Transitioning To Advanced Therapies For DFUs: Are Four Weeks And 50 Percent The Magic Numbers?

When do you make the transition to advanced modalities for diabetic foot ulcers? With this question in mind, these authors discuss key diagnostic pointers and offer salient insights from the literature on when physicians should consider advanced modalities to facilitate improved healing and outcomes.

The treatment of diabetic foot ulcers can be a long, multifaceted task. Not only does one need to address the actual ulcer, clinicians need to consider other contributing factors such as foot deformities, biomechanics, glycemic control, ischemia, and peripheral and autonomic neuropathy.1,2 For these reasons, the diabetic foot ulcer often proves recalcitrant to certain treatment modalities and can be a challenging feat for many patients and practitioners alike.

   Advanced therapies may be beneficial to patients with chronic diabetic foot ulcers. However, in order to consider the use of these modalities, one must examine the ulcer etiology, review the clinical findings, ensure a proper workup, determine if there is adequate vascularity and assess the length of time to adequate healing.

   In regard to the aforementioned etiological factors, the most significant predictor of diabetic foot ulcer formation is neuropathy. Peripheral neuropathy is basically altered sensation, which creates a basis for skin breakdown in the presence of pressure areas. Autonomic neuropathy impairs capillary vasodilatation in response to injury. While understanding that one of the main etiologies of ulcer formation is neuropathy, it is also very important to understand what leads to neuropathy in the patient with diabetes.

   Abnormalities in the polyol pathway and inadequate nerve regeneration are direct results of neuropathic changes in the patient with diabetes.2 The effects of diabetes impair wound healing by altering protein and lipid metabolism, and affect granulation tissue formation. Due to these alterations, there is a significant lack of normal enzymatic glycosylation. Excess glucose binds to lipids and proteins without any proper glycosylation, and become products that accumulate over surface cell membranes and proteins. These products become known as advanced glycation end products (AGEs), which are seen on extracelluar matrix proteins such as laminin, vitronectin and collagen. These matrix proteins become altered by advanced glycation end products through cross-linking, which produces tissue stiffness, granulation tissue and basement membrane thickening in arterioles and capillaries.

   Microangiopathy and atherosclerotic disease also impede adequate wound healing, and are highly prevalent in patients with diabetes. Diminished blood flow plays a crucial role in the development of ulceration and is a strong barrier to cellular proliferation and wound healing.3

   Chronic wounds, in particular, are extremely complex and slow to heal due to constant inflammation affecting the healing process. Chronic wounds are unable to enter the proliferative phase of healing and develop over time due to edema, inadequate perfusion, poor nutrition, infection, trauma and certain rheumatologic factors. Another huge contributor to chronic wounds is matrix metalloproteinase, which modifies the extracellular matrix by metabolizing collagen, elastins and proteoglycans. This in turn affects tissue reabsorption, remodeling, platelet aggregation, macrophage and neutrophil function, cell migration, and angiogenesis.2

   Infection also impedes wound healing and is usually a consequence, rather than a cause, of ulceration. Infection allows the entry of microorganisms and subsequent multiplication of these microorganisms. In view of the fact that a diabetic foot infection has the potential to threaten the limb, appropriate diagnosis and therapy are urgently required. Having a way to evaluate healing potential for a particular therapy may help physicians change to more aggressive therapies earlier in the treatment process in efforts to drastically lower infection risks and prevent lower extremity amputations.

   While the understanding of the etiology of diabetic foot ulcers continues to progress, treatment therapies are advancing and amputation rates are declining.

Essential Diagnostic Considerations

Patients with diabetes who present with ulcerations on the foot usually have arterial insufficiency as evidenced by weakly or non-palpable pedal pulses, ischemic changes in the setting of gangrene, or skin atrophy.2 The ulcerations are typically located on the plantar aspect of the foot in weightbearing areas such as plantar metatarsal head regions. One may also find ulcerations at the distal aspect of pedal digits. This is due to the effects of motor neuropathy leading to retrograde buckling, which results in hammertoe formation, creating callosities and subsequent ulceration. Sensory neuropathy in the patient with diabetes can be characterized by a decreased or absent light touch sensation when one tests specific pedal areas with a 10-gram Semmes-Weinstein monofilament.2

   Osteomyelitis is always an underlying concern in the face of any ulceration, especially ulcerations that are chronic in nature. Radiographs, magnetic resonance imaging and triphasic bone scans are excellent diagnostic modalities, and can help tailor treatment protocols. Clinicians may also obtain wound cultures from infected wounds in efforts to optimize appropriate antibiotic therapy.2

   Vascular insufficiency is another consideration when dealing with diabetic ulcers.2,3 Various vascular studies can help assess the hemodynamics of vascular insufficiency. Unfortunately, one vascular study that is not very beneficial to the patient with diabetes is the ankle-brachial pressure index (ABI), which is often falsely elevated since patients with diabetes have calcified vessels that will not compress. Pulse volume recordings (PVRs) may prove more accurate in determining the significance of arterial disease in patients with diabetes than an ABI.2

   Magnetic resonance angiography is another useful tool for imaging atherosclerotic disease. Healing cannot occur in the presence of hypoxia, which can still persist even post-revascularization.1 Measuring the transcutaneous oxygen tension (TcPO2) proves helpful in these cases since a value above 30 mmHg suggests a high healing potential.2

A Pertinent Overview Of Treatment Options For Diabetic Foot Ulcerations

The cost to manage foot disorders is estimated at several billion dollars annually.4,5 Researchers have estimated that in the United States, 4.6 to 13.7 billion dollars are spent every year for the treatment of diabetic peripheral neuropathy and its complications. This dollar amount accounts for approximately 27 percent of the direct medical costs of diabetes.6 Successful clinical management of diabetic foot ulcers not only has the potential to reduce the cost of caring for these patients, it can improve the patient’s quality of life by reducing comorbidities.

   Various authors have reported on treatment options for diabetic foot ulcers. These modalities include advanced moist wound therapy; periodic wound debridement to remove bacterial biofilm and hyperkeratosis; bioengineered tissue or skin substitutes; growth factors; electric stimulation; and negative pressure wound therapy (NPWT).6-14 Many factors can influence the outcome of treatment. These factors include the nature of the ulcer, the presence of infection, patient adherence, appropriate offloading and the mechanisms of action of the therapy. Even with all appropriate measures, some wounds still fail to heal.

What The Literature Reveals About The Prognostic Value Of The Percentage Of Wound Area Reduction At Four Weeks

Due to the complexity of diabetic foot ulcers and the difficulty it takes to heal them, some studies have reported that an area reduction greater than or equal to 50 percent at four weeks of treatment is a good prognostic indicator about an ulcer’s ability to heal at 12 or 20 weeks.

   In particular, Sheehan and his colleagues published a study describing that diabetic foot wounds that do not heal by at least 50 percent in the first four weeks of treatment have less than a 10 percent chance of closing by week 12.15 They studied the healing rate of 203 patients with chronic diabetic foot ulcers receiving standard wound care therapies. They also looked at the healing ability of ulcers as a direct correlation with their percent area of reduction.

   This large prospective study from 2003 has been widely cited in the recent literature because it revealed that patients who did not reduce their wound area by approximately 50 percent at the four-week average had a very low probability of healing. The study authors further concluded that physicians need to re-evaluate diabetic foot wounds on a regular basis so they can redirect treatment if a wound is not healing as expected.

   Boulton and colleagues also noted that the failure to reduce the size of an ulcer after four weeks, even with appropriate debridement and pressure reduction, should prompt consideration of adjunctive therapy. They noted this in 2004 when they developed a clinical practice article for neuropathic diabetic foot ulcers, which was published in The New England Journal of Medicine.16 The authors reviewed literature about the general management of diabetic foot ulcers and treatment options such as infection management, offloading, routine debridement, glycemic control, and the use of growth factors and tissue-engineered skin. Boulton and co-authors recommend the use of adjunctive treatment options such as tissue-engineered skin when a patient has not had a 50 percent decrease in wound size at four weeks.

   Snyder and colleagues did a post-hoc analysis about percent area reduction and an ulcer’s ability to heal at four weeks in 2010.17 The study looked at two previously conducted studies consisting of patients with type 1 diabetes and patients with type 2 diabetes. Both groups (study A and study B) received debridement, a saline-moistened gauze dressing covered with dry gauze (wet to dry) and adhesive fixation sheets. Both groups also utilized therapeutic footwear and received offloading instructions.

   For study A, 133 patients had a pre-trial standard of care treatment for two weeks and had a full thickness DFU on the heel or plantar foot greater than 1 cm2. The ulcer was essentially the same size during the two-week pre-trial period. There were 117 patients in study B but they did not receive standard of care treatment prior to the study.

   In study A, 57 percent (39 out of 69) of patients with a diabetic foot ulcer had a percent area reduction greater than or equal to 50 percent by week four. Fifty-two percent (38 out of 73) of patients with diabetic foot ulcers in study B healed by 12 weeks. Five percent of diabetic foot ulcers in study A and 2 percent in study B healed at 12 weeks with a percent area reduction of less than 50 percent at four weeks.

   Lavery and co-workers also studied the progression of the postoperative diabetic foot by evaluating the percent wound area reduction at one week and four weeks.18 The patients in this study had large, non-ischemic, diabetic foot wounds following partial amputations. The 16-week randomized clinical study of 129 patients compared outcomes of patients who had negative wound pressure therapy (NPWT) using the vacuum assisted closure (VAC, KCI) system in 77 patients versus moist wound therapy in 85 patients.

   The results of the study revealed that the percent wound area reduction at one week was predictive of complete wound healing at 16 weeks.18 Wounds that had a 15 percent or greater percent wound area reduction at one week had a 68 percent chance of healing versus a 32 percent healing rate for wounds that did not reach a 15 percent wound area reduction.

   Furthermore, the percent wound area reduction at four weeks was predictive of complete closure at 16 weeks.18 Wounds that had a percent wound area reduction of 60 percent or greater at four weeks had a 77 percent chance of healing versus 30 percent for those wounds that did not reach a 60 percent wound area reduction. Wounds treated with NPWT at one week had an 18.9 percent wound area reduction, which was associated with a 60 percent chance of healing. Wounds treated with moist wound therapy at one week had a 9.9 percent wound area reduction, which was associated with a 39 percent chance of healing.

In Conclusion

Currently, the American Diabetic Association states that 8.3 percent of the current population has diabetes.19,20 This percentage includes 18.8 million people diagnosed with the disease and an estimated 7.0 million people who are undiagnosed.19,20 In 2007, complications from diabetes contributed to a total of 231,404 deaths.20 Complications such as diabetic foot ulcers are responsible for more hospitalizations than any other complication of diabetes. In 2006, surgeons performed approximately 65,700 non-traumatic lower-limb amputations in people with diabetes.19,20

   Pathological conditions such as peripheral neuropathy, foot deformities and trauma predispose patients to diabetic foot ulcers. Limb loss is a significant risk in patients with diabetic foot ulcers, particularly if treatment has been delayed.21,22 When it comes to patients with diabetes and neuropathy, even if successful management results in healing of the foot ulcer, the recurrence rate is 66 percent and the amputation rate rises to 12 percent.22,23

   It is also crucial to remember that proper offloading and debridement contribute significantly to the healing process.3 Additionally, if there is any presence of infection within a diabetic wound, one must provide primary treatment with appropriate antibiotics in order for proper wound healing to occur.

   Overall, the review of the literature advocates that the advanced therapies that reign superior in diabetic wound healing are negative pressure wound therapy and bioengineered skin substitutes. Furthermore, it appears that the 50 percent reduction in ulcer area and four weeks of treatment protocol are indeed the magic numbers that predict the healing potential of a diabetic ulceration, and determine whether the treatment course remains unchanged or warrants adjunctive therapy.

   Dr. Houston is a third-year resident at Yale New Haven Hospital in New Haven, Conn.

   Dr. Mohamed is a second-year resident at the Yale New Haven Hospital in New Haven, Conn.

   Dr. Blume is an Assistant Clinical Professor of Surgery in the Department of Orthopaedics and Rehabilitation at the Yale University School of Medicine. He is the Director of Limb Preservation at the Yale New Haven Hospital in New Haven, Conn. Dr. Blume is a Fellow of the American College of Foot and Ankle Surgeons.

References

1. Fife C. Is HBOT cost-effective for diabetic foot ulcers? Podiatry Today. 2009:22(6):18-24.
2. Stillman R, Steinberg J. Current concepts in treating diabetic foot wounds. Podiatry Today. 2003:16(3):12-18.
3. Landsman A. Emerging concepts in healing diabetic foot ulcers. Podiatry Today. 2011;24(3):42-28.
4. Mulder G, Armstrong D, Seaman S. Standard, appropriate, and advanced care and medical-legal considerations: part one — diabetic foot ulcerations. Wounds. 2003;15(4):92–106.
5. Reiber GE, Lipsky BA, Gibbons GW. The burden of diabetic foot ulcers. Am J Surg. 1998; (176 2A Suppl):5S-10S.
6. Malay D, Margolis D, et al. The Incidence and risks of failure to heal after lower extremity amputation for the treatment of diabetic neuropathic foot ulcer. J Foot Ankle Surg. 2006;45(6):366–374.
7. Wound Ostomy and Continence Nurses Society (WOCN). Guideline for management of wounds in patients with lower-extremity arterial disease. Wound Ostomy and Continence Nurses Society, Glenview, IL. 2002.
8. Blume P, Walters J. et al. 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):631-636.
9. Martson WA, Hanft J, Norwood P, Pollak R. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care. 2003;26(6):1701–1705.
10. Veves A, Falanga V, Armstrong DA, Sabolinski ML. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial. Diabetes Care. 2001;24(2):290-295.
11. Robson MC, Payne WG, Garner WL, Biundo J, Giacalone VF, Cooper DM, Ouyang P. Integrating the results of phase IV (postmarketing) clinical trial with four previous trials reinforces the position that Regranex (becaplermin) gel 0.01% is an effective adjunct to the treatment of diabetic foot ulcers. J Appl Res. 2005;5:35–45.
12. Mannari RJ, Payne WG, Ochs DE, Walusimbi M, Blue M, Robson MC. Successful treatment of recalcitrant, diabetic heel ulcers with topical becaplermin (rh-PDGF-BB) gel. Wounds. 2002;14(3):116 –121.
13. Peters EJ, Lavery LA, Armstrong DG, Fleischli JG. Electric stimulation as an adjunct to heal diabetic foot ulcers: a randomized clinical trial. Arch Phys Med Rehabil. 2001;82(6):721–725.
14. Argenta LC, Morykwas MJ. Vacuum-assisted closure: a new method for wound control and treatment: clinical experience. Ann Plast Surg. 1997;38(6):563–576.
15. Sheehan P, Jones P. A percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete wound healing in a 120-week prospective trial. Diabetes Care. 2003;26(6):1879-1882.
16. Boulton A, Kirsner R, Vileikyte L. Neuropathic diabetic foot ulcers. N Engl J Med. 2004;351(1):48-55.
17. Snyder R, Cardinal M. A post-hoc analysis of reduction in diabetic foot ulcer size at 4 weeks as a predictor of healing by 12 weeks. Ostomy Wound Management. 2010;56(3):44-50.
18. Lavery L, Barnes S, et al. Prediction of healing for postoperative diabetic foot wounds based on early wound area progression. Diabetes Care. 2008;31 (1): 626-636.
19. American Diabetes Association. National Diabetes Fact Sheet 2011. https://www.diabetes.org/diabetes-basics/diabetes-statistics/
20. Centers for Disease Control and Prevention. National Diabetes Fact Sheet: General Information and National Estimates on Diabetes in the United States, 2011. Atlanta, GA, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011. https://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf
21. Ramsey SD, Newton K, Blough D, McCulloch DK, Sandhu N, Reiber GE, et al. Incidence, outcomes, and cost of foot ulcers in patients with diabetes. Diabetes Care. 1999;22(3):382-387.
22. Rowe VL. Diabetic ulcers. Available at https://emedicine.medscape.com/article/460282-treatment . Accessed December 10, 2011.
23. Galkowska H, Olszewski WL, Wojewodzka U, Rosinski G, Karnafel W. Neurogenic factors in the impaired healing of diabetic foot ulcers. J Surg Res. 2006;134(2):252-258.