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Diabetes Watch

Keys To Diagnosing, Stratifying And Treating Neuroischemic Ulcerations

The majority of limb loss in the United States is due to a combination of neuropathy, ischemia and infection.1 Populations affected by diabetes mellitus and peripheral arterial disease (PAD) are at particularly high risk for amputation.1 One can define the at-risk diabetic foot as one with a combination of syndromes with various degrees of neuropathy, ischemia and infection, potentially leading to destruction of skin and deep tissue structures, and ultimately resulting in limb loss or even loss of life. 

The prevalence of diabetic foot ulcers differs across the globe with sources estimating a range between four to 27 percent worldwide.1 The Eurodial study in 2007 showed that the presence of PAD in patients with diabetes is a strong predictor of non-healing foot ulcers.2,3 In addition, patients with diabetes had more severe disease in the distal arteries in comparison to those without diabetes.2 

The prevalence of PAD in patients with diabetes ranges from 10 to 60 percent.1 Oyibo and colleagues noted that 52.3 percent of diabetic foot ulcers were neuroischemic, 36 percent neuropathic and 11.7 percent purely ischemic.4 Given the high prevalence of PAD in patients with diabetes, it is important that we recognize the rapidly growing category of neuroischemic ulcers. Proper categorization of a diabetic foot ulcer may lead one to different management strategy. 

Current Insights On The Clinical Assessment Of Peripheral Arterial Disease In Patients With DFUs 

When assessing PAD, it is important to understand that PAD is a spectrum. This spectrum starts as a mild asymptomatic process, can shift to more moderate disease characterized by intermittent claudication and eventually progresses to a more severe disease characterized by chronic limb-threatening ischemia (CLTI). The goal of evaluating a patient with a foot ulcer is not only to identify the presence or absence of PAD, but to assess the severity of PAD if it is present. 

The typical signs of PAD include symptoms of intermittent claudication, rest pain, diminished or absent pedal pulses, decrease in hair growth to the foot and toes, dystrophic toenails, atrophic skin, dependent rubor, and slow to non-healing foot ulcerations. These are the classic subjective and objective findings that we all learned in school and residency training. Although the above findings help us make the diagnosis of PAD, a lack of these findings does not rule out PAD. 

The truth is that we underdiagnose PAD and underestimate its severity until it is too late. A paradigm shift in our approach to PAD should focus on figuring out where the patient is along the aforementioned PAD spectrum. In other words, does the patient have mild, moderate or severe PAD? 

One of the basic tenets of the clinical examination is a thorough vascular exam. This includes palpation of the femoral, popliteal, posterior tibial and dorsalis pedis arteries. Absent or weak pulses are abnormal findings, and may indicate a presence of hemodynamically significant arterial occlusion or stenosis.5 

If the pulse examination is abnormal, the next step is to obtain non-invasive arterial studies. Since greater than 50 percent of diabetic foot ulcers are considered neuroischemic, we should have a very low threshold for ordering and interpreting these non-invasive studies.6 These non-invasive studies include the ankle-brachial index (ABI), toe-brachial index (TBI) and toe pressures. The ABI and TBI are important vascular assessment tools, and both are reproducible and fairly accurate in the assessment of PAD. 

However, ABI values, may be falsely elevated in patients with diabetes due to calcified and non-compressible arteries.5 In this case, the toe pressure is the most accurate assessment of PAD at the level of the forefoot as digital calcifications are much less common than at the level of the ankle. Multiple studies demonstrate that a toe pressure of at least 40 mmHg is a good indicator of healing a diabetic foot ulcer.6 A toe pressure of 30 mmHg or less is marginal, and is highly predictive of non-healing.6 If one cannot obtain toe pressures due to prior amputation or ulceration, transcutaneous oxygen pressure (TcPO2) is considered the next best modality for assessing perfusion.7 However, one should analyze the results of TcPO2 with caution as it is not as accurate and reproducible as the other aforementioned physiologic studies. 

Using The WIfI Classification System To Stratify Vascular Risk 

The next step is to risk stratify patients based on their hemodynamic studies. Current classification systems fall short in capturing the full spectrum of the severity of PAD as it relates to the diabetic foot. The Fontaine and Rutherford classifications that are commonly in use for threatened limbs and PAD are purely ischemic models. Similarly, the commonly used Wagner and University of Texas wound classification systems do not elaborate on the spectrum and severity of PAD. 

In 2014, The Society for Vascular Surgery Lower Extremity Guidelines Committee recognized the pitfalls associated with prior classification systems and the need for a more comprehensive system as it relates to neuroischemic ulcers.7 The result was a classification system for threatened lower limbs, categorizing and grading (from zero to three) the three major risk factors leading to amputation: wound, ischemia and foot infection (WIfI). 

The ischemia portion of the WIfI classification relies on the value of any of the following: ABI, ankle pressure or toe pressure, and enables physicians to risk stratify ischemia along a spectrum of mild, moderate and severe disease.7 Earlier recognition along the spectrum of the disease process allows for earlier intervention and salvage of limbs. Furthermore, the WIfI classification system is validated to predict major amputation rates. The higher the grade for each category, the higher the risk of the patient undergoing an amputation within one year.7 

Managing PAD In Patients With Neuroischemic Ulcers 

We must recognize the high prevalence of PAD in patients with diabetes and the rapidly growing category of neuroischemic ulcers. The use of the WIfI system is one of many steps toward a shift in assessing patients who are at high risk for limb loss. With this in mind, one should not use this system as a stand-alone tool but rather as starting point for systematic evaluation and early PAD recognition. 

Having a high index of suspicion for diagnosing neuroischemic ulcers will allow for earlier detection and diagnosis of PAD. Once one makes the diagnosis of a neuroischemic ulcer, it is imperative that we assess the grade of ischemia. Ischemia grade 2 or grade 3 based on the WIfI system should trigger one to obtain a vascular surgery consultation.7 The obvious goal is to avoid missing the PAD component that can significantly affect wound healing process but could easily be addressed via early and appropriate vascular intervention. 

It is important to mention here that we are not advocating that all neuroischemic ulcers will require vascular intervention to achieve healing. However, without adequately assessing the severity of the arterial disease by stratifying the patient into the various categories of ischemia, we are missing the necessary information in our decision-making process. The close relationship between diabetic foot ulcers and PAD cannot be overstated. Accordingly, the vascular-podiatry collaboration is truly the new standard of care for neuroischemic ulcerations. 

Concluding Thoughts 

Patients with diabetic foot complications are among the most complex and vulnerable of all patient populations. The main risk factor for major amputation in the diabetic foot is ischemia of the affected limb. It is important that clinicians do not assess ischemia as a static disease process but instead risk stratify patients with ischemia along a spectrum of severity. The partnership among the podiatric surgeon and vascular surgeon is a logical one. Early recognition of PAD by the podiatric surgeon can lead to early intervention by the vascular surgeon. The complementary skills and knowledge of podiatric and vascular surgeons are instrumental in healing ulcers, and minimizing the risk of major amputations.  

Dr. Krepkiy is a Limb Preservation Fellow at the University of California, San Francisco. 

Dr. Dini is an Associate Clinical Professor at the University of California, San Francisco Orthopaedic Trauma Institute and is an Assistant Professor with the California School of Podiatric Medicine at Samuel Merritt University. 

Dr. Reyzelman is a Co-Director of the University of California, San Francisco Center for Limb Preservation and the Diabetic Foot. He is a Professor at the California School of Podiatric Medicine at Samuel Merritt University. Dr. Reyzelman is board-certified by the American Board of Foot and Ankle Surgery. 

Diabetes Watch
By Viktoriya Krepkiy, DPM, Monara Dini, DPM and Alexander M. Reyzelman, DPM

1. Reiber GE. Epidemiology of foot ulcers and amputations in the diabetic foot. In: Bowker JH, Pfeifer MA, eds. The Diabetic Foot. St Louis, MO: Mosby; 2001:13-32. 

2. Prompers L, Huijberts M, Apelqvist J, et al. Optimal organization of health care in diabetic foot disease: introduction to the Eurodiale study. Int J Low Extrem Wounds. 2007;6(1):11-17. 

3. Prompers L, Schaper N, Apelqvist J, et al. Prediction of outcome in individuals with diabetic foot ulcers: focus on the differences between individuals with and without peripheral arterial disease. The EURODIALE study. Diabetologia. 2008;51(5):747-755. 

4. Oyibo SO, Jude EB, Voyatzoglou D, Boulton AJM. Clinical characteristics of patients with diabetic foot problems: changing patterns of foot ulcer presentation. Pract Diabet Int. 2001;19(1):10-12. 

5. Apelqvist J, Larsson J, Agardh CD. The importance of peripheral pulses, peripheral edema and local pain for the outcome of diabetic foot ulcers. Diabet Med.1990;7(7):590- 594. 

6. Wang Z, Hasan R, Firwana B, et al. A systemic review and meta-analysis of tests to predict wound healing in diabetic foot. J Vasc Surg. 2016; 63(2):29-33 

7. Mills JL, 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(1):220034. 

Additional References 

8. Singh B, Armstrong DG, Lipsky BA. Preventing foot ulcer in persons with diabetes. JAMA. 2005;293(2):217-222. 

9. 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(8):1679- 1685. 

10. Galkowska H, Podbielska A, Olszewski WL, et al. Epidemiology and prevalence of methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis in patients with diabetic foot ulcers: focus on the differences between species isolated from individuals with ischemic vs. neuropathic foot ulcers. Diabetes Res Clin Pract. 2009;84(2):187-193. 

11. Ndip A, Jude EB, Emerging evidence for neuroischemic diabetic foot ulcers: model of care and how to adapt practice. Int J Low Extrem Wounds. 2009;8(2):82-94. 

12. Aboyans V, Ho E, Denenberg JO, Ho LA, Natarajan L, Criqui MH. The association between elevated ankle systolic pressures and peripheral occlusive arterial disease in diabetic and nondiabetic subjects. J Vasc Surg. 2008;48(5):1197-1203. 

13. de Graaff JC, Ubbink DT, Legemate DA, Tijssen JG, Jacobs MJ. Evaluation of toe pressure and transcutaneous oxygen measurements in management of chronic critical leg ischemia: a diagnostic randomized clinical trial. J Vasc Surg. 2003;38(3):528-534. 

14. Khan NA, Rahim SA, Anand SS, Simel DL, Panju A. Does the clinical examination predict lower extremity peripheral arterial disease? JAMA. 2006;295(5):536-546. 

15. 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(6):1563-1573. 

16. Tay WL, Lo ZJ, Hong Q, Yong E. Toe pressure in predicting diabetic foot ulcer healing: A systemic review and meta-analysis. Ann Vasc Surg. 2019;60:371-378. 

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