The duplex scan has been proven to be a reliable non-invasive diagnostic tool1 and its accuracy was confirmed by many studies in the general population with digital subtraction angiography2.

In diabetic patients, occlusive peripheral arterial disease presents some morphologic peculiarities: obstructions are usually distal, calcific, and more prevalent than stenoses3,4. Such a morphological picture is particularly evident in diabetic patients with critical limb ischemia (CLI) 5.

In our diagnostic protocol, the duplex scanning is carried out by vascular surgeons of our hospital in order to assess noninvasively the morphological alterations of the occlusive disease and also to provide our endovascular radiologist with useful indications of whether to perform an antegrade ipsilateral, contralateral or brachial approach6. In our experience we found a great difference on results from duplex scanning compared to those from arteriography, especially when the duplex examination was not performed in our hospital by skilled vascular surgeons.

Therefore, we designed this study in order to compare the diagnostic agreement between arteriography and duplex ultrasound scanning performed either in non specialized centres (Group A) or carried out by vascular surgeons of our hospital (Group B), who have expertise in diabetic patients with critical limb ischemia.

Protocol: All diabetic patients referred to our Diabetic Foot Centre for foot lesions or for rest pain were assessed for the presence of CLI with the TransAtlantic Inter-Society Consensus (TASC II) criteria11. CLI was detected if transcutaneous oxygen tension (TcPO2 – TCMTM3, Radiometer GMBH, Cophenagen, Denmark) at the dorsum of the foot was < 30 mmHg and ankle pressure was < 70 mmHg when measurable (no patent or non-compressible foot arteries at the ankle level because of medial calcifications) with a continuous wave (CW) Doppler instrument (DIADOP 50, Mediland s.r.l. Varedo, Milan, Italy).

In all patients with CLI duplex scanning was performed and an arteriography and revascularization (when possible) were carried out. In case a duplex scanning had not been previously performed by the referring institution, the procedure was then carried out by vascular surgeons of our Institute (group B). The duplex study was performed in the noninvasive vascular laboratory of the Vascular Surgery Unit of our Institute, using an Acuson Sequoia 512 ultrasound machine (Acuson Corporation, 1220 Charleston Road, Mountain View CA). The lower limb arterial axis was examined along its length, Duplex signals were traced distally to under the malleolus, when possible. In all patients with CLI a digital subtraction arteriography was carried out. Digital subtraction arteriograms were performed by means of a biplanar method using an antegrade or contralateral trans-femoral or brachial approach.

For both, duplex and arteriography results the information was derived by printed results of the case history, using the definition of “stenosis” and “occlusion”.

Of the duplex scanning and the angiographic study, we considered for the statistical analysis in the ischemic limb the common plus superficial femoral arterial segments, the popliteal artery, the anterior tibial artery, the posterior tibial artery, the anterior tibial artery, the posterior tibial artery, and the peroneal artery The iliac arteries were characterized in a very few duplex studies in group A: therefore a comparison between these arterial segments was not carried out. Peak systolic velocity was reported in only 11 cases of group A and, therefore, this parameter was not compared between the two groups.

Statistical analysis: We reported the descriptive statistics as average values and standard deviation of continuous variables, and as percentages of the discrete variables. The difference between detected variables was evaluated by Student’s t-test for continuous variables, or chi square test for discrete variables. The 95% level has been adopted to ascertain the confidence intervals and 5% level has been considered to test the null hypothesis. We have compared the diagnostic accuracy level of Doppler examination with that of the angiographic study: we assessed the consistency between the two procedures when duplex examination was carried out either in “dedicated diabetic foot centers” or in centers without specific expertise. Then, we carried out an indirect comparison resorting to chi square test in the two groups of patients.

The Stata 10.0 software package (Statistics/Data Analysis, Stata Corporation, 4905 Lakeway Drive, College Station, Texas 77845 USA, 800-STATA-PC) was used.

During 2010, 344 diabetic patients were admitted to our foot centre because of CLI in 360 limbs according to the TASC 2007 parameters11. In 268 (74.4%) patients (group A) a Duplex scanning had previously been performed in other centres; in the remaining 92 (25.6%) patients (group B) who had not previously undergone a duplex study, the procedure was carried out in our Institute by experienced vascular surgeons. No significant difference was found between the two groups regarding the recorded demographics and clinical characteristics of the two patient groups.

Some results from duplex examination in group A were missing: the iliac trunk was not evaluated in 3 patients, the popliteal artery in 1 patient, the anterior tibial artery in 7, the posterior tibial artery in 9, and the peroneal artery was not evaluated in 119 patients. In group B patients the peroneal artery was not evaluated in 3 patients. In group A the iliac arteries were characterized in a very few tests and a comparison between these arterial segments was not carried out. Similarly, the determination of peak systolic velocity was not routinely performed and therefore no such comparisons between groups could be made.

All patients underwent arteriography in our center. Obstructions > 50% of vessel diameter were located exclusively in the proximal (femoral/popliteal) axis in 10 limbs (2.8%), exclusively in the distal (infrapopliteal) axis in 103 (28.6%) limbs, and in both proximal and distal axis in 247 limbs (68.6%). Figure 1 shows the localization of the obstruction in the ischemic limb.

In Group A the accuracy of the duplex scan performed in proximal arteries (femoral and popliteal) was not significantly different from that carried out in patients of group B: χ2 = 3.50, p = 0.062.

However, the difference between the accuracy of infrapopliteal artery (anterior tibial, posterior tibial, and peroneal) duplex scanning performed in Group A and that one performed in group B was highly significant: χ2 = 21.2, p <0.001.

Table 1 reports the percentage of stenoses and occlusions of ischemic limb in group A and B.

Table 2 reports the matched results in each evaluated artery of the ischemic limb in group A and B.

This is a retrospective study: the analysis of the concordance between duplex and arteriography was performed during the evaluation of the data of a prospective study of feasibility of PTA in diabetic patients with CLI. The data were collected using the printed reports enclosed in the case history of the patients. This prevented us from doing a methodologically robust comparison (ie: arteriography results compared by blinded observers, etc). On the other hand, duplex accuracy was evaluated in a real (Italian) world.

Duplex scanning is a safe, inexpensive and accurate diagnostic tool to map the locations and to describe the severity of occlusive arterial disease in the lower limbs7. This is true for non diabetic patients,but is it also true for the diabetic patients ? For diabetic patients the American Diabetes Association, in a Position Statement dated December 2003, indicated that duplex scanning was a potential diagnostic tool in patients eligible for revascularization, together with magnetic resonance arteriography8. However, in our opinion, it is not clear whether this procedure might be useful also in diabetic patients with CLI: only a few studies have evaluated the feasibility and accuracy of such an exam in these patients9,10. The January 2007 edition of the Inter-Society Consensus (TASC II) defined duplex scanning as a procedure with a “widespread availability, without relative risk and complications, without contraindications”. However, also some weaknesses are recognized, as duplex scanning is a very “operator-dependent technique”, and because “calcified segments are difficult to assess”11. We strongly agree with this statement. In fact, in our clinical practice we noticed a consistent discrepancy between results from duplex analyses performed elsewhere and arteriographic pictures. This was particularly evident in the case of infrapopliteal arterial examinations. Such a discrepancy was less evident when examinations were performed by vascular surgeons of our Institute, who are skilled in occlusive arterial disease in diabetic patients. It is important to clarify how in the USA, the execution of a duplex scan is conducted by a specialised non-physician operator, and a physician is required for the interpretation of the test. In Italy, both the execution and interpretation is carried out by a physician, usually a vascular surgeon.

This prompted us to perform this analysis with the aim of comparing the accuracy of examinations performed in skilled facilities with those obtained in non-skilled ones, rather than simply comparing the accuracy of the procedure itself. The results of the study have fully confirmed our suspicions of the inaccuracy in the tests performed in general laboratories, without expertise in occlusive peripheral arterial disease of diabetic patients.

There is a great consensus in literature on the optimal accuracy of duplex scanning in proximal arteries13,14. In our study the inconsistency between the accuracy of proximal arteries examination performed by skilled or non-skilled operators was not dramatic. However, if one considers that duplex scanning guide the interventionist’s choice of site’s puncture (ipsilateral, contralateral or brachial puncture), an error of almost 14% may be deemed considerable. This is an important tool for the endovascular operators. For this reason, we believe that the results obtained from a duplex scan performed in general facilities cannot be considered as “optimal”.

Instead, there is currently a lack of consensus on the accuracy of infrainguinal arterial examination even in the general population. In some studies the accuracy appeared to be optimal also in the infrainguinal arteries, while in others it was not satisfactory and definitely lower than that obtained in the proximal arterial examination15-20. In our data the accuracy of infrapopliteal artery examination performed in a general laboratory significantly worsened. In particular, the evaluation of the peroneal artery was missing in most cases. Nonetheless, when such evaluation was performed the accuracy was very poor. In our experience, we revascularize by peripheral transluminal angioplasty (PTA) or bypass graft surgery (BPG) just in this artery for a reasonable percentage of our CLI diabetic patients where this is the only patent artery below the knee21.

Our data clearly has shown that in diabetic patients the accuracy of infrapopliteal examination was dramatically lower when duplex scanning was performed by non experienced operators as compared to that obtained from studies performed by operators with expertise. Moreover, the accuracy was even lower in the case of peroneal artery examination22.

Therefore, we fully agree with the conclusions of the recent study of Moneta stating that “physicians interpreting vascular laboratory studies should be part of structures that can offer proper training and credentialing”. We believe this is particularly true when such tests are performed in diabetic patients.23

The use of duplex scanning as an alternative to arteriography in the decision making regarding revascularization has been matter of debate. 24-28 Our data has shown that in diabetic patients candidates for revascularization in infrapopliteal arteries, especially in the peroneal artery, duplex scanning was not adequate to guide decision making pertaining to surgical revascularization 29 . This also held true when the exam was performed by skilled physicians with expertise in diabetic peripheral arterial disease.

In order to obtain a good consistency with arteriographic images of the femoral artery, duplex scanning in diabetic patients with CLI must be performed by a highly skilled and experienced physician (Italy) or vascular technologist (USA). This is an important tool for the endovascular operators. The unsatisfactory accuracy of the duplex also performed by experienced physicians in the infrapopliteal axis was not adequate to guide decision making in surgical revascularization. If, in the future, the vascular ultrasonography instruments will be of higher-quality and operators will be well-trained, then duplex scanning may represent an alternative to conventional arteriography even in diabetic patients.

Competing interests: None declared.

1. Ramaswami G, Al-Kutoubi A, Nicolaides AN, Dhanjil S, Griffin M, Belcaro G, Coen LD. The role of duplex scanning in the diagnosis of lower limb arterial disease. Ann Vasc Surg 1999; 13:494-500.

2. Collins R, Burch J, Cranny G, Aguiar-Ibáñez R, Craig D, Wright K, Berry E, Gough M, Kleijnen J, Westwood M. Duplex ultrasonography, magnetic resonance angiography, and computed tomography angiography for diagnosis and assessment of symptomatic, lower limb peripheral arterial disease: systematic review. BMJ 2007;16:1257-66.

3. Jude EB, Oyibo SO, Chalmers N, Boulton AJ. Peripheral arterial disease in diabetic and nondiabetic patients. A comparison of severity and outcome. Diabetes Care 2001; 24:1433-7.

4. van der Feen C, Neijens FS, Kanters SD, Mali WP, Stolk RP, Banga JD. Angiographic distribution of lower extremity atherosclerosis in patients with and without diabetes. Diabet Med 2002;19:366-70.

5. Kansal NK, Handman Clinical features and diagnosis of macrovascular disease.In: Veves A, Giurini JM, LoGerfo FW eds The Diabetic Foot, Humana Press 2002, pages 113-125

6. Faglia E, Dalla Paola L, Clerici G, Clerissi J, Graziani L, Fusaro M, Gabrielli L, Losa S, Stella A, Gargiulo M, Mantero M, Caminiti M, Ninkovic S, Curci V, Morabito A. Peripheral angioplasty as the first-choice revascularization procedure in diabetic patients with critical limb ischemia: prospective study of 993 consecutive patients hospitalized and followed between 1999 and 2003. Eur J Vasc Endovasc Surg 2005;29:620-7.

7. Bradbury AW, Adam DJ. Diagnosis of peripheral arterial disease of the lower limb. BMJ 2007;334:1229-30.

8. American Diabetes Association Peripheral Arterial Disease in People with Diabetes. Diabetes Care 2003;26:333-41

9. Ascher E, Marks NA, Hingorani AP, Schutzer RW, Mutyala M. Duplex-guided endovascular treatment for occlusive and stenotic lesions of the femoral-popliteal arterial segment: a comparative study in the first 253 cases. J Vasc Surg 2006, 6:1230-7.

10. Koelemay MJ, Legemate DA, Reekers JA, Koedam NA, Balm R, Jacobs MJ. Interobserver variation in interpretation of arteriography and management of severe lower leg arterial disease. Eur J Vasc Endovasc Surg 2001;21:417-22.

11. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG; TASC II Working Group. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 2007;45 Suppl S:S5-67.

12. Faglia E, Clerici G, Clerissi J, Mantero M, Caminiti M, Quarantiello A, Curci V, Lupattelli T, Morabito A. When is a technically successful peripheral angioplasty effective in preventing above-the-ankle amputation in diabetic patients with critical limb ischaemia ? Diabet Med 2007;24:823-9.

13. Moneta GL, Yeager RA, Antonovic R, Hall LD, Caster JD, Cummings CA, Porter JM. Accuracy of lower extremity arterial duplex mapping. J Vasc Surg 1992;15:275-83.

14. Koelemay MJ, den Hartog D, Prins MH, Kromhout JG, Legemate DA, Jacobs MJ. Diagnosis of arterial disease of the lower extremities with duplex ultrasonography. Br J Surg 1996; 83:404-9.

15. Favaretto E, Pili C, Amato A, Conti E, Losinno F, Rossi C, Faccioli L, Palareti G. Analysis of agreement between Duplex ultrasound scanning and arteriography in patients with lower limb artery disease. J Cardiovasc Med 2007; 8:337-41.

16. Larch E, Minar E, Ahmadi R, Schnürer G, Schneider B, Stümpflen A, Ehringer H. Value of color duplex sonography for evaluation of tibioperoneal arteries in patients with femoropopliteal obstruction: a prospective comparison with anterograde intraarterial digital subtraction angiography. J Vasc Surg 1997; 25:629-36.

17. Aly S, Jenkins MP, Zaidi FH, Coleridge Smith PD, Bishop CC. Duplex scanning and effect of multisegmental arterial disease on its accuracy in lower limb arteries. Eur J Vasc Endovasc Surg 1998;16:345-9.

18. Sensier Y, Fishwick G, Owen R, Pemberton M, Bell PR, London NJ. A comparison between colour duplex ultrasonography and arteriography for imaging infrapopliteal arterial lesions. Eur J Vasc Endovasc Surg 1998;15:44-50.

19. Karacagil S, Löfberg AM, Granbo A, Lörelius LE, Bergqvist D. Value of duplex scanning in evaluation of crural and foot arteries in limbs with severe lower limb ischaemia–a prospective comparison with angiography. Eur J Vasc Endovasc Surg 1996;12:300-3.

20. Grassbaugh JA, Nelson PR, Rzucidlo EM, Schermerhorn ML, Fillinger MF, Powell RJ, Zwolak RM, Cronenwett JL, Walsh DB. Blinded comparison of preoperative duplex ultrasound scanning and contrast arteriography for planning revascularization at the level of the tibia J Vasc Surg 2003;37:1186-90.

21. Abularrage CJ, Conrad MF, Hackney LA, Paruchuri V, Crawford RS, Kwolek CJ, LaMuraglia GM, Cambria RP. Long-term outcomes of diabetic patients undergoing endovascular infrainguinal interventions. J Vasc Surg. 2010 Aug;52(2):314-22.e1-4. Epub 2010 Jun 29.

22. Dosluoglu HH, Cherr GS, Lall P, Harris LM, Dryjski ML. Peroneal artery-only runoff following endovascular revascularizations is effective for limb salvage in patients with tissue loss.J Vasc Surg. 2008 Jul;48(1):137-43. Epub 2008 May 23.

23. Moneta GL, Zierler RE, Zierler BK. Training and credentialing in vascular laboratory diagnosis. Semin Vasc Surg 2006;19:205-9.

24. Ascher E, Markevich N, Schutzer RW, Kallakuri S, Hou A, Nahata S, Yorkovich W, Jacob T, Hingorani AP. Duplex arteriography prior to femoral-popliteal reconstruction in claudicants: a proposal for a new shortened protocol. Ann Vasc Surg 2004;18:544-51.

25. Katsamouris AN, Giannoukas AD, Tsetis D, Kostas T, Petinarakis I, Gourtsoyiannis N. Can ultrasound replace arteriography in the management of chronic arterial occlusive disease of the lower limb? Eur J Vasc Endovasc Surg 2001;21:155-9.

26. Mazzariol F, Ascher E, Salles-Cunha SX, Gade P, Hingorani A. Values and limitations of duplex ultrasonography as the sole imaging method of preoperative evaluation for popliteal and infrapopliteal bypasses. Ann Vasc Surg 1999;13:1-10.

27. Avenarius JK, Breek JC, Lampmann LE, van Berge Henegouwen DP, Hamming JF. The additional value of angiography after colour-coded duplex on decision making in patients with critical limb ischaemia. A prospective study. Eur J Vasc Endovasc Surg 2002;23:393-7.

28. Luján S, Criado E, Puras E, Izquierdo LM. Duplex scanning or arteriography for preoperative planning of lower limb revascularisation. Eur J Vasc Endovasc Surg 2002; 24:31-6.

29. Hingorani AP, Ascher E, Marks N. Duplex arteriography for lower extremity revascularization. Perspect Vasc Surg Endovasc Ther 2007;19:6-20.

Data reported as recently as 2007 by the Centers for Disease Control (CDC), has estimated that nearly 7.8% of the US population or about 23.6 million Americans are diabetic, with the population growing at alarming rates leading to severe impacts on American society1. According to the CDC National Diabetes Fact Sheet, there were a reported 1.5 million new cases of diabetes in 2006 among individuals 20 years or greater, and diabetes was the 7th leading cause of death listed on 2006 US death certificates1. It has been further estimated that by the year 2025 nearly 300 million people worldwide will be diagnosed with diabetes2, showing that the population of diabetic persons is expected to greatly increase over the next 15 years. Among this population, the lifetime incidence of developing a diabetic foot ulcer (DFU) has been estimated to be as high as 15%3.

Despite the numerous available treatments, these ulcerations commonly become chronic wounds. This presents a huge burden to patients with diabetes as well as to the healthcare system, with costs estimated at nearly $13,200 per ulcer-related episode4.

Hospitalization for ulcer care as the reason for hospital admission is $3000 a day and amputations at over $50,000 not considering the collateral risk of revision and mortality.

The most cost effective way to minimize complications is to attain wound closure as expeditiously as possible. Therefore, as the population of diabetic persons continues to rise in the future, finding a method to quickly and adequately close and/or prevent ulcerations will be of the utmost importance.

Based on the 1999 American Diabetes Association5 consensus statement on DFU care, it is generally believed that foot ulcerations in patients with diabetes become chronic wounds due to the numerous co-morbidities compared to the average patient. Co-morbidities commonly encountered in the diabetic patient include abnormal biomechanics, vascular and/or arterial compromise, diminished protective sensation, renal disease, and altered nutritional status. These factors not only put the diabetic patient at risk for the development of ulcerations, but also impede the effectiveness of treatments.

Typically, conventional care techniques for the treatment of DFUs have focused on four major concepts: debridement of necrotic or devitalized tissue, controlling infection, offloading, and maintaining a moist wound environment. Although there may be variations as to the exact means employed, these concepts have been the basis of several published DFU treatment guidelines. In 2003, Sheehan and colleagues noted that an ulcer that fails to reduce in size by at least 50% at the 4 week mark has less than a 10% chance of closing by 12 weeks with good conventional care.6

The authors of this study therefore felt that achieving at least a 50% reduction in wound size in 4 weeks time could strongly predict whether a wound will go on to closure. In 2006, the Wound Healing Society published evidence-based treatment guidelines supporting the re-evaluation of wound treatment for chronic wounds that have shown less than 50% reduction in area after 4 weeks of treatment with standard care methods alone.7 This was based on data collected in a prospective multicenter study of 203 patients with DFU’s, which suggested that the four week mark is a good point to evaluate wound healing. It is at this juncture, the failure of a wound to reduce in size by 50% in 4 weeks, that Boulton et al suggested the use of additional advanced wound care products8. Such products include Pre-market approval (PMA) approved products, negative pressure, hyperbaric oxygen (HBO) and pulsed radio frequency therapies. Such advanced therapies could therefore be considered to achieve wound closure in a timely manner, and thus prevent any further morbidity so commonly associated with chronic DFUs.

With the advent of Evidence-Based Medicine (EBM) and the importance that this evidence has in directing patient care, many physicians have begun to take a step back and revaluate their practice patterns. Therefore, the aim of this work is to provide a reference and guidance (algorithm) to what the data indicate regarding timeliness and treatment options, realizing that no two patients are the same and all care should be individualized to the patient.

Utilizing the evidence that has been published, our algorithm (Figure 1) has been developed and is currently being used for the treatment of numerous DFUs. The systematic approach begins with initial patient assessment in which patients are classified, based on clinical criteria, as being either low risk or moderate to high risk DFU patients. Low risk DFU patients are generally patients who develop new foot ulcerations, without a previous history of ulcerations, show no evidence infection being present, and who have documented palpable pedal pulses. Patients that fall into the moderate to high risk category tend to be patients with wounds probing to bone, ulcerations greater than 30 days duration, or patients with additional co-morbidities including renal disease, a previous history of ulceration or amputation, an elevated HbA1c, and decreased albumin/pre-albumin levels. Anyone with one or a combination of these factors is someone who may be at a higher risk for experiencing a non-healing ulceration and therefore, may have a greater chance of developing a serious complication.

Anyone with one or a combination of these factors is someone who may be at a higher risk for experiencing a non-healing ulceration and therefore, may have a greater chance of developing a serious complication.

Figure 1: Evidence Based Approach Algorithm to treating DFUs

After the initial patient assessment, a complete medical history and exam along with a comprehensive lower extremity exam is performed. The lower extremity exam includes a visual assessment of the lower extremity, vascular assessment with a Doppler probe, and a neurological exam, including 10-G monofilament assessment, vibratory sensation, proprioception, and reflex testing. , The orthopedic exam includes testing of muscle strength, gait analysis, range of motion of the foot and ankle, as well as visual inspection for any structural deformities, such as bunions or hammertoes. From this history and physical assessment, patients can be assigned a risk category which will direct what treatment path to follow. Basic wound care principles are followed for both groups and include debridement of necrotic and devitalized tissue, infection control, offloading of the ulceration, and maintenance of a moist wound environment. Throughout the treatment, vascular assessment is made and monitored. For any patient with an ankle brachial index (ABI) measurement of less than 0.8, an appropriate vascular referral is made. Infection is also closely monitored and patients are assessed at each visit for signs of cellulitis or osteomyelitis. Controlling infection is extremely important as several studies have found infection to be strongly correlated with increased risk of amputation9. In fact, a large cohort study conducted by Lavery and colleagues (2006) found that an infected DFU increased the risk of hospitalization by nearly 56 times and amputation by nearly 155 times.10 Interestingly, all independent risk factors for infection identified in the study mirror the at-risk comorbidities or patient history (ulcer probing to bone, ulcer history of greater than 30 days, peripheral vascular disease, recurrent ulcer and traumatic etiology) that place our Veterans in a moderate to high risk category. One thing that also needs to be considered is that many of our patients present with multiple risk factors that multiply their risk for complications. Signs or symptoms of infection that most commonly present with DFUs include: increased redness, increased warmth, swelling, purulent exudate, increased pain or tenderness, and constitutional symptoms (nausea, vomiting, fever, chills). With the development of these symptoms, wound cultures are taken and confirmed infections are treated with appropriate measures.

For low risk patients, the algorithm specifies that wounds are measured and progress is assessed weekly. Wounds are treated appropriately following conventional wound care guidelines, and, if at 2 weeks the ulcer is increasing in size or showing no change, an alternate form of therapy may be considered. As long as the wound continues to show weekly progress, the current form of treatment is continued. At 4 weeks, if the wound does not show at least 50% reduction in ulcer area, an advanced form of therapy, such as a living skin equivalent (LSE; i.e. Dermagraft® or Apligraf®), is recommended due to the stagnant nature of the wound. Again, as long as the wound shows at least 50% reduction in area in 4 weeks, the wound is measured or assessed weekly and the current modality of treatment is continued. For moderate to high risk patients, the algorithm outlines that in these patients an advanced form of therapy, such as an LSE, should be used initially as long as infection is controlled and appropriate vascular status is present. While these moderate to high risk patients are often excluded from Food and Drug Administration (FDA) clinical trials, we have seen good success with a human fibroblast derived dermal substitute (i.e. Dermagraft®) at closing ulcers and reducing complications.

The typical requirement for FDA approval is to demonstrate a 12-week closure mark significantly faster than conventional wound care. The LSEs have demonstrated faster closure when used weekly per FDA approvals to treat DFUs. They have also proven to reduce the complications such as infection and amputation. Negative pressure and pulsed radio frequency are not approved under the PMA process because they are not intended to provide direct closure. There is also reported clinical experience in using the human fibroblast-derived dermal substitute in combination with both therapies to promote closure in patients with exposed bone and deep wounds.11,12 Collagen-based products and extracellular matrix products are considered alternative dressings because they provide collagen to the wound. While they can be beneficial to some patients they have not demonstrated faster closure than wet-dry dressings in FDA approved trials.

Expeditious and complete wound healing is the definitive goal in the treatment of DFUs. The longer a wound remains open, the greater the risk of complications, such as infection and subsequent amputation. Using an evidence-based approach helps determine which patients and when those patients are best suited for advanced therapies such as LSEs. This therefore allows the clinician to facilitate improved outcomes in healing chronic ulcers in patients with diabetes. By following this algorithm it is possible to increase closure rate of DFU’s, decrease complications associated with chronic ulcers, as well as prevent future amputations which often are the result of longstanding DFUs.

1. Centers for Disease Control and Prevention. National Diabetes Fact Sheet: general information and national estimates on diabetes in the United States. 2007.

2. Snyder R, Cardinal M, Dauphinee D, et al. A post-hoc analysis of reduction in diabetic foot ulcer size at 4 weeks as a predictor of healing by 12 weeks. Ostomy Wound Manage 2010;56(3):44-50.

3. Sanders, LJ. Diabetes mellitus: prevention of amputation. JAPMA 1994; 84:322-328.

4.Stockl K, Vanderplas A, Tafesse E, et al. Costs of lower-extremity ulcers among patients with diabetes. Diabetes Care 2004;27(9):2129-2134.

5. American Diabetes Association. Consensus Development conference on diabetic foot wound care. Diabetes Care. 1999 ; 22 1354-1356

6. Sheehan P, Jones P, Caselli A, et al. Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial. Diabetes Care 2003;26:1879-1882.

7. Steed DL, Attinger C, Colaizzi T, et al. Guidelines for the treatment of diabetic ulcers. Wound Repair Regeneration 2006;14:680-692.

8. Boulton AJ, Kirsner RS, Vileikyte L. Clinical practice. Neuropathic diabetic foot ulcers. N Engl J Med 2004;351:48–55

9. Snyder RJ and Hanft JR. Diabetic foot ulcers – effects on quality of life, costs, and mortality and the role of standard wound care and advanced care therapies in healing: a review. Ostomy Wound Management 2009;5(11):28-38.

10. Lavery LA, Armstrong DG, Wunderlich RP, et al. Risk factors for foot infections in individuals with diabetes. Diabetes Care 2006;29(6):1288-1293.

11. Frykberg RG, Tierney E, Tallis A, Klotzbach T: Cell Proliferation Induction: Healing Chronic Wounds Through Low-Energy Pulsed Radiofrequency. Int J Low Extrem Wounds. 8:45-51, 2009

12. Frykberg R, Martin E, Tallis A, Tierney E. A case history of multimodal therapy in healing a complicated diabetic foot wound: negative pressure, dermal replacement and pulsed radio frequency energy therapies. Int Wound J 2011; 8:132–139

The Arab world refers to Arabic speaking countries expanded from the Atlantic Ocean in the west to the Arabian Gulf in the east and from the Mediterranean Sea in the north to the horn of Africa and Indian Ocean in the southeast (Figure 1)1. One of the great challenges faced the Arab countries is the lack of research and lack of publications on health problems. Diabetic foot problems are among the major complications that may face any diabetic patient at any time of his or her life. Diabetic foot disease represents a real challenge to the health providers caring for these patients and health system in general.

In 2005 the International Diabetes Federation (IDF) published a position statement about common diabetes complications.2 In this statement , data from epidemiological studies have indicated that between 40 – 70% of all lower extremity amputations are related to diabetes. Eighty five percent of all amputations related to diabetes are preceded by foot ulcers. Researchers established that between 49-85% of all amputations can be prevented2 . This means that significant reductions in amputation rates can be achieved by adopting well structured preventive policies. Due to a lack of publications on diabetes and its complications in the Arab world , we usually encourage our readers to apply the rule of 15 to understand the significance of this problem (Table 1)

In 2007,the treatment of diabetes and its complications in the United States cost around 116 billion American dollars on its direct expenses, and at least 33% of these costs were linked to the treatment of foot ulcers.3 Notably, the higher the ulcer grade the higher the cost of care.3 The cost of care of diabetes and its complications in Arab countries, in comparison with the United States and Europe, unfortunately has a small budget directed to it.4

In the Arab region the prevalence of diabetes has been rising dramatically within the last two decades. This may be attributed to the changes that occurred in the Arab world cultures towards westernization.5 Interestingly, the prevalence of diabetes related complications are still low in the Arab countries located in the western regions and become higher towards the eastern Arabic countries. This finding needs more investigation and it is an area for ongoing research. Six of the Arab countries located in the East have among the top ten highest diabetes prevalences in the list published by the IDF (Table 2)

We propose the concept of a “diabetic foot continuum”. This is the environment where the interaction of diabetic foot risk factors work together to produce diabetic foot problems. (Figures 2 and 3) In the following section we will discuss several of the important risk factors contributing to diabetic foot problems in our region of the World.

Figure 2: Global map highlighting the Arab Regions

Figure 3: Diabetic foot continuumFigure 3: Diabetic foot continuum

Neuropathy:

Studies in the Arab world showed a prevalence of neuropathy ranging between 38-94% in diabetic foot cases. (6,7,8) Sensory neuropathy is a major component leading to the development of diabetic foot ulceration. Loss of protective sensations such as pain may predispose the patients to recurrent injuries without feeling its occurrence. For example, we have observed a case of a diabetic patient with poor self foot care presenting with an abscess on the dorsum of the foot due to the presence of a foreign body (piece of glass) for more than three months.

Motor neuropathy leads to atrophy of the small muscles of the foot and this will lead to foot deformities. Development of foot deformities with lack of foot care awareness and lack of proper foot wear in Arabian patients significantly contributes to the increasing problems of foot complications in our diabetic patients.

Autonomic neuropathy that leads to dry, cracked skin with fissures is a common presentation in clinical practice. The unique character of weather in most of Arab countries (hot, dry) make it very difficult to change the cultural beliefs about footwear. Sandals are the commonest foot wear in the Arab countries and most particularly, the traditional sandals. (Figure 4)

Vasculopathy:

Avicenna (980-1037 AD) ,the famous Arab doctor, described diabetic foot gangrene and the association between diabetes and foot problems.9 The prevalence of lower extremity vasculopathy is varied based on the method used to detect the vasculopathy. In this regard, the prevalence of peripheral vascular disease in the Arab population ranges between 50 – 78.7% 7, 8, 10.

Life style:

In many Arab world countries, the life style is sedentary. In a comparative international study of populations11 , physical activity prevalence across 20 countries using the international physical activity questionnaire (IPAQ), Saudi Arabia was the only Arab country to participate. This study reported that the prevalence of low, moderate and high physical activity in Saudi Arabian subjects was 40%, 33.8%, and 26.2% respectively, while it was 15.9%, 22.1% and 62% ,respectively, in the United States.

Overweight and obese diabetic patients develop foot problems by creating extra load in deformed or injured feet. Obesity has become an epidemic problem worldwide and particularly in the east Mediterranean and Middle East region. Unfortunately, 3 – 9% of preschool children have been found to be either overweight or obese.12 In school children, this prevalence reached 12-25%. 12 Marked increases in prevalence of obesity has been noted among adults ranging from 15-45%; in women it reached 35-75% and in adult men 30-60%. 12

The prevalence of diabetic foot disease varies considerably in the Arab world (Table 3), but there are some factors shared between most of the Arab countries that make it high:

1) Weather and foot wear:

In most Arab countries the weather is hot and dry most of the year. This makes the habit of wearing closed shoes and socks rejected by many patients and instead they prefer to wear sandals. Sandals do not offer the protection afforded by closed foot wear since they expose feet to heat, dryness and injuries.

2) Habits:

Walking bare-footed especially inside the home is still a common habit in many regions of the Arab world

3) Religion:

Ninety percent (90%) of Arab populations are Muslims. They pray five times per day where the feet have to be washed before praying. These maneuvers help patients to inspect their feet as well as clean them. Washing feet before praying and the praying itself offer some sort of physical massage to the feet. Trimming the nails is a habit encouraged by Islam, but it should be done properly so as not to harm the toes. Also, every year millions of Muslims engage in the holy practice of Hajj. Among them are many persons with diabetes who may sustain unnoticed physical harm to their feet. Diabetes education and foot care is therefore an important issue before going to do Hajj.

4) Education:

The percentage of illiterate people is higher in the Arab world than in western countries. Lack of education leads to unawareness of diabetic foot problems and their prevention. Interestingly, one study showed that 90% of screened diabetic patients had poor knowledge about their disease and 96.3% had poor awareness about its control.13

5) Traditional medicine:

Herbal medicine and herbal medications are still commonly used in many Arab countries. We have observed many diabetic foot complications presenting for medical care after severe deterioration due to treatments with traditional herbal medications.

6) Health care system and health care providers:

Health resources available for diabetes care and diabetic foot management differs considerably among Arab countries and still the management of the diabetic foot is not based on a multidisciplinary team approach. Due to the frequency and long hospital stays, diabetic foot cases usually consume a considerable part of the health care budgets. For this reason the hospitals’ administrative staff and health care providers are somewhat reluctant to admit patients with diabetic foot problems in their early presentation. This of course results in more complicated problems and subsequently, more amputations.

7) Rehabilitation :

Physical and social rehabilitation is still an underdeveloped field in Arab countries. Patients with amputations may wait for a long time before they can be provided with an orthotic device. Frequently the cost inhibits the patient from seeking appropriate help. Unfortunately, patients isolate themselves after amputation and live a lonely, depressed life. In addition to this, a lack of employment for amputees has a very negative impact on their life and that of their families.

Nonetheless, the future is looking bright as there are many efforts to improve the outcome of diabetes and its complications in many Arab countries. In Saudi Arabia, for instance, there are about 20 well equipped diabetes centers with highly trained health care providers. Also, in Sudan there is a pioneer project to initiate a series of diabetic foot care centers throughout the country. The IDF supports a number of Arab countries to train physicians on how to deliver proper care to diabetic foot patients. The Saudi Ministry of Health cooperated with the University of Toronto to conduct an international wound care course (IWCC) in 2008-2009. Also, many well designed training programs and symposiums have been organized to focus on the issue of diabetes and its complications.

Diabetes care in the Arab world is still in its early stages and much research in this area is urgently needed. Health authorities need to implement preventive policies and invest more financial capital on training programs and problem awareness programs. A structured multidisciplinary approach should be encouraged in the field of diabetes care. Finally, the need for national registries is urgently required in Arab countries to assess the impact of the disease and our outcomes as we strive to improve our delivery of more effective diabetic foot care programs.

Numerous clinical references highlight the economic impact of treating diabetic foot ulcers (DFUs).1-4 As the rate of American patients diagnosed with diabetes mellitus increases each year so does the group of patients most susceptible to developing DFUs, namely those over the age of 65.5-6 Recent figures revealed that from 1980 through 2008 the number of diabetic Medicare beneficiaries aged 65 or older increased from 2.3 million to 7.4 million, representing a greater than 300% increase.7 This is truly alarming to those who care for veterans in the Veterans Affairs system as the number of patients being cared for and treated in the Federal segment continues to escalate. Many veteran patients with diabetes present with numerous metabolic and clinical abnormalities that predispose to ulceration including peripheral neuropathy, peripheral arterial disease (PAD), poor glucose control, foot deformities, and even callus. 8,9,10 Long standing, non-healing diabetic foot ulcers complicated by infection, renal failure, and/or PAD are important components in the causal pathways leading to amputation. 11,12 Both foot ulcers and lower extremity amputations have been shown to be associated with higher mortality than found in those diabetic patients without such complications. 13 As this trend continues and more patients present to the healthcare provider in the outpatient clinic with potentially, limb threatening disorders, a strict care path must be implemented.

Specific treatment strategies must be established based on available clinical research and evidence-based outcomes to insure that patients are being treated with the most cost effective and proven therapies available. Since it has been estimated that 77% of all costs incurred in treating DFUs are due to inpatient costs, the importance of employing clinically effective treatments becomes clearly evident.14 In one study, the risk of hospitalization was 55.7 times greater for patients who developed a lower extremity infection and their risk for amputation is 154.5 times compared to a non-infected DFU. 15 Accordingly, infection and amputation are major causes of hospital costs incurred in the patient with diabetic foot ulcer that fails to heal in an optimum time frame. Unhealed DFUs greater than 30 days is independently associated with a 4.7 times increased risk for infection.15 When an infection becomes established in a person with diabetes, a blunted immune response, and reduced peripheral blood flow, the bacteria can invade beyond local soft tissue and ultimately infect contiguous bone (i.e., osteomyelitis). Once bone infection has occurred, inpatient admission for parenteral antibiotics over extended periods and potential removal of infected bone by various resections or amputation strategies is required.

Since many diabetes related admissions are due to infected DFUs, their attendant costs are high. One study investigating 1995-96 Medicare claims data revealed average costs of $25,713 (2011 USD) per episode of inpatient care in patients with an ulcer.16 Such events result in escalating costs through extended hospital stays, operations, excessive morbidity and even mortality.17

The goal of wound care is to establish an aggressive and effective strategy to heal the wound as expeditiously as possible to prevent those complications (such as infection or gangrene) that require inpatient admission. In this paper, we will discuss how we utilized available clinical evidence as a basis for implementing aggressive algorithm based medical practices to heal DFUs. Using such protocols to guide the care of increasingly more complex wounds and complicated patients can result in improved patient outcomes, fewer inpatient admissions, fewer amputations, and accordingly, lower costs.

Depending on source claims and insurance provider analyzed, costs of healing DFUs and amputation procedures are variable and are based upon medication costs, clinic visit charges, hospitalization charges, and various finite costs. Regardless, the consistent finding in the majority of medical reviews is that caring for patients with a DFU is an expensive but necessary process since the alternative of having an unhealed ulcer may be more devastating. On average, diabetic patients with foot ulcers have been estimated to have over 13.5 outpatient visits per year and are hospitalized 0.25 times per year for their DFU and hospitalized 1.5 times per year for any reason.18 The costs of caring for patients impacted by this life-altering illness increases with each episode. Harrington et al. conservatively estimated that it costs over $28,000 (2011 USD) per year in Medicare reimbursement per patient with a lower extremity ulcer. 16 The economic burden of diabetes continues to escalate and thus the collateral damage of other medical issues is multiplied. It has been noted that as many as 20% of diabetic patients who undergo lower extremity amputation return to the hospital for another amputation within 12 months.19 This highlights the importance of a prevention strategy versus allowing the typical amputation cascade to continue unabated.

In the last decade, there have been four evidence-based treatment protocols published recommending the utilization of FDA-approved agents to heal DFUs at a faster rate than conventional wet-to-dry wound care. Much confusion is apparent when discussion of “PMA” or “BLA” versus “510K” or “HCT/P” products is brought up in medical dialogue. The critical differentiator is that PMA (Pre-Market Approval) products or BLA (Biologics License Application) product have been shown in comparative randomized clinical trials (approved by the FDA) to heal DFUs more completely and faster than conventional therapy alone.. There are only three products that have this designation: PMA products Dermagraft® (Advanced BioHealing) and Apligraf® (Organogenesis), and the BLA product Regranex® (Healthpoint Biotherapeutics). Other wound products available to healthcare providers have been cleared vs. approved as “510K” or “HCT/P” (human cellular and tissue based product) designation.

HCT/P products are regulated by the FDA to allow for human cells or tissue intended for implantation, transplantation, infusion, or transfer into a human recipient. The FDA generally permits products regulated solely as human tissue to be commercially distributed without premarket clearance or approval or randomized clinical trials to demonstrate efficacy. 510K products use a pre-existing similar device in the market called a “predicate device” for comparison. It does not have the FDA “approval” but rather a 510K product is generally referred to as “510K cleared device” that can be marketed and sold since it is similar to an already existing device identified by the FDA as available device prior to May 28, 1976. No randomized clinical trials to prove efficacy are required for this process.

As a result, these agents have been “cleared” for wound management but are not FDA-indicated to heal wounds. As with this critical difference, various consensus panels and published guidelines provide support as to when use of PMA products should be implemented. Sheehan and colleagues found that the percent change in wound area of DFUs over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial.20 While the trial study agent failed to show efficacy, they were able to determine with high sensitivity and specificity that any DFU that fails to reduce in size by at least 50% in the first 4 weeks of therapy is unlikely to heal in a reasonable period of time. The American Diabetes Association Consensus Development Conference (1999) stated that “Any wound that remains unhealed after 4 weeks is cause for concern, as it is associated with worse outcomes, including amputation”.21 In 2004 Boulton and colleagues stated “The failure to reduce the size of an ulcer after four weeks of treatment that includes appropriate debridement and pressure reduction should prompt consideration of adjuvant therapy.” 22 Therefore, therapy that has been shown in randomized controlled clinical trials to demonstrate efficacy in healing DFUs compared to conventional therapy (PMA and BLA products) should be considered after 4 weeks if the DFU achieved less than a 50% PAR (Percent Area Reduction) in wound size. I n certain higher-risk patient subgroups with increased risk of poor outcomes, such as those with a history of renal insufficiency, prior amputation, or poor metabolic state, this timeline may be considered longer than clinically necessary. While the recommendations for early intervention with advanced therapies are cited extensively in the literature, there are limited outcome data available to support what implementing this into clinical practice can provide in regards to patient outcomes, amputation prevention, and overall economic impact.

The providers at the authors’ High Risk Foot Clinic implemented such a strategy based on the hypothesis that an evidence-based therapy would increase consistency of treatment approach, provide rapid wound progression, and ultimately provide an aggressive treatment of wounds not responding to conventional therapy. All of these factors would be evaluated to determine if enhanced patient outcomes and lower cost could be documented. We believe that our treatment protocol effectively promotes our goal of limb preservation. Although costs are certainly of importance, reduction or prevention of amputation is our primary outcome of interest. As previously mentioned, avoidance of hospitalization necessitated by infection or gangrene has been demonstrated to decrease not only costs but also morbidity and mortality. 17

Our center is one of the largest High Risk Foot Ulcer Clinics within the Veterans Affairs Health Care System. The volume of patients with DFUs alone has grown by 20% in the last two years with almost 4,000 DFU patient encounters in 2010. Patients are referred to this clinic if the following are observed: 1) the patient has not responded to conventional care as defined by less than 50% PAR at four weeks; or 2) the patient has a non-healing postoperative wound. The amputation rates for the eight years prior to 2009 had never been below 3.0% in any calendar year. In July of 2009, the Phoenix VA High Risk Clinic began utilizing a human fibroblast-derived dermal substitute (HFDS) in concert with a continued focus on the basic tenets of wound care: debridement, infection control, validation of vascular status, and aggressive off-loading. In those patients who did not achieve the 50% PAR level at four weeks, HFDS was also implemented. Dermal replacement therapy was occasionally used with concurrent Negative Pressure Wound Therapy (NPWT) to promote granulation and rapid closure. A primary goal of treatment has been to rapidly heal foot ulcers in order to minimize the need for hospitalization and amputation. In the presence of necrosis, gangrene, and PAD, revascularization and partial foot amputation are performed to allow for limb preservation. Accordingly, a healed minor amputation is considered to be a limb salvaging procedure. Indeed, major amputations have frequently been avoided by using this strategy in patients otherwise destined for limb loss.

1. Ramsey et al. Incidence, outcomes and cost of foot ulcers in patients with diabetes. Diabetes Care. 1999;22:382-7. [Conversion from 1995 to 2011 medical costs at: http://www.halfhill.com/inflation.html (accessed 14Feb2011)].

2. Harrington et al. A cost analysis of diabetic lower-extremity ulcers. Diabetes Care. 2000;23:1333-8. [Conversion from 1996 to 2011 medical costs at: http://www.halfhill.com/inflation.html (accessed 14Feb2011)].

3. Gordois et al. The health care costs of diabetic peripheral neuropathy in the US. Diabetes Care. 2003;26:1790-5.

4. Ragnarson TG and Apelqvist J. Health-economic consequences of diabetic foot lesions. Clin Infect Dis. 2004;39 Suppl 2:S132-S139.

5. Margolis D, Malay DS, Hoffstad OJ, et al. Incidence of diabetic foot ulcer and lower extremity amputation among Medicare beneficiaries, 2006 to 2008. Data Points #2 (prepared by the University of Pennsylvania DEcIDE Center, under Contract No. HHSA29020050041I). Rockville, MD: Agency for Healthcare Research and Quality. January 2011. AHRQ Publication No. 10(11)-EHC009-1-EF.

6. Margolis D, Malay DS, Hoffstad OJ, et al. Prevalence of diabetes, diabetic foot ulcer, and lower extremity amputation among Medicare beneficiaries, 2006 to 2008. Diabetic Foot Ulcers. Data Points #1 (prepared by the University of Pennsylvania DEcIDE Center, under Contract No. HHSA29020050041I). Rockville, MD: Agency for Healthcare Research and Quality. February 2011. AHRQ Publication No. 10(11)-EHC009-EF.

7. Ashkenazy R, Abrahamson MJ. Medicare cov¬erage for patients with diabetes. A national plan with individual consequences. J Gen Intern Med 2006;21(4):386-392.

8. Reiber, G. E., L. Vileikyte, et al. (1999). “Causal pathways for incident lower-extremity ulcers in patients with diabetes from two settings.” Diabetes Care 22(1): 157-62.

9. Boyko, E. J., J. H. Ahroni, et al. (1999). “A prospective study of risk factors for diabetic foot ulcer. The Seattle Diabetic Foot Study.” Diabetes Care 22(7): 1036-42.

10. Frykberg RG, Zgonis T, Armstrong DG, Driver VR, Giurini JM, Kravitz SR, Landsman AS, Lavery LA, Moore JC, Schuberth JM, Wukich DK, Andersen C and Vanore JV: Diabetic foot disorders. A clinical practice guideline (2006 revision). J Foot Ankle Surg 45:S1-66, 2006

11. Pecoraro, R. E., G. E. Reiber, et al. (1990). Pathways to diabetic limb amputation: basis for prevention. Diabetes Care 13: 513-521.

12. Adler, A. I., E. J. Boyko, et al. (1999). “Lower-extremity amputation in diabetes. The independent effects of peripheral vascular disease, sensory neuropathy, and foot ulcers.” Diabetes Care 22(7): 1029-35.

13. Moulik, P. K., R. Mtonga, et al. (2003). “Amputation and mortality in new-onset diabetic foot ulcers stratified by etiology.” Diabetes Care 26(2): 491-4.

14. Stockl et al. Costs of lower-extremity ulcers among patients with diabetes. Diabetes Care. 2004;27:2129-34.

15. Lavery et al. Risk factors for foot infections in individuals with diabetes. Diabetes Care. 2006;29:1288-93.

16. Harrington et al. A cost analysis of diabetic lower-extremity ulcers. Diabetes Care. 2000;23:1333-8. Conversion from 1996 to 2011 medical costs at: http://www.halfhill.com/inflation.html (accessed 14Feb2011).

17. Faglia et al. New ulceration, new major amputation, and survival rates in diabetic subjects hospitalized for foot ulceration from 1990 to 1993. Diabetes Care. 2001;24:78-83.

18. Margolis DJ, Malay DS, Hoffstad OJ, et al. Economic burden of diabetic foot ulcers and amputations. Diabetic Foot Ulcers. Data Points #3 (prepared by the University of Pennsylvania DEcIDE Center, under Contract No. HHSA290200500411). Rockville, MD: Agency for Healthcare Research and Quality. January 2011. AHRQ Publication No. 10(11)-EHC009-2-EF.

19.Reiber GE, Boyko EJ and Smith DG. Lower extremity foot ulcers and amputations in diabetes. In Diabetes in America, 2nd Ed. Harris MI, Cowie CC, Stern MP, et al. (Editors): National Institutes of Health (DHHS Publication 95-1468), Washington, DC, 1995;409-428.

20. Sheehan et al. Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial. Diabetes Care. 2003;26:1879-82.

21. American Diabetes Association. Consensus development conference on diabetic foot wound care, 7-8 April 1999, Boston Massachusetts. Diabetes Care. 1999;22:1354-60.

22. Boulton et al. Neuropathic diabetic foot ulcers. N Engl J Med. 2004;351:48-55.

23. Carls G.S. et al. The economic value of specialized lower-extremity medical care by podiatric physicians in the treatment of diabetic foot ulcer. JAPMA March/April 2011;101:2

24. Zhang Y, Hogan P: (Poster Abstract) Cost-effectiveness of a human fibroblast-derived dermal substitute for the treatment of diabetic foot ulcers in Medicare and commercially insured populations. American Diabetes Association Annual Scientific Meeting, San Diego, CA, June, 2011

Necrotizing fasciitis is a rapidly spreading infection involving skin, superficial fascia and subcutaneous fat. In our institute we frequently encounter necrotizing fasciitis, about one case every week.11 However, this case posed a unique challenge to us in management and we were successful in salvaging his limbs. We attribute the cause of this rare presentation of necrotizing fasciitis and bilateral forefoot gangrene to the fact that patient had developed thermal burns and mechanical injury resulting from dipping of the foot in the hot water and subsequent massaging.

The practices of barefoot walking, dipping the foot in hot water and also massaging the leg for pain relief, are very common practices in India. 12-13 It leads to a breach in the skin and entry of the microorganism(s), which results in necrosis of superficial fascia and subcutaneous tissue containing blood vessels and nerves.

Inflammation induces venous microthrombosis, arterial vasculitis, local hemorrhage and secondary skin infarctions. Infection can spread to underlying muscles resulting in myonecrosis. Blister or bullae formation can also commonly occur. Creatinine Phospokinase (CPK) concentration is a useful marker of muscle necrosis. 14 This patient had a very high serum creatine kinase levels (1074.5 U/L).

The presented case highlights the consequences of improper methods of pain relief as mentioned above. Such practices should be condemned, as they could be limb threatening and life threatening especially in diabetic patients.

Necrotizing fasciitis is rightly described as a “flesh eating” bacterial disease. This case of necrotizing fasciitis of both lower limbs along with bilateral gangrene of the forefoot is extremely rare and to our knowledge has not yet been reported.

1] Wilson B. Necrotizing fasciitis. Am Surg 1952;18:416-31.

2] Mc Henry CR, Piotrowski JJ, Petrinic D, Malangoni MA. Determinant of mortality in necrotizing soft tissue infections. Ann Surg 1995;221:558-563.

3] Wong CH, Chang HC, Pasupathy S, et.al. Necrotizing fasciitis: clinical presentation, microbiology and determinants of mortality. J Bone Joint Surg, Am 2003;85A:1454-1460.

4] Voros D, Pissiotis C, Georgantas D, et.al. Role of early and aggressive surgery in the treatment of severe necrotizing soft tissue infections. Br J Surg 1993;80:1190-1191.

5] Rea WJ, Wyrick WJ. Necrotizing fasciitis. Ann Surg 1970;172:957-964.

6] Green RJ, Dafoe DC, Raffen TA. Necrotizing fasciitis. Chest 1996;110:219-229.

7] Wang KC , Shih CH. Necrotizing fasciitis of the extremities. J Trauma 1992;32:259-264.

8] Majeski J, Majeski E. Necrotizing fasciitis: improved survival with early recognition by tissue biopsy and aggressive surgical treatment. South Med J 1997;90:1065-1068.

9] Elliot DC, Kufera JA, Myers RA. Necrotizing soft tissue infections: risk factors for mortality and strategies for management. Ann Surg 1996;224:672-683.

10] Amit K, Ajit K, et.al. Triple site necrotizing fasciitis in a diabetic patient: A case report. J Diab Foot Complications 2009;1:76-79.

11] Amit K, Ajit K, et.al. Surgical outcome of necrotizing fasciitis in diabetic lower limbs.  J Diab Foot Complications 2009;1:80-84.

12] Vijay V, Snehalatha C, Ramachandran A. Socio-cultural practices that may effect the development of the diabetic foot. IDF Bulletin 1997:42:10-2.

13] Vijay V, Narasimham A, Senna R, Snehalatha C, Ramachandran A. Clinical profile of diabetic foot infections in South India- A retrospective study. Diabetic Medicine 2000;17:215-8.

14] Smeets L, Bous A, Heymans O. Necrotizing fasciitis: case report and review of literature. Acta Chir Belg 2007;107:29-36

Most of the Indian physicians – turned podiatrists advocate inserting a foam insole (with a hole cut into the region of the plantar ulcer) into a one size larger shoe for offloading.11 Unfortunately, such an insole is often ill fitted and can cause an “edge effect” or even new ulcers.11 This approach has not done well with most of our patients because many patients are reluctant to purchase new shoes, especially when the existing shoes are relatively new. Economical factors, in addition to the costs of podiatric care, also contribute to this reluctance.

At our foot clinic, we developed the aforementioned “Samadhan System of offloading”.10 It is based on the following principles: 1) simplicity—easy to make, 2) no special training is required, 3) affordability, and 4) effective offloading. The Samadhan System has a removable (Samadhan-R) and an irremovable version (Samadhan-IR). 11

Clinicians from developing countries are advised to improvise modalities as materials or facilities are available to them to improve health care.10 The Samadhan System of offloading shows that clinical research does not necessarily require a huge expense. As devices like the Samadhan System are further tested, they can be adopted by even the richest nations, where more expensive options may not be available to the poor.10

1] Most RS, Sinnock P: The epidemiology of lower extremity amputations in diabetic individuals. Diabetes Care 1983, 6:87–91.

2] Pecoraro RE: Chronology and determinants of tissue repair in diabetic lower extremity ulcers. Diabetes 40:1305–1313, 1991

3] American Diabetes Association: Consensus Development Conference on Diabetic Foot Wound Care. Diabetes Care 22: 1354, 1999.

4] Frykberg RG: Diabetic foot ulcers: pathogenesis and management. Am Fam Physician 66:1655–1662, 2002.

5] Lavery LA, Armstrong DG, Wunderlich RP, Tredwell JL, Boulton AJM: Predictive value of foot pressure assessment as part of a population-based diabetes disease management program. Diabetes Care 26: 1069–1073, 2003.

6) Boulton AJ: Pressure and the diabetic foot: clinical science and offloading techniques. Am J Surg 187:17S–24S, 2004.

7] Armstrong DG, Nguyen HC, Lavery LA, van Schie CH, Boulton AJM, Harkless LB: Offloading the diabetic foot wound: a randomized clinical trial. Diabetes Care 24: 1019–1022, 2001

8] Brem H, Sheehan P, Boulton AJ: Protocol for treatment of diabetic foot ulcers. Am J Surg 187:1S–10S, 2004.

9] Reiber GE, Smith DG, Carter J, Fotieo G, Deery HG, 2nd, Sangeorzan JA, Lavery L, Pugh J, Peter-Riesch B, Assal JP, del Aguila M, Diehr P, Patrick DL, Boyko EJ: A comparison of diabetic foot ulcer patients managed in VHA and non-VHA settings. J Rehabil Res Dev 38:309 –317, 2001.

10] Shankhdhar K. Improvisation Is the Key to Success: The Samadhan System. Adv Skin Wound Care 2006; 19: 379-82.

11] Shankhdhar K, Shankhdhar LK, Shankhdhar U. Shankhdhar S.Diabetic Foot Problems in India: An overview and Potential Simple Approaches in a Developing Country Current Diabetes Reports 2008, 8:452–457.

Normal wound healing occurs in several progressive, overlapping stages, beginning with clot formation. This is followed by inflammation, new tissue formation and finally tissue remodeling. Multiple cell types are involved in the process, and genetic control of events is regulated in a temporal, spatial, and cell-type specific manner.1, 2 While normal progression of wound healing follows this general pattern, dysregulated wound repair frequently occurs in patients with diabetes1, 3, 4 and peripheral artery disease (PAD),5 resulting in chronic, non-healing wounds. These often show signs of chronic inflammation without normal progression to later wound healing stages, a possible indication of inappropriate stalling of the wound in the inflammatory phase of wound repair.

Often refractory to standard of care treatment, chronic lower extremity wounds represent a challenging medical complication. With almost 8% of the American population estimated with diabetes,6 and PAD affecting 12-20% of the US population age 65 and over,7 the development and implementation of effective therapies to treat such wounds is a critical medical need. Pulsed radio frequency energy (PRFE) has been shown to promote the healing of chronic wounds that were otherwise unresponsive to standard of care treatment,8, 9 including chronic lower extremity wounds in diabetic patients. Although the use of this biophysical treatment paradigm has been shown to be an effective treatment modality for pain and edema and soft tissue wounds, little is known about the biological mechanisms underlying these effects.

By performing microarray analysis of PRFE-treated human dermal fibroblasts and keratinocytes in culture, we previously found that PRFE treatment results in increased expression of many genes involved in the inflammatory stage of wound repair in a temporally regulated manner, including the upregulation of cytokines, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs).10 Here, we evaluate the impact of PRFE treatment on the expression of genes involved in angiogenesis and tissue remodeling. We have found that PRFE treatment is followed by a rapid increase in transcripts encoding factors involved in these processes, including cyclins, growth factors, cell adhesion-related proteins, and DNA replication factors.

These results suggest that PRFE regulates a sequence of gene expression events that lead to healing of chronic wounds in the diabetic patient by promoting progression of the chronic wound beyond chronic inflammation to angiogenesis and tissue remodeling.

Cell culture. Human epidermal keratinocyte (HEK) and human dermal fibroblasts (HDF) were purchased from Cell Applications, Inc. (San Diego, CA), and cultures maintained as previously described.10

PRFE field conditions and treatment. PRFE treatment was performed by exposing cells to the signal from a PRFE device (Provant®, Regenesis Biomedical, Inc.), which emits a 27.12 MHz radio frequency (RF) signal. Energy parameters and treatment conditions used were as previously described.10 Control cells received no PRFE treatment.

Cell synchronization and cell cycle analysis. Cell synchronization studies were performed as previously described.10 Briefly, cells were synchronized using mevastatin (compactin), to synchronize cells in early G1 phase of the cell cycle. 30 minutes prior to exposure to PRFE, cells were released from the G1 by treating with a 100-fold excess of mevalonate. Cell synchronization was verified using bromodeoxyuridine (BrdU) incorporation and detection with BrdU-specific antibodies (Roche) as previously described.10

Total RNA isolation. Cells were treated with PRFE field, or left as untreated controls, and total RNA was isolated according to the method of Chomczynski and Sacchi.11 Cells were harvested for total RNA at the times indicated in the figures.

cDNA array analysis. Microarrays and reagents were purchased from BD Biosciences-Clontech (Palo Alto, CA). In general, each sample combined at least 3 plates. Total RNA (1-2 ug) was labeled with 32P-dATP using reverse transcriptase (RT) from Clontech (Palo Alto, CA) as described by the manufacturer, purified by column chromatography, and used as probe for cDNA array hybridization.

Gene expression analysis. Autoradiographs were scanned at 200 dpi and analyzed using Atlas Image software (BD Biosciences-Clontech, Palo Alto, CA). Two reference genes, GAPDH and ribosomal protein L13a, were used to normalize the cDNA array expression profiles. Further gene expression analysis was performed with Gene Linker software (Predictive Patterns Software, Canada).

Reverse transcription (RT) and polymerase chain reaction (PCR). Cells were treated with PRFE and RNA isolated as described above. Reverse transcription of the total RNA was performed using the SuperScript First Strand system from Invitrogen (Carlsbad, CA), following the manufacturer’s instructions and as previously described.10 cDNA was amplified by polymerase chain reaction (PCR). PCR products were electrophoresed on 2% agarose gels, photographed, and specific DNA fragments quantitated using Scion Image.

The effect of PRFE on the expression of genes involved in angiogenesis and tissue remodeling in HDF and HEK cells. The impact of PRFE treatment on the expression of genes involved in angiogenesis and wound remodeling was assessed using microarray analysis of cultured human dermal fibroblasts (HDF) and human epidermal keratinocytes (HEK). Relative transcript levels of factors involved in these processes were determined at multiple time points following PRFE treatment using cDNA microarray analysis and confirmed by RT-PCR. Microarray results were grouped according to gene product functionality using the following groups: (A) transcription factors, (B) cyclins and their related kinases, (C) DNA synthesis proteins, (D) cell adhesion-related proteins, and (E) growth factors and their receptors. In both cell types, PRFE treatment resulted in an increase in relative transcript levels for multiple factors in each functional group, detected as early as 5 and 15 minutes after PRFE treatment for HDF cells (Fig. 1) and HEK cells (Fig. 2), respectively.

Figure 1: Functional grouping of microarray analysis of gene expression after PRFE treatment of HDF cells. Gene lists were developed to place expression data in functional groups. Expression groups related to gene products involved in angiogenesis and tissue remodeling are shown. (A) Transcription factors, (B) cyclins and their related kinases, (C) DNA synthesis proteins, (D) cell adhesion-related proteins, and (E) growth factors and their receptors. Expression levels are relative to the zero hour control.		Figure 2: Functional grouping of cDNA array analysis of gene expression after PRFE field treatment of HEK cells. Expression groups related to gene products involved in angiogenesis and tissue remodeling are shown. (A) Transcription factors, (B) cyclins and their related kinases, (C) DNA synthesis proteins, (D) cell adhesion-related proteins, and (E) growth factors and their receptors. Expression levels are relative to the zero hour control.

Next, to further characterize the effect of PRFE on the expression of factors involved in these processes, the effect of PRFE on gene expression in synchronized cells was examined. HDF and HEK cells were synchronized in G1, followed by release and subsequent microarray analysis at multiple time points. For PRFE-treated cells, PRFE treatment was performed 30 minutes after release from the G1 block. In both cell types, PRFE treatment led to a robust increase of transcripts in all functional groups (Fig. 3), most notably at 15 minutes in synchronized HDF cells, and at 5 hours in synchronized HEK cells, following PRFE treatment.

Figure 3: Functional expression matrix for synchronized HDF and HEK cells treated with PRFE Expression groups related to gene products involved in angiogenesis and tissue remodeling are shown. For HDF cells: (A) adhesion related genes, (B) cyclins and their related kinases, (C) DNA synthesis proteins, and (D) growth factors and their receptors. For HEK cells: (E) growth factors and their receptors, (F) transcription factors, (G) cyclins and their related kinases, and (H) DNA synthesis proteins. Data are expressed relative to untreated synchronized control cells.

To understand the overall effect of PRFE on temporal gene expression, cDNA arrays were used to obtain expression data for 1,176 genes in synchronized HDF and HEK cells following PRFE treatment. Data was clustered by time point, regardless of functional group, for control and PRFE-treated synchronized cells. Microarray analysis revealed that the majority of expression changes occurred more rapidly in PRFE-treated cells compared to control cells in both cell types (HEK cells, Fig. 4; HDF cells, data not shown), though typically later in synchronized HEK cells than that seen for synchronized HDF cells. In synchronized HEK cells, a large induction of gene expression occurred five hours following PRFE treatment (Fig. 4, cluster C-PRFE treated) followed by another large-scale induction of gene expression eight hours after treatment (Fig. 4, cluster D-PRFE treated). In the untreated cells more than 80% of the genes were expressed at the eight hour time point (Fig. 4, cluster D-control), with very little expression changes occurring at earlier time points for the genes analyzed.

Figure 4: cDNA array analysis of synchronized HEK cells treated with a PRFE field. HEK cells were synchronized using mevastatin treatment for 36 hours. Cells were released from cell cycle block using a 100X excess of mevalonate. Expression matrices of cDNA array data of synchronized cells, both control and PRFE field-treated. Each set of data was divided in four groups based on expression. Data is expressed relative to zero hour control.

Finally, PRFE treatment led to an increased rate of progression to S phase by 6-8 hours in synchronized HDF cells, and by 4 to 6 hours in synchronized HEK cells relative to synchronized control cells (data not shown). This is in agreement with rapid transcript level increases noted for factors involved in cell proliferation in both cell types following PRFE treatment.

Keratinocytes and fibroblasts play important functions during wound repair, impairments of which are associated with delayed or chronically stalled wound healing in many metabolic disorders.1, 3, 4, 12 To understand the mechanisms underlying PRFE therapy-mediated effects during wound healing, we used a microarray approach to look at the effect of PRFE on the expression of factors involved in the wound healing process in human keratinocyte and fibroblast cell lines. In a previous article we showed that PRFE treatment upregulated mRNA levels of numerous factors important for the inflammatory phase of wound healing.10 In this report, we focus on the effects of PRFE treatment on factors involved in subsequent stages of the wound healing process.

The effect of PRFE on factors involved in the proliferative and tissue remodeling phases of wound healing.

Angiogenesis, the formation of granulation tissue, and tissue remodeling are complex processes involving participation of numerous factors and signaling pathways. Here, we find that mRNA levels of many of these factors are upregulated following exposure to PRFE. In both cell types examined, PRFE treatment resulted in increased mRNA levels for multiple subunits of integrins (Fig. 1D, Fig. 2D, Fig. 3A), cell surface receptors that interact with components of the extracellular matrix (ECM) and surface molecules on other cells. Directly involved in cell motility, integrins also regulate a number of cell processes such as proliferation and survival.13, 14 During wound healing, they are important for re-epithelialization, angiogenesis, and wound contraction,1, 14-16 and binding to their ligands can mediate cell-signaling events important for expression of other factors involved in wound repair.17

Transcript levels of multiple cyclins and DNA replication factors, factors that regulate cell division, were also upregulated following PRFE treatment in both cell types, with particularly rapid and synchronous increases following treatment of synchronized HDF cells (Fig. 3C). During wound repair, properly controlled cell proliferation is necessary for the formation of new tissue, and proliferation defects in keratinocytes and fibroblasts have been reported in diabetic foot ulcers and chronic venous leg ulcers.1, 4, 12 Specific cyclins are critical to progression through checkpoints in the cell cycle,18, 19 and cell synchronization studies suggest that PRFE exposure increases the rate of progression though the cell cycle.

Dysregulation of wound healing in metabolic disorders.

Impaired wound healing is a frequent complication of conditions with underlying metabolic dysfunction, such as in as in diabetes, metabolic syndrome, and PAD. In such cases, numerous physiological factors are thought to contribute to dysregulated wound repair. In diabetes, this includes impairments related to growth factor production, angiogenesis, quality of granulation tissue formation, keratinocyte and fibroblast proliferation and migration, and extracellular matrix (ECM) deposition.1, 3, 4 In addition, lack of synchrony within the wound can also occur, with progression through different phases of wound repair occurring at different rates throughout the wound,1 or non-progression through the wound healing cycle and wound stalling in a chronic inflammatory state (Fig. 5).28, 29 The underlying cause of such disorders is a topic of intense research, and several hypotheses have been proposed. Disruptions in insulin and leptin signaling are hallmarks of several metabolic disorders, and disruption of these pathways has important systemic effects on metabolism.30 Dysregulated wound healing associated with these disorders is thought to be primarily due to these widespread metabolic abnormalities.

Figure 5: A cyclic model for wound healing. For complete healing of acute or chronic wounds, the cellular mechanisms involved can be modeled in stages progressing through a cycle. In patients with chronic wounds due to diabetes, peripheral vascular disease, or improper off-loading leading to pressure ulcers, wounds may be blocked or stalled in inflammation.5, 28, 29 PRFE, negative pressure wound therapy (NPWT), and compression (for Venous ulcers) may accelerate wound healing by inducing genes which allow for the transition of the wound through the stall point promoting transition to angiogenesis and granulation tissue formation and the completion of wound healing.10, 35, 36

However, abnormal repair is likely confounded by the fact that both leptin and insulin signaling pathways appear to function directly in wound repair as well.31-34

In conclusion, we have shown that PRFE can mediate robust, and often synchronous, mRNA upregulation for a wide range of factors involved in the wound healing process. Since improper wound healing in metabolic disorders is multifactorial, therapies that facilitate wound healing by promoting multiple wound repair pathways, as evidence suggests for PRFE therapy, have great potential as treatment options for chronic wounds.

The authors would like to thank the Dr. Berens laboratory at the Barrow Neurological Institute. The research was supported by a grant from The Wallace Foundation and by Regenesis Biomedical, Inc.

1] Falanga V. Wound healing and its impairment in the diabetic foot. Lancet 2005; 366(9498):1736-43.

2] Gurtner GC, Werner S, Barrandon Y, et al. Wound repair and regeneration. Nature 2008; 453(7193):314-21.

3] Blakytny R, Jude E. The molecular biology of chronic wounds and delayed healing in diabetes. Diabet Med 2006; 23(6):594-608.

4] Brem H, Tomic-Canic M. Cellular and molecular basis of wound healing in diabetes. J Clin Invest 2007; 117(5):1219-22.

5] Gist S, Tio-Matos I, Falzgraf S, et al. Wound care in the geriatric client. Clin Interv Aging 2009; 4:269-87.

6] National Diabetes Fact Sheet, 2007. Department of Health and Human Services, Centers for Disease Control and Prevention 2007.

7] Statistical Fact Sheet – 2008 Update: Peripheral Arterial Disease – Statistics. American Heart Association 2008.

8] Frykberg R, Tierney E, Tallis A, et al. Cell proliferation induction: healing chronic wounds through low-energy pulsed radiofrequency. Int J Low Extrem Wounds 2009; 8(1):45-51.

9] Porreca EG, Giordano-Jablon GM. Treatment of Severe (Stage III and IV) Chronic Pressure Ulcers Using Pulsed Radio Frequency Energy in a Quadriplegic Patient. Eplasty 2008; 8:e49.

10] Moffett J, Griffin NE, Ritz MC, et al. Pulsed radio frequency energy field treatment of cells in culture results in increased expression of genes involved in the inflammation phase of lower extremity diabetic wound healing. The Journal of Diabetic Foot Complications 2010; 2(3):57-64.

11] Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal.Biochem. 1987; 162(1):156-159.

12] Harding KG, Moore K, Phillips TJ. Wound chronicity and fibroblast senescence–implications for treatment. Int Wound J 2005; 2(4):364-8.

13] Truong H, Danen EH. Integrin switching modulates adhesion dynamics and cell migration. Cell Adh Migr 2009; 3(2):179-81.

14] Schultz GS, Wysocki A. Interactions between extracellular matrix and growth factors in wound healing. Wound Repair Regen 2009; 17(2):153-62.

15] Distler JH, Hirth A, Kurowska-Stolarska M, et al. Angiogenic and angiostatic factors in the molecular control of angiogenesis. Q J Nucl Med 2003; 47(3):149-61.

16] Hinz B. Formation and function of the myofibroblast during tissue repair. J Invest Dermatol 2007; 127(3):526-37.

17] Steffensen B, Hakkinen L, Larjava H. Proteolytic events of wound-healing–coordinated interactions among matrix metalloproteinases (MMPs), integrins, and extracellular matrix molecules. Crit Rev Oral Biol Med 2001; 12(5):373-98.

18] Blagosklonny MV, Pardee AB. The restriction point of the cell cycle. Cell Cycle 2002; 1(2):103-110.

19] Planas-Silva MD, Weinberg RA. The restriction point and control of cell proliferation. Curr.Opin.Cell Biol. 1997; 9(6):768-772.

20] Robson MC, Phillips LG, Lawrence WT, et al. The safety and effect of topically applied recombinant basic fibroblast growth factor on the healing of chronic pressure sores. Ann Surg 1992; 216(4):401-6; discussion 406-8.

21] Brem H, Kodra A, Golinko MS, et al. Mechanism of sustained release of vascular endothelial growth factor in accelerating experimental diabetic healing. J Invest Dermatol 2009; 129(9):2275-87.

22] Fang RC, Galiano RD. A review of becaplermin gel in the treatment of diabetic neuropathic foot ulcers. Biologics 2008; 2(1):1-12.

23] Jazwa A, Kucharzewska P, Leja J, et al. Combined vascular endothelial growth factor-A and fibroblast growth factor 4 gene transfer improves wound healing in diabetic mice. Genet Vaccines Ther; 8:6.

24] Bao P, Kodra A, Tomic-Canic M, et al. The role of vascular endothelial growth factor in wound healing. J Surg Res 2009; 153(2):347-58.

25] Gillis P, Savla U, Volpert OV, et al. Keratinocyte growth factor induces angiogenesis and protects endothelial barrier function. J Cell Sci 1999; 112 ( Pt 12):2049-57.

26] Kim IY, Kim MM, Kim SJ. Transforming growth factor-beta : biology and clinical relevance. J Biochem Mol Biol 2005; 38(1):1-8.

27] Pastar I, Stojadinovic O, Krzyzanowska A, et al. Attenuation of the transforming growth factor beta-signaling pathway in chronic venous ulcers. Mol Med; 16(3-4):92-101.

28] Eming SA, Krieg T, Davidson JM. Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol 2007; 127(3):514-25.

29] Pierce GF. Inflammation in nonhealing diabetic wounds: the space-time continuum does matter. Am J Pathol 2001; 159(2):399-403.

30] Taubes G. Insulin resistance. Prosperity’s plague. Science 2009; 325(5938):256-60.

31] Fantuzzi G, Faggioni R. Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol 2000; 68(4):437-46.

32] Frank S, Stallmeyer B, Kampfer H, et al. Leptin enhances wound re-epithelialization and constitutes a direct function of leptin in skin repair. J Clin Invest 2000; 106(4):501-9.

33] Liu Y, Petreaca M, Yao M, et al. Cell and molecular mechanisms of keratinocyte function stimulated by insulin during wound healing. BMC Cell Biol 2009; 10:1.

34] Ring BD, Scully S, Davis CR, et al. Systemically and topically administered leptin both accelerate wound healing in diabetic ob/ob mice. Endocrinology 2000; 141(1):446-9.

35] Saxena V, Orgill D, Kohane I. A set of genes previously implicated in the hypoxia response might be an important modulator in the rat ear tissue response to mechanical stretch. BMC Genomics 2007; 8:430.

36] Scherer SS, Pietramaggiori G, Mathews JC, et al. The mechanism of action of the vacuum-assisted closure device. Plast Reconstr Surg 2008; 122(3):786-97.

Ill-fitting shoe gear is a known risk factor for the development of foot ulceration in patients with diabetes, particularly in the setting of neuropathy and foot deformity. Reiber describes these factors of trauma, neuropathy and deformity as a causative pathologic triad in the development of lower-extremity ulceration1. Apelqvist et al confirmed the role of participating external stresses, specifically ill-fitting shoes, as a contributing etiology to ulcer development in a series of neuropathic diabetic patients2. Nixon et al further demonstrated that patients with diabetic foot ulceration were five times as likely to have poor fitting shoes compared to a cohort with appropriately sized shoes3. And several authors have provided evidence as to the potential protective benefits of therapeutic footwear with respect to the diabetic foot.4-6 Three studies have previously demonstrated prevalence rates of incorrect shoe size in specialized patient populations,3,7,8 but this investigation aimed to evaluate shoe size perception in a previously unstudied group of patients: those with diabetes at a large, inner-city United States clinic presenting for initial foot evaluation.

1. International Diabetes Federation (IDF), 2007.
2. Palumbo PJ, Melton LJ, 3rd. Peripheral Vascular Disease and Diabetes. Washington, DC: Government printing office. NIH publication 85-1468, 1985.
3. Jude EB, Unsworth PF. Optimal treatment of infected diabetic foot ulcers. Drugs Aging 2004;21(13):833-50.
4. International Diabetes Foundation (IDF), 2007.
5. Moretti B, Notarnicola A, Maggio G, Moretti L, Pascone M, Tafuri S, et al. The management of neuropathic ulcers of the foot in diabetes by shock wave therapy. BMC Musculoskelet Disord 2009;10:54.
6. Horswell RL, Birke JA, Patout CA, Jr. 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(12):1743-6.
7. McCartney T. Wound healing and care in the infected diabetic foot. West Indian Med J 2001;50 Suppl 1:27-8.
8. Gottrup F. Oxygen in wound healing and infection. World J Surg 2004;28(3):312-5.
9. Tandara AA, Mustoe TA. Oxygen in wound healing–more than a nutrient. World J Surg 2004;28(3):294-300.
10. Quinn MT, Gauss KA. Structure and regulation of the neutrophil respiratory burst oxidase: comparison with nonphagocyte oxidases. J Leukoc Biol 2004;76(4):760-81.
11. Cianci P. Advances in the treatment of the diabetic foot: Is there a role for adjunctive hyperbaric oxygen therapy? Wound Repair Regen 2004;12(1):2-10.
12. Niinikoski J. Current concepts of the role of oxygen in wound healing. Annales Chirugiae et Gynaecologia. 90 2001;Supplement 215:9-11.
13. Gordillo GM, Sen CK. Revisiting the essential role of oxygen in wound healing. Am J Surg 2003;186(3):259-63.
14. Breuer HW, Breuer J, Berger M. Transcutaneous oxygen pressure measurements in type I diabetic patients for early detection of functional diabetic microangiopathy. Eur J Clin Invest 1988;18(5):454-9.
15. Amini M, Parvaresh E. Prevalence of macro- and microvascular complications among patients with type 2 diabetes in Iran: a systematic review. Diabetes Res Clin Pract 2009;83(1):18-25.
16. Ditzel J, Standl E. The problem of tissue oxygenation in diabetes mellitus. I. Its relation to the early functional changes in the microcirculation of diabetic subjects. Acta Med Scand Suppl 1975;578:49-58.
17. Said HK, Hijjawi J, Roy N, Mogford J, Mustoe T. Transdermal sustained-delivery oxygen improves epithelial healing in a rabbit ear wound model. Arch Surg 2005;140(10):998-1004.
18. Fife CE, Buyukcakir C, Otto G, Sheffield P, Love T, Warriner R, 3rd. Factors influencing the outcome of lower-extremity diabetic ulcers treated with hyperbaric oxygen therapy. Wound Repair Regen 2007;15(3):322-31.
19. Lyon KC. The case for evidence in wound care: investigating advanced treatment modalities in healing chronic diabetic lower extremity wounds. J Wound Ostomy Continence Nurs 2008;35(6):585-90.
20. Roeckl-Wiedmann I, Bennett M, Kranke P. Systematic review of hyperbaric oxygen in the management of chronic wounds. Br J Surg 2005;92(1):24-32.
21. Guo S, Counte MA, Gillespie KN, Schmitz H. Cost-effectiveness of adjunctive hyperbaric oxygen in the treatment of diabetic ulcers. Int J Technol Assess Health Care 2003;19(4):731-7.
22. Wunderlich RP, Peters EJ, Lavery LA. Systemic hyperbaric oxygen therapy: lower-extremity wound healing and the diabetic foot. Diabetes Care 2000;23(10):1551-5.
23. Landau Z, Schattner A. Topical hyperbaric oxygen and low energy laser therapy for chronic diabetic foot ulcers resistant to conventional treatment. Yale J Biol Med 2001;74(2):95-100.
24. Gorman DF, Harding PE, Roberts AP, Gilligan JE, Capps RA, Parsons DW. Topical hyperbaric oxygen for treatment of diabetic foot ulcers. Diabetes Care 1988;11(10):819.
25. Jude EB, Apelqvist J, Spraul M, Martini J. Prospective randomized controlled study of Hydrofiber dressing containing ionic silver or calcium alginate dressings in non-ischaemic diabetic foot ulcers. Diabet Med 2007;24(3):280-8.
26. Driver VR, Hanft J, Fylling CP, Beriou JM, Autologel Diabetic Foot Ulcer Study G. A prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers. Ostomy Wound Manage 2006;52(6):68-70, 72, 74 passim.
27. Veves A, Sheehan P, Pham HT. A randomized, controlled trial of Promogran (a collagen/oxidized regenerated cellulose dressing) vs standard treatment in the management of diabetic foot ulcers. Arch Surg 2002;137(7):822-7.
28. Blume PA, Walters J, Payne W, Ayala J, Lantis J. Comparison of negative pressure wound therapy using vacuum-assisted closure with advanced moist wound therapy in the treatment of diabetic foot ulcers: a multicenter randomized controlled trial. Diabetes Care 2008;31(4):631-6.
29. Margolis DJ, Gelfand JM, Hoffstad O, Berlin JA. Surrogate end points for the treatment of diabetic neuropathic foot ulcers. Diabetes Care 2003;26(6):1696-700.
30. Margolis DJ, Kantor J, Berlin JA. Healing of diabetic neuropathic foot ulcers receiving standard treatment. A meta-analysis. Diabetes Care 1999;22(5):692-5.