic neuropathy and diabetic angiopathy lead to serious infectious complications which are very difficult to combat and may finally lead to the amputation of a lower limb. The aim of the study was to evaluate the quality of life, the level of acceptance of the illness and the nutritional status of patients after lower limb amputation due to diabetes. METHODS: Ninety-nine patients (23 men and 76 women) were enrolled into the study. They had all undergone lower limb amputation due to diabetic foot and were treated in the Department of General and Oncological Surgery. The following questionnaires were used: the WHO Quality of Life-BREF (WHOQOL-BREF), the Mini Nutritional Assessment (MNA), the Acceptance of Illness Scale (AIS) and the anonymous specific socio-demographic characteristics questionnaire. RESULTS: The diabetes-related amputees were revealed to have a higher QoL within the social domain (mean score 64.48), an intermediate QoL - within the environmental domain (mean score 63.04) and the mental domain (mean score 59.61), and a lower QoL - within physical (somatic) domain (mean score 54.69). There was no statistical correlation between genders or between all the domains of QoL (P > 0.05). The mean MNA score was 22.66, which means that patients were at risk of malnutrition. There were statistical differences between women and men as regards nutritional status (P = 0.034). The mean AIS score was 27.65 (27.09 women and 29.48 men), which means that the respondents accept their disease. There was no statistical correlation between gender and the acceptance of the disease (P = 0.288). There was not statistical correlation between age and QoL (P > 0.05). There were statistical differences between age and nutritional status (P < 0.05), and between age and acceptance of the illness (P = 0.044). CONCLUSIONS: The better the quality of life was in all the domains, the better the level of acceptance of illness was. The less malnourished the patient was, the better their quality of life was in all the domains.

A Comprehensive Review of the Pathogenesis, Diagnosis, and Management of Diabetic Foot Infections.

GENERAL PURPOSE: To review an approach to diabetic foot infections (DFIs), including acute osteomyelitis, while also discussing current practices and the challenges in diagnosis and management. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant will1. Identify the risk factors for developing DFIs.2. Outline diagnostic techniques for assessing DFIs.3. Select the assessment techniques that support a diagnosis of osteomyelitis.4. Choose the appropriate pharmacologic and nonpharmacologic treatment options for patients who have DFIs. ABSTRACT: Diabetic foot ulcers result from a combination of peripheral neuropathy, vascular compromise, and repetitive trauma. Approximately 50% of individuals with diabetic foot ulcers will develop a diabetic foot infection (DFI), and 20% of individuals with a DFI will develop osteomyelitis. Herein, the authors review an approach to DFIs including acute osteomyelitis and discuss current practices and challenges in diagnosis and management.The diagnosis of a skin and soft tissue DFI is based on clinical criteria. A bone biopsy is considered the criterion standard for diagnosis of osteomyelitis; however, biopsy is not always feasible or available. Consequently, diagnosis can be made using a combination of clinical, biochemical, and radiographic findings. X-ray is the recommended imaging modality for initial evaluation; however, because of its lower relative sensitivity, advanced imaging may be used when clinical suspicion remains after negative initial testing.The microbiology of skin and soft tissue DFIs and osteomyelitis is similar. Staphylococcus aureus and other Gram-positive cocci are the most common pathogens identified. Deep cultures are preferred in both DFI and osteomyelitis to identify the etiologic pathogens implicated for targeted antimicrobial therapy. Management also requires a multidisciplinary approach. Surgical debridement in those with deep or severe infections is necessary, and surgical resection of infected bone is curative in cases of osteomyelitis. Finally, appropriate wound care is critical, and management of predisposing factors, such as peripheral neuropathy, peripheral arterial disease, tinea, and edema, aids in recovery and prevention.

Ginsenoside Rg1 promoted the wound healing in diabetic foot ulcers via miR-489-3p/Sirt1 axis.

PURPOSE: Diabetic foot ulcers (DFUs) are common complications of high severity for diabetes. Ginsenoside Rg1 (Rg1) has the potential for diabetes and cardiovascular diseases therapy. This research aimed at exploring the regulation of Rg1 on DFUs treatment and the underlying mechanism. METHODS: Human umbilical vein endothelial cells (HUVECs) incubated with high-glucose culture medium were established for induction of diabetes model. The MTT assay, Annexin V/PI assay and oxidative stress detection were carried out on high-glucose-induced HUVECs. Dual-luciferase reporter assay was performed to prove the interaction of miR-489-3p and Sirt1. DFUs model was established to determine the efficiency of Rg1 and miR-489-3p in wound closure of DFUs in vivo. RESULTS: Rg1 promoted cell proliferation, migration and angiogenesis, and reduced cell apoptosis in high-glucose-induced HUVECs. Knockdown of miR-489-3p alleviated the high-glucose-induced damage to HUVECs, while overexpression of miR-489-3p attenuated the protection effects of Rg1. Overexpression Sirt1 promoted wound healing in DFUs and Sirt1 was a direct target of miR-489-3p. In addition, animal experiments demonstrated that Rg1 promoted wound closure by regulating miR-489-3p/Sirt1 axis. CONCLUSIONS: Rg1 alleviated the DFUs by increasing Sirt1 expression via miR-489-3p downregulation and promoting activation of PI3K/AKT/eNOS signaling.

Associations between Nutrients and Foot Ulceration in Diabetes: A Systematic Review.

We reviewed the literature to evaluate potential associations between vitamins, nutrients, nutritional status or nutritional interventions and presence or healing of foot ulceration in diabetes. Embase, Medline, PubMed, and the Cochrane Library were searched for studies published prior to September 2020. We assessed eligible studies for the association between nutritional status or interventions and foot ulcers. Fifteen studies met the inclusion criteria and were included in this review. Overall, there is a correlation between poor nutritional status and the presence of foot ulceration or a delay in healing. However, there is not enough data to reach conclusions about whether the relationships are causal or only association. Further research is required to test whether any forms of nutritional supplementation improve foot ulcer healing.

The Design of Individual Orthopedic Insoles for the Patients with Diabetic Foot Using Integral Curves to Describe the Plantar Over-Pressure Areas.

Identification of over-pressure areas in the plantar side of the foot in patients with diabetic foot and reduction of plantar pressure play a major role in clinical practice. The use of individual orthopedic insoles is essential to reduce the over-pressure. The aim of the present study is to mark the over-pressure areas of the plantar part of the foot on a pedogram and describe them with high accuracy using a mathematical research method. The locally over-pressured areas with calluses formed due to repeated injuries were identified on the patients' pedograms. The geometric shapes of the over-pressure areas were described by means of the integral curves of the solutions to Dirichlet singular boundary differential equations. Based on the mathematical algorithm describing those curves, the computer programs were developed. The individual orthopedic insoles were produced on a computer numerical control milling machine considering the locally over-pressured areas. The ethylene vinyl acetate polymers of different degrees of hardness were used to produce the individual orthopedic insoles. For the over-pressure areas, a soft material with a hardness of 20 Shore A was used, which reduces the pressure on the plantar side of the foot and increases the contact area. A relatively hard material with a hardness of 40 Shore A was used as the main frame, which imparts the stability of shape to the insole and increases its wear life. The individual orthopedic insoles produced by means of such technology effectively reduce the pressure on the plantar side of the foot and protect the foot from mechanical damage, which is important for the treatment of the diabetic foot.

Assessment of heart rate variability (HRV) in subjects with type 2 diabetes mellitus with and without diabetic foot: correlations with endothelial dysfunction indices and markers of adipo-inflammatory dysfunction.

BACKGROUND: Some studies have suggested that patients with diabetes and foot complications have worse cardiovascular and cerebrovascular risk profiles, higher degrees of endothelial dysfunction and arterial stiffness and a higher inflammatory background than patients with diabetes without diabetic foot complications. Patients with diabetes mellitus have an alteration in the sympathovagal balance as assessed by means of heart rate variability (HRV) analysis, which is also related to the presence of endothelial dysfunction. Other studies suggest a possible role of inflammation coexisting with the alteration in the sympathovagal balance in favor of the atherosclerotic process in a mixed population of healthy subjects of middle and advanced age. AIMS: The aim of this study was to evaluate the degree of alteration of sympathovagal balance, assessed by HRV analysis, in a cohort of patients with diabetes mellitus with diabetic foot and in control subjects without diabetic foot compared with a population of healthy subjects and the possible correlation of HRV parameters with inflammatory markers and endothelial dysfunction indices. METHODS: We enrolled all patients with diabetic ulcerative lesions of the lower limb in the Internal Medicine with Stroke Care ward and of the diabetic foot outpatient clinic of P. Giaccone University Hospital of Palermo between September 2019 and July 2020. 4-h ECG Holter was performed. The following time domain HRV measures were analyzed: average heart rate, square root of the mean of successive differences of NN (RMSSD), standard deviation or square root of the variance (SD), and standard deviation of the means of the NN intervals calculated over a five-minute period (SDANN/5 min). The LF/HF ratio was calculated, reactive hyperemia was evaluated by endo-PAT, and serum levels of vaspine and omentin-1 were assessed by blood sample collection. RESULTS: 63 patients with diabetic foot, 30 patients with diabetes and without ulcerative complications and 30 patients without diabetes were enrolled. Patients with diabetic ulcers showed lower mean diastolic blood pressure values than healthy controls, lower MMSE scores corrected for age, lower serum levels of omentin-1, lower RHI values, higher body weight values and comparable body height values, HF% and LF/HF ratio values. We also reported a negative correlation between the RHI value and HRV indices and the expression of increased parasympathetic activity (RMSDD and HF%) in subjects with diabetic foot and a statistically significant positive correlation with the LF/HF ratio and the expression of the sympathovagal balance. DISCUSSION: Patients with diabetic foot show a higher degree of activation of the parasympathetic system, expressed by the increase in HF values, and a lower LF/HF ratio. Our findings may corroborate the issue that a parasympathetic dysfunction may have a possible additive role in the pathogenesis of other vascular complications in subjects with diabetic foot.

Deteriorated regional calf microcirculation measured by contrast-free MRI in patients with diabetes mellitus and relation with physical activity.

OBJECTIVE: To evaluate regional calf muscle microcirculation in people with diabetes mellitus (DM) with and without foot ulcers, compared to healthy control people without DM, using contrast-free magnetic resonance imaging methods. METHODS: Three groups of subjects were recruited: non-DM controls, DM, and DM with foot ulcers (DM + ulcer), all with ankle brachial index (ABI) > 0.9. Skeletal muscle blood flow (SMBF) and oxygen extraction fraction (SMOEF) in calf muscle were measured at rest and during a 5-min isometric ankle plantarflexion exercise. Subjects completed the Yale physical activity survey. RESULTS: The exercise SMBF (ml/min/100 g) of the medial gastrocnemius muscle were progressively impaired: 63.7 ± 18.9 for controls, 42.9 ± 6.7 for DM, and 36.2 ± 6.2 for DM + ulcer, p < 0.001. Corresponding exercise SMOEF was the lowest in DM + ulcers (0.48 ± 0.09). Exercise SMBF in the soleus muscle was correlated moderately with the Yale physical activity survey (r = 0.39, p < 0.01). CONCLUSIONS: Contrast-free MR imaging identified progressively impaired regional microcirculation in medial gastrocnemius muscles of people with DM with and without foot ulcers. Exercise SMBF in the medial gastrocnemius muscle was the most sensitive index and was associated with HbA1c. Lower exercise SMBF in the soleus muscle was associated with lower Yale score.

Factors Associated With Key Outcomes in Diabetes Related Foot Disease: A Prospective Observational Study.

OBJECTIVE: Diabetic foot disease is a serious and common complication of diabetes mellitus. The aim of this study was to assess limb and patient factors associated with key clinical outcomes in diabetic patients with foot ulcers. METHODS: This was a prospective observational study of diabetic patients with foot wounds admitted to a major tertiary teaching hospital in South Australia or seen at associated multidisciplinary foot clinics between February 2017 and December 2018. Patient demographic and clinical data were collected, including limb status severity assessed by the WIfI system and grip strength. Participants were followed up for 12 months. The primary outcomes were major amputation, death, amputation free survival, and completion of healing of the index wound within one year. RESULTS: A total of 153 participants were recruited and outcome data were obtained for 152. Forty-two participants underwent revascularisation during the research period. Eighteen participants (11.8%) suffered major amputation of the index limb and 16 (10.5%) died during follow up. Complete wound healing was achieved in 106 (70%) participants. There was a statistically significant association between WIfI stage and major amputation (subdistribution hazard ratio [SHR] 2.75), mortality (hazard ratio [HR] 2.60), amputation free survival (odds ratio [OR] 0.32), and wound healing (SHR 0.69). There was also a statistically significant association between time to healing and grip strength (SHR 0.50), and previous amputations (major or minor) (SHR 0.57). CONCLUSION: This prospective study supports the ability of the WIfI classification system to predict one year key clinical outcomes in a diabetic population with foot ulcers. It also demonstrated that grip strength may be a useful predictor of wound healing.

Application of a simple skin stretching system and negative pressure wound therapy in repair of complex diabetic foot wounds.

The management of complex diabetic foot wounds with large skin defects poses a challenge for surgeons. We presented a simple skin stretching system and negative pressure wound therapy for the repair of complex diabetic foot wounds to examine the effectiveness and safety.A total of 16 patients with diabetic foot ulcers were retrospectively reviewed between January 2015 and October 2020. All patients underwent the treatment by 3 stages. In stage 2, these difficult-to-close wounds of diabetes foot were residual. This method was applied to the wounds with a median defect size of 20.42 cm2 (range, 4.71-66.76 cm2).The median time for closure of complex diabetic foot wounds was 14 days ranging from 8 to 19 days. With respect to the absolute rates of reduction, it was observed with a median of 1.86 cm2/day, ranging from 0.29 cm2/day to 8.35 cm2/day. In accordance with the localization of the defect, the patients were divided into 3 groups: side of the foot (37.5%), dorsum of the foot (50.0%), and others (12.5%). There was no statistical difference between side of the foot and dorsum of the foot in terms of the median defect size with P = 0.069 (Kruskal-Wallis test). Otherwise, there were statistically significant differences regarding the median time and the median absolute rates (P < 0.05; Kruskal-Wallis test). No severe complications were encountered in this study.In summary, our results show that application of the simple skin stretching system and NPWT is an effective and safe approach to complex diabetic foot wounds. Nevertheless, more attention should be paid to the appropriate patient selection and intraoperative judgment to ensure wound closure and avoid undue complications.

SGLT2 inhibitors and lower limb complications: an updated meta-analysis.

BACKGROUND: To exam the associations between the use of sodium glucose co-transporter 2 inhibitor (SGLT2i) and the risk of lower limb complications, and to analyze the associated factors. METHODS: Pubmed, Medline, Embase, the Cochrane Center Register of Controlled Trials for Studies and Clinicaltrial.gov were searched from the inception to November 2020. Randomized controlled trials of SGLT2i conducted in population containing diabetic patients with reports of amputation, peripheral arterial disease (PAD) and diabetic foot (DF) events were included. Random-effect model, fixed-effect model and meta-regression analysis were accordingly used. RESULT: The numbers of SGLT2i users versus non-SGLT2i users in the analyses of amputation, PAD and DF were 40,925/33,414, 36,446/28,685 and 31,907/25,570 respectively. Compared with non-SGLT2i users, the risks of amputation and PAD were slightly increased in patients with canagliflozin treatment (amputation: OR = 1.60, 95% CI 1.04 to 2.46; PAD: OR = 1.53, 95 % CI 1.14 to 2.05). Meta-regression analyses indicated that greater weight reduction in SGLT2i users was significantly associated with the increased risks of amputation (ß = - 0.461, 95% CI - 0.726 to - 0.197), PAD (ß = - 0.359, 95% CI - 0.545 to - 0.172) and DF (ß = - 0.476, 95% CI - 0.836 to - 0.116). Lower baseline diastolic blood pressure (ß = - 0.528, 95% CI - 0.852 to - 0.205), more systolic blood pressure reduction (ß = - 0.207, 95% CI - 0.390 to - 0.023) and more diastolic blood pressure reduction (ß = - 0.312, 95% CI - 0.610 to - 0.015) were significantly associated with the increased risks of amputation, PAD and DF respectively in patients with SGLT2i treatment. CONCLUSIONS: The risks of amputation and PAD were slightly increased in patients with canagliflozin treatment. Reductions in body weight and blood pressure were associated with lower limb complications in patients with SGLT2i treatment.

Differentiation of Diabetic Foot Ulcers Based on Stimulation of Myogenic Oscillations by Transient Ischemia.

PURPOSE: Diabetic foot ulceration is a chronic complication characterized by impaired wound healing. There is a great demand for a diagnostic tool that is able to monitor and predict wound healing. PATIENTS AND METHODS: Oscillations in the microcirculation, known as flowmotion, can be monitored very distinctly and precisely using the Flow Mediated Skin Fluorescence (FMSF) technique. The flowmotion response to hypoxia was measured quantitatively in 42 patients with diabetic foot ulcers. RESULTS: The flowmotion response to hypoxia parameters FM(R) and HS were used to differentiate the diabetic foot ulcers and correlate them with clinical status. In some cases, FMSF measurements were continued over the period of a year in order to monitor disease progress. The clinical status of the quarter of patients with the highest HS values (group A, HS = 50.2±18.3) was compared to the quarter with the lowest HS values (group B, HS = 4.3±1.7). The patients in the group B were identified as having low prognosis for healing and were characterized by higher incidences of hypertension, hyperlipidemia, prevalent CVD, neuropathy and nephropathy. CONCLUSION: Impaired flowmotion responses to hypoxia induced by transient ischemia can be used for differentiation of diabetic foot ulcers and identification of cases with low prognosis for healing.

Plantar soft tissues and Achilles tendon thickness and stiffness in people with diabetes: a systematic review.

BACKGROUND: Diabetes mellitus is associated with changes in soft tissue structure and function. However, the directionality of this change and the extent to which either tissue thickness or stiffness contributes to the pathogenesis of diabetes-related foot ulcerations is unclear. Hence, this systematic review aims to summarise the existing evidence for soft tissue structural differences in the feet of people with and without diabetes. METHODS: In compliance with MOOSE and PRISMA guidelines, AMED, CINAHL, MEDLINE, ProQuest Health & Medical Collection, ProQuest Nursing & Allied Health Database, and Web of Science electronic databases were systematically searched for studies published from database inception until 1st October 2020 [Prospero CRD42020166614]. Reference lists of included studies were further screened. Methodological quality was appraised using a modified critical appraisal tool for quantitative studies developed by McMaster University. RESULTS: A total of 35 non-randomised observational studies were suitable for inclusion. Within these, 20 studies evaluated plantar tissue thickness, 19 studies evaluated plantar tissue stiffness, 9 studies evaluated Achilles tendon thickness and 5 studies evaluated Achilles tendon stiffness outcomes. No significant differences in plantar tissue thickness were found between people with and without diabetes in 55% of studies (11/20), while significantly increased plantar tissue stiffness was found in people with diabetes in 47% of studies (9/19). Significantly increased Achilles tendon thickness was found in people with diabetes in 44% of studies (4/9), while no significant differences in Achilles tendon stiffness were found between people with and without diabetes in 60% of studies (3/5). CONCLUSIONS: This systematic review found some evidence of soft tissue structural differences between people with and without diabetes. However, uncertainty remains whether these differences independently contribute to diabetes-related foot ulcerations. The heterogeneity of methodological approaches made it difficult to compare across studies and methodological quality was generally inadequate. High-quality studies using standardised and validated assessment techniques in well-defined populations are required to determine more fully the role of structural tissue properties in the pathogenesis of diabetes-related foot ulcerations.

Evaluation of revascularization benefit quartiles using the Wound, Ischemia, and foot Infection classification system for diabetic patients with chronic limb-threatening ischemia.

OBJECTIVE: The Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification system was developed to stratify the risk of 1-year major amputation. Recently, the WIfI scores were used to define the estimated revascularization benefit quartiles ranging from high benefit (Q1) to questionable benefit (Q4). The aim of our study was to evaluate the revascularization benefit quartiles in a cohort of diabetic patients presenting with chronic limb-threatening ischemia (CLTI). METHODS: All diabetic patients presenting to our multidisciplinary diabetic foot and wound clinic (June 2012 to May 2020) who underwent lower extremity revascularization for CLTI were included. The affected limbs were graded using the WIfI system and assigned to an estimated benefit of revascularization quartile as previously published. One-year major amputation, complete foot healing, secondary patency, and amputation-free survival were calculated among the quartiles using Kaplan-Meier curve analyses and compared using Cox proportional hazards models. RESULTS: Overall, 136 diabetic patients underwent revascularization of 187 limbs (mean age, 64.9 ± 11.2 years; 63.2% male; 58.8% black). The limbs were revascularized using an endovascular approach for 66.8% and open surgery for 33.2%. Of the 187 limbs, 27.3% had a high estimated benefit of revascularization (Q1), 31.6% had a moderate estimate benefit of revascularization (Q2), 20.3% had a low estimated benefit of revascularization (Q3), and 20.9% had a questionable benefit of revascularization (Q4). The estimated 1-year major amputation rates were 7.2% ± 4.1% for Q1, 3.8% ± 2.6% for Q2, 7.0% ± 4.8% for Q3, and 25.7% ± 7.5% for Q4 (P = .006). The estimated 1-year foot healing rates were 87.3% ± 5.7% for Q1, 84.8% ± 5.6% for Q2, 83.8% ± 7.4% for Q3, and 68.2% ± 9.1% for Q4 (P = .06). The overall secondary patency (P = .23) and amputation-free survival (P = .33) did not significantly differ among the groups. Using Cox proportional hazard modeling, the Q4 group had a significantly greater risk of major amputation compared with Q1 (hazard ratio, 4.26; 95% confidence interval, 1.15-15.70). Of the 14 limbs requiring major amputation, 9 (56.3%) had a patent revascularization at the time of amputation, including one of three limbs in Q1, two of two limbs in Q2, no limb in Q3, and six of nine limbs in Q4. CONCLUSIONS: The questionable estimated revascularization benefit quartile using the WIfI classification system is significantly associated with 1-year major amputation in diabetic patients presenting with CLTI. Limbs with a questionable benefit of revascularization (Q4) will frequently require major amputation despite a patent revascularization, suggesting that the wound size and infection burden are the driving factors behind the elevated risk of major amputation in this group. Our findings support the previously described use of the WIfI classification system to predict revascularization benefit among diabetic patients with CLTI.