Lower Extremity Major and Minor Amputations in the High Risk Patient

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 economic burden caused by lower ex- are variable and must be constantly evaluated and tremity infections leading to amputations 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

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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 (recombinant 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 clinical 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-

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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 epidemiology 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 discharges consisted of diabetics with ulcerations.15 34% of peripheral vascular disease procedures and 64% of amputations 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 disease 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 diabetic 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 extremity 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 infectious disease specialists should be consulted, if necessary.24 Non-invasive vascular studies Vascular surgical procedures, should be completed when evalu- although often initially successful, frequently fail ating all patients with chronic non-healing ulcerations and vascular over time. surgery should be consulted in the setting of PAD.24 Arterial blood flow must be restored prior to debride- if a patient is expected to live beyond commonly results in necessity of par- ment or amputation for a successful two years, open revascularization is tial foot or limb amputation.3 Distal outcome. If arterial flow cannot be generally recommended.21 However, lower-limb amputations (i.e., partial reconstituted via open bypass or an endovascular surgery does hold an or complete toe amputation, partial endovascular approach, a BKA or important place in modern practice ray amputation, total ray amputation, AKA may be the necessary ampu- due to reduced surgical complica- Lisfranc joint amputation, trans-meta- tation of choice. If the patient does tions and faster recovery rates, and tarsal amputation (TMA), Chopart have adequate blood flow, the sur- is often chosen over open revascular- joint amputation, sub-total calcanec- geon will evaluate the extent of the ization for this reason.22 tomy, etc.), when unavoidable, are infectious process and amputate at 62 Vascular surgical procedures, al- performed to treat severe wound pa- the appropriate level. though often initially successful, fre- thology and are considered to be ad- For example, in the setting with quently fail over time. According to vanced limb salvaging procedures, as minimal involvement of a toe, a par- one study, limb loss with a patent by- they can prevent the need for partial tial toe amputation may be warrant- pass is reported to be only be 4%-9% leg amputation, if successful.25 ed. Although less may seem more effective.23 However, within the ampu- appropriate, there are times when tation group, the incidence of amputa- Partial Leg Amputations amputating further proximally and tions performed with a patent bypass Partial leg amputations are major removing unaffected toes is warrant- is higher (up to 50%) in certain pa- surgeries and include below-knee ed (such as TMA) due to biomechan- tient subgroups, including those with amputation (BKA) and above-knee ical benefit. For example, if a patient diabetes mellitus, end stage renal disease, and limited runoff.23 This goes to show that despite vigorous efforts by the medical and surgical teams, these Partial leg amputations are major surgeries high-risk patients may go on to limb and include below-knee amputation (BKA) and loss, as this is the natural progression of the disease. above-knee amputation (AKA) and come with higher The vast economic burden of the aforementioned is projected to wors- mortality and morbidity rates as compared to en as time goes on and the rate of the limb salvaging amputations. diabetes increases. However, modern-day limb preservation team services have been shown to reduce costs associated with foot ulcers.3,14,24 amputation (AKA) and come with has gangrene of digits 1, 2, and 4, higher mortality and morbidity rates the patient may benefit from a TMA A Multidisciplinary Team as compared to the limb salvaging over amputation of the affected digits Approach amputations. Before choosing a type alone. A multidisciplinary team ap- of amputation procedure, the sur- Overall, the long-term outcomes proach to treatment of the diabetic geon must evaluate the entire clinical of major amputations have been sug- foot could lead to avoidance of 47% status of the patient including but gested to include a five-year survival of amputations.3 Higher cost in treat- not limited to nutrition, kidney func- rate of 30%-40%.26 The long-term ment of wound care is associated tion, blood glucose control, cardiac outcomes of minor amputation is de- with ulceration, infection, hospital- reserve, neuropathy, and anemia. A batable due to the lack of literature, ization, and amputation. Therefore, complete evaluation of the patient’s but one study suggests a survival rate prevention is cost-effective.14 How- ulcer must be done, which includes of 89.3% at one year and 43.5% at ever, early referral is needed for pre- imaging studies (i.e., x-rays, mag- five years.27 Although good outcomes vention to be successful.14 netic resonance imaging (MRI), com- Continued on page 64

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Amputations (from page 62) will eventually allow for developing References an improved standard of care model 1 De Godoy JM, de Godoy MF, Batiga- are common, distal minor amputa- that can decrease major amputations lia F, Travolo AR, Monteiro EH. Lower-ex- tions in the high-risk patient popula- and improve the durability of distal tremity amputation: a 6 year follow-up tion often lead to the need for more limb-preserving procedures. study in Brazil. J Orthop Surg (Hong proximal amputation, with one study Amputation prevention has re- Kong)). 2005; 13(2): 164-166. 2 Pecoraro RE, Reiber GE, Burgess reporting the need of almost 42.4% ceived increased attention in the Vet- EM: Pathways to diabetic limb amputa- of partial 1st ray amputees going on erans Health Administration (VHA) tion: Basis for prevention. Diabetes Care 13:513-21, 1990. 3 Driver, VR, Fabbi, M, Lavery, L, Lower limb amputation Gibbons, G. The costs of diabetic foot: the economic case for the limbsalvage to treat foot ulcers with infections and/or ischemia team. Journal of Vascular Surgery. 2010; 52 (12S): 17S-22S. remains a real problem. 4 Hackethal, V. Progress stalled in diabetic foot ulcers; major unmet need. Advances in Therapy. 2014; 31: 817-836. 5 Opportunity analyzer: diabetic foot to a more proximal amputation with- over the years. In 1993, a special ulcers-opportunity analysis and forecasts 28 in an average time of 25 months. VHA directive established the Pres- to 2017-event-driven update, Market Re- Surgical amputation gives the benefit ervation Amputation Care and Treat- search Store. Jan 2014. of treating the patient’s infection or ment Program, mandating a multidis- 6 Ziegler-Graham K, MacKenzie EJ, chronic foot ulcer immediately and, ciplinary team at each facility to track Ephraim PL, Travison TG, Brookmeyer R. if the surgery is successful, many every patient with amputations and Estimating the Prevalence of Limb Loss in 64 patients do very well with custom those at risk for limb loss.15 As part of the United States: 2005 to 2050. Archives shoes and/or prostheses. this directive, discharge records con- of Physical Medicine and Rehabilitation Delaying treatment within high- tained in the Patient Treatment File 2008;89(3):422-9. 7 Owings M, Kozak LJ, National Cen- risk patient populations often leads from all VHA hospitals between 1989 ter for Health S. Ambulatory and Inpatient to amputation, which may cause to 1998 were analyzed to determine Procedures in the United States, 1996. potential decreased patient quality the overall effect of the program. The Hyattsville, Md.: U.S. Dept. of Health and of life and definitive loss of millions total number of discharges with am- Human Services, Centers for Disease Con- of dollars in healthcare costs. De- putations over a 10-year period de- trol and Prevention, National Center for spite this, surgery does not come clined by 80 discharges per year.15 Health Statistics; 1998. without risk. In general, any am- This directive is ongoing and cur- 8 Moxey, PW, Gogalniceanu, P, putation holds the risk of infection, rently is due to expire in August of Hinchliffe, RJ, Loftus, IM, Jones, KJ, bleeding, severe pain, phantom 2017. Despite this, lower limb ampu- Thompson, MM, Holt, PJ. Lower extremi- pain, significant edema, nerve dam- tation to treat foot ulcers with infec- ty amputations-a review of global variabil- ity in incidence. Diabetic Medicine. 2011; age, wound dehiscence, and death. tions and/or ischemia remains a real 28 1144-1153. Minor amputation (i.e. partial foot problem. Although the amputation 9 International Diabetes Federation amputation) holds a significantly rate has decreased, it is important to (IDF) Diabetes Atlas 6th Edition, 2014. lesser risk than major amputation study the outcomes of patients who 10 Centers for Disease Control and (i.e. partial leg amputation) and have already undergone both distal Prevention (CDC), National Center for this must be considered. Patient se- minor limb preserving amputations Chronic Disease Prevention and Health lection is very important. and proximal major amputations. Promotion, National Diabetes Statistics Frail patients with end-stage There is a lack of research in this Report, 2014. Department of Health and renal disease may not live through a area, and these data may direct an Human Services, USA. 11 major amputation (or even a minor improved standard of care and help Schofield CJ, Libby G, Brennan GM, MacAlpine RR, Morris AD, Leese GP. Mor- amputation for that matter) and thus us understand what impacts the du- tality and hospitalization in patients after all benefits versus risks should be rability of distal limb procedures. amputation: a comparison between pa- identified in order for the patient to A principal investigator-initiated tients with and without diabetes. DARTS/ have the best outcome and quality of retrospective chart review of ampu- MEMO Collaboration. Diabetes Care. life. tations has been developed at the VA 2006; 29 (10): 2252-2256. and focuses on major and minor sur- 12 http://www.idsociety.org/2012_Di- VHA Directive gical amputation types of the lower abetic_Foot_Infection_Guideline/#sthash. The structure of the medical data extremity to treat infections (i.e., os- GP7zRT4j.dpuf. 13 storage and the large relevant vet- teomyelitis, soft tissue emphysema, Pandian G, Hamid F, Hammond eran patient population with mod- necrotizing fasciitis, gangrene, chronic M. Rehabilitation of the Patient with Pe- ripheral Vascular Disease and Diabetic erate- and high-risk disease for limb non-healing ulcer) mainly secondary Foot Problems. In: DeLisa JA, Gans BM, loss presents a unique opportunity to diabetic mellitus and/or peripheral editors. Philadelphia: Lippincott?Raven; to collect real world data and accu- arterial disease (PAD)/critical limb 1998. rately examine the outcomes. This ischemia at the PVAMC. PM Continued on page 66

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Amputations (from page 64) 21 Conte, MS. Diabetic revasculariza- Dr. Diehl is currently an tion: endovascular versus open bypass-do attending podiatric sur- 14 Driver, VR, Leon, JM. Health eco- we have an answer? 2012. Seminars in geon at the Providence nomic implications for wound care and Vascular Surgery. 2012. V25 (2): 108-114. VA Medical Center limb preservation. Journal of Managed 22 Gupta, PK, Horan, SM, et al. Chron- in Rhode Island. She Care Medicine. 2008. 11 (1): 13-19. ic mesenteric ischemica: endovascular earned her DPM from 15 Mayfield JA, Reiber G E, Maynard C: versus open revascularization. Journal of the Temple University The epidemiology of Lower-Extremity Dis- Endovascular Therapy. 2010: 17:540-549. School of Podiatric Med- ease in Veterans with Diabetes. Diabetes 23 Khan, MUS, Lall, P, Harris, LM, icine. She completed her Care, volume 27, Supplement 2, May 2004. Dryjski, ML, Dosluoglu, HH. Predictors residency at New York 16 Greer N, Foman N, Dorrian J, et of limb loss despite a patent endocascu- Methodist Hospital in Brooklyn, NY and then al. DVA Health Services Research & De- lar-treated arterial segment. Journal of went on to complete her fellowship under Vickie velopment Service Evidence–based syn- Vascular Surgery. 2009; 49: 1440-6. R. Driver, MS, DPM at the Limb Preservation thesis Program Queri: Advanced Wound 24 Driver, VR, Madsen, J, Russell, GA. Research Fellowship Program at the Providence Care Therapies for Non-healing Diabetic Reducing amputation rates in patients VA Medical Center in Rhode Island. Venous and Arterial Ulcers a Systematic with diabetes at a military medical center. Dr. Allen received a Review Nov 2012.18.VHA Directive 2012- Diabetes Care. 2005; 28 (2): 248-253. Master of Public Health 020 Aug 2013 Prevention of Amputation 25 Driver, VR, Goodman, RA, Fabbi, degree from Northern in Veterans Everywhere Program. M, French, M, Andersen, CA. The im- Illinois University and 17 Dillingham TR, Pezzin LA, MacK- pact of a podiatric lead limb preservation a Doctor of Podiatric enzie EJ. Limb amputation and limb defi- team on disease outcomes and risk pre- Medicine degree from ciency: epidemiology and recent trends in diction in the diabetic lower extremity: a Kent State University the United States. South Med J. 2002; 95: retrospective cohort study. Journal of the College of Podiatric 875-883. American Podiatric Medical Association. Medicine. She complet- 18 Uzzaman, MM, Jukaku, S, Kambal, 2010. 100 (4): 235-241. ed a 3-year podiatric 66 A, Hussain, ST. Assessing the long-term 26 Marshall C, Stansby G. Amputation. medicine and surgery residency at the Atlanta outcomes of minor lower limb amputa- Surgery. 2008; 26 (1): 21-24. Veterans Affairs Medical Center. She recently tions: a 5-year study. Angiology. 2011; 27 Sheahan MG, Hamdan AD, Veraldi completed a 2-year American College of Foot 62(5) 365-371. JR, et al. Lower extremity minor ampu- and Ankle Surgeons Limb Preservation, Tissue 19 Garcia-Lavin, S, Fabbi, M, Eber- tations: the roles of diabetes mellitus and Repair, and Regeneration research fellow- hardt, R, Driver, VR. Noninvasive diag- timing of revascularization. J Vasc Surg. ship at the Providence VA Medical Center in nostics for critical limb ischemia. Advanc- 2005; 42(3):476-480. Rhode Island, where she worked as a research es in Wound Care. Volume 2. 2010. Mary 28 Borkosky, SL, Roukis, TS. Incidence sub-investigator for several complicated pro- Ann Liebert, Inc. USA. 259-266. of repeat amputation after partial first ray spective randomized controlled clinical trials, 20 Norgen, L, Hiatt, WR, Dormandy, amputation associated with diabtes melli- as well as supervised residents and fellows as JA, Nehler, MR, Harris, KA, Fowkes, FGR. tus and peripheral neuropathy: an 11 year an attending podiatric surgeon. Inter-Society Consensus for the Manage- review. The Journal of Foot and Ankle Ms. French is current- ment of Peripheral arterial Disease (TASC Surgery. 2013; 52(3): 335-33815. Interna- ly a research associate II). Journal of Vascular Surgery. 2007. tional Diabetes Federation Diabetes Atlas at the Providence VA S5A-S67A. 6th Edition 2014. Medical Center is a researcher with over 25 years of experi- ence. As a seasoned medical writer she has contributed to over 20 publications, as well as, mentoring new investigators and medical writers. Ms. French has been accredited by the Association of Clinical Research Profes- sionals (ACRP) since 1999. Dr. Driver has a distinguished career in the field of podiatric medicine and surgery, with a special emphasis on limb preservation and wound healing. She is nationally and in- ternationally regarded as a premiere clinician, surgeon, researcher and educator. She has proudly served for 8 years on the Board of Directors for The Advancement of Wound Care Association (AAWC). She now holds the distinguished honor of being president for this national organization.

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