THE DIABETIC FOOT Lower Extremity Major and Minor Amputations in the 57 High Risk Patient These procedures come with high morbidity and mortality rates. BY KIRSTI A. DIEHL, DPM, LATRICIA ALLEN, DPM, MPH, MICHAEL FRENCH, JD, AND VICKIE R. DRIVER, DPM artial lower limb ampu- ripheral arterial disease (PAD). The healing. For example, patients with tation is a common out- literature recognizes that approxi- ischemic wounds may require revas- come in the high risk pa- mately 80%-85% of non-traumatic cularization to restore proper blood tient with lower extremity chronic ulcerations, isch- Pemia, and infection. The significant Factors leading to the chronicity of a wound decline in the quality of life and eco- nomic burden caused by lower ex- are variable and must be constantly evaluated and tremity infections leading to ampu- tations in the high risk population treated to promote wound healing. warrants further study in order to better understand the elements that improve limb viability and the caus- amputations are preceded by lower flow to heal. al factors related to major limb loss extremity ulcers.2,3 Diabetic neuropathic ulcers re- (below or above the knee).1 Complications of non-heal- sulting from increased pressure due The unfortunate pathway to am- ing wounds increase the longer the to osseous deformities may require putation in the high risk patient with wound is present. Factors leading to a variety of podiatric surgical inter- a lower limb ulceration or infection the chronicity of a wound are vari- ventions, conservative methods to can be caused by major and minor able and must be constantly evalu- offload the area, such as total contact etiologies, mainly diabetes and pe- ated and treated to promote wound © Stuart Miles | Dreamstime.com Continued on page 58 www.podiatrym.com NOVEMBER/DECEMBER 2015 | PODIATRY MANAGEMENT THE DIABETIC FOOT Amputations (from page 57) tremity amputations. Approximate- It has been estimated by the ly 185,000 lower limb amputations United States government that ap- casting, or advanced wound healing occur in the United States of America proximately two out of every five therapies. Of note, only three prod- annually, with the majority (54%) Americans will develop type 2 diabe- ucts are approved by the Food and performed to treat peripheral arterial tes at some point during their adult Drug Administration (FDA) to treat disease (PAD) with or without diabe- lives.10 These statistics correspond diabetic foot ulcers (Figure 1). tes.6,7 Diabetes has recently reached with high expense, with costs in the pandemic status with approximately United States reported in 2014 to be Topical Wound Healing Agents 387 million people worldwide suffer- around $612 billion (see Figure 2).9 Apligraf and Dermagraft are both ing from the disease and 4.9 million Chronic diabetes causes peripheral bio-engineered skin substitutes (by deaths in 2014 caused directly by di- arterial disease (PAD) and sensory Organogenesis) and Becaplermin (Re- abetes.8,9 It is estimated that in the neuropathy, a combination that leads granex) is a recombinant platelet-de- United States, 29.1 million people (or to ulcers, diabetic foot infections, and rived growth factor (PDGF) applied 9.3% of population) have diabetes, often the need for lower extremity topically as a gel.4,5 The forecast for with 21 million being diagnosed and amputation.11 other diabetic foot ulcer treatments 8.1 million being undiagnosed.10 Continued on page 61 is promising, with multiple products currently in clinical trial (Figure 1). Topical wound healing agents likely to be available within the next FIGURE 1: five years include: Aclerastide by Derma Sciences (angiotensin analog Diabetic Foot Ulcer NorLeu3-A1-7 with the active pharma- 4,5 58 ceutical ingredient DSC127), Trafer- Wound Care Products min by Olympus Biotech (recombi- nant human basic fibroblast growth FDA approved: factor engineered using Escherichia coli), and CureXcell® by Macrocure Regranex/Becaplermin Recombinant platelet-derived (activated leukocyte suspension).4,5 (by Smith & Nephew) growth factor (PDGF) The two first topical antibacterials are Pharmacologic wound also likely to be on the market within healing agent the next five years: Locilex™ by Dipex- Apligraf® Cultured cells from neonatal foreskin and ium Pharmaceuticals (Pexiganan ac- (by Organogenesis) bovine type 1 collagen etate cream 1%) and Cogenzia by In- Bioengineered bi-layered nocoll (gentamicin collagen sponge).5 skin substitute In the more distant future, gene encoding growth factors via viral Dermagraft® Human neonatal dermal fibroblasts vectors, cytokine inhibition, topical (by Organogenesis) neuropeptides, and stem cell-based Bioengineered skin substitute therapies may be available.4 Unfor- tunately, the cost of the aforemen- Clinical trials in progress: tioned wound care products (old and new) is high and, without consistent Aclerastide Angiotensin analog NorLeu3-A(1-7), off-loading and debridement, failure (by Derma Sciences) active pharmaceutical ingredient DSC127 of the products is likely, and the risk Wound healing agent for partial limb amputation remains.4 Trafermin Recombinant human basic fibroblast growth Common Complications (by Olympus Biotech) factor engineered using Escherichia coli Common complications affecting Wound healing agent diabetic and ischemic patients are ® chronic and poor healing lower ex- CureXcell Activated leukocyte suspension (by Macrocure) tremity ulcers, soft tissue and bone Wound healing agent infections requiring a plethora of clin- ical outpatient visits, multiple hospital Locilex™ Pexiganan acetate cream 1% admissions for intravenous (IV) an- (by Dipexium Pharmaceuticals) tibiotics, use of expensive adjunctive treatments (i.e., hyperbaric oxygen Cogenzia Gentamicin collagen sponge therapy and negative pressure wound (by Innocoll) therapy), and surgical procedures that often lead to non-traumatic lower ex- NOVEMBER/DECEMBER 2015 | PODIATRY MANAGEMENT www.podiatrym.com THE DIABETIC FOOT FIGURE 2: Diabetes Statistics9,10 n People with DM globally (387 million) n People with DM in U.S.A. (29.1 million) n People undiagnosed globally (179 million) n People undiagnosed in the U.S.A. (8.1 million) Millions n People with prediabetes in U.S.A. (86 million) n Deaths cause by DM globally (4.9 million) 0 50 100 150 200 250 300 350 400 Amputations (from page 58) lesion.20 If a lesion is suspected, it must be localized, usu- ally through conventional angiogram.20 About 50% of patients who have foot amputations Revascularization is then completed if adequate ves- die within five years, which is a worse mortality rate than sels or collateral vessels are seen proximal and distal most cancers.12 It has been reported that 55% of diabetics to the occlusion via open surgery versus endovascular 61 with a lower extremity amputation will require amputa- surgery.20,21 The gold standard is open revascularization, tion of the contralateral leg within two to three years.13 Continued on page 62 Foot ulcers are expensive to treat, with uncomplicated diabetic foot ulcers costing up to $8,000 and infected foot ulcers up to $17,000.14 If amputation is required to resolve the ulcer, the cost skyrockets to $45,000.14 In 1998, a large study obtained the hospital discharge records for all veterans hospitals to examine the epidemiol- ogy of lower extremity disease in veterans with diabetes.15 It was found that only 16% of the population was com- prised of diabetics; however, half of all patients hospital- ized due to lower extremity ulcerations had diabetes.15 A more recent study from 2012 stated that 20% of veterans using the Veterans Health Affairs Hospitals are affected by diabetes (or more than one million veterans at any given time).16 The 1998 study showed that 10,532 hospital dis- charges consisted of diabetics with ulcerations.15 34% of peripheral vascular disease procedures and 64% of ampu- tations were performed on patients with diabetes.15 Vascular Disease as an Etiology 82% of vascular-related lower extremity amputations in the United States are associated with diabetes; however PAD, with or without diabetes, is another leading cause of lower extremity amputation.17-19 PAD is a progressive dis- ease and leads to Critical Limb Ischemia (CLI) in its most advanced form.19 The global prevalence of PAD is overall 3%-10% with an increase to 15%-30% in age groups greater than 70 years old, and is even greater in the dia- betic population.19 Of patients with CLI, 50% will require revascularization and 25% will require amputation.19 Initial work-up for PAD is prompted by risk factors (i.e., smoking history, claudication, diabetes, lower ex- tremity ulceration, etc.).20 Non-invasive vascular studies, using ankle brachial index (ABIs) and pulse volume re- cordings (PVRs), may or may not indicate an occlusive www.podiatrym.com NOVEMBER/DECEMBER 2015 | PODIATRY MANAGEMENT THE DIABETIC FOOT Amputations (from page 61) Unfortunately, within the United puted tomography scan (CT scan)), States, limb preservation teams are possible bone biopsy if osteomyelitis which surpasses endovascular pro- habitually consulted late in the dis- is suspected, debridement, post-de- cedures in terms of durability and re- ease process, after foot infections have bridement wound culture and sen- duced re-occurrence. For this reason, caused significant pathology, which sitivity (with gram stain), and infec- tious disease specialists should be consulted, if necessary.24 Non-invasive vascular studies Vascular surgical procedures, should be completed