Diagnosis and Management of Diabetic Foot Complications” Is Published by the American Diabetes Association, 2451 Crystal Drive, Arlington, VA 22202

Diagnosis and 2018 Management of CONTRIBUTING AUTHORS ANDREW J.M. BOULTON, MD, DSC (HON), FACP, FRCP Diabetic Foot Professor of Medicine, University of Manchester, Manchester, U.K., and Visiting Professor of Medicine, University of Miami Miller School of Medicine, Complications Miami, FL

DAVID G. ARMSTRONG, DPM, MD, PHD Professor of Surgery, Keck School of Medicine of the University of Southern California and Director, Southwestern Academic Limb Salvage Alliance (SALSA), Los Angeles, CA

ROBERT S. KIRSNER, MD, PHD Chairman and Harvey Blank Professor, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL

CHRISTOPHER E. ATTINGER, MD Professor of Plastic Surgery, Georgetown University School of Medicine and MedStar Health, Washington, DC

LAWRENCE A. LAVERY, DPM, MPH Professor of Plastic Surgery, Orthopaedic Surgery, and Physical Medicine and Rehabilitation, University of Texas Southwestern Medical Center, Dallas, TX

BENJAMIN A. LIPSKY, MD, FACP, FIDSA, FRCP (LONDON), FFPM RCPS (GLASG) Green Templeton College, University of Oxford, U.K., and Emeritus Professor of Medicine, University of Washington College of Medicine, Seattle, WA

JOSEPH L. MILLS, SR., MD, FACS Reid Professor of Surgery and Chief, Division of Vascular Surgery and Endovascular Therapy, Baylor College of Medicine, Houston, TX

JOHN S. STEINBERG, DPM, FACFAS Professor of Plastic Surgery, Georgetown University School of Medicine and This publication has been supported by unrestricted educational grants to the MedStar Health, Washington, DC American Diabetes Association from Healogics, Inc., and Organogenesis, Inc. “Diagnosis and Management of Diabetic Foot Complications” is published by the American Diabetes Association, 2451 Crystal Drive, Arlington, VA 22202. Contact: 1-800-DIABETES, professional.diabetes.org.

The opinions expressed are those of the authors and do not necessarily reflect those of Healogics, Inc., Organogenesis, Inc., or the American Diabetes Association. The content was developed by the authors and does not represent the policy or position of the American Diabetes Association, any of its boards or committees, or any of its journals or their editors or editorial boards.

© 2018 by American Diabetes Association. All rights reserved. None of the contents may be reproduced without the written permission of the American Diabetes Association. Andrew J.M. Boulton, MD, DSc (Hon), FACP, FRCP1,2 Diagnosis and David G. Armstrong, DPM, MD, PhD3,4 Robert S. Kirsner, MD, PhD2 Christopher E. Attinger, MD5,6 Management of Lawrence A. Lavery, DPM, MPH7 Benjamin A. Lipsky, MD, FACP, FIDSA, FRCP (London), FFPM, Diabetic Foot RCPS (Glasg)8,9 Joseph L. Mills, Sr., MD, FACS10 Complications John S. Steinberg, DPM, FACFAS5,6

ABSTRACT | At least half of all amputations occur in people with diabe- tes, most commonly because of an infected diabetic foot ulcer. A thor- ough understanding of the causes and management of diabetic foot ulceration is essential to reducing lower-extremity amputation risk. This compendium elucidates the pathways leading to foot ulcers and enumer- ates multiple contributory risk factors. The authors emphasize the impor- tance of appropriate screening and wound classification and explain when patients should be referred for specialist care, targeted education, or therapeutic shoes or insoles. They provide a comprehensive review of treatment approaches, including devices for foot lesion off-loading and aggressive wound debridement through mechanical, enzymatic, autolytic, biologic, and surgical means. Because infection and peripheral artery disease are key contributors to amputation risk, the authors dis- cuss the diagnosis and management of these conditions in detail. They also review the expanding armamentarium of evidence-based adjunc- tive treatments for foot ulcers, including growth factors, skin substitutes, stem cells, and other biologics. Because Charcot neuroarthropathy is a 1 serious but frequently missed condition in people with diabetic neuropa- University of Manchester, Manchester, U.K. 2University of Miami Miller School of thy, the authors explain the differential diagnosis of the hot, swollen foot Medicine, Miami, FL that is a hallmark of this condition. The article ends with an overview of 3Keck School of Medicine of the University four strategies for maintaining a foot in remission, followed by a brief of Southern California, Los Angeles, CA look at the future of diabetic foot care. 4Southwestern Academic Limb Salvage Alliance (SALSA), Los Angeles, CA 5Georgetown University School of oot problems in diabetes are common and costly, and people Medicine, Washington, DC 6MedStar Health, Washington, DC Fwith diabetes make up about half of all hospital admissions for 7University of Texas Southwestern Medical amputations. In the United Kingdom, people with diabetes account Center, Dallas, TX for more than 40% of hospitalizations for major amputations and 8Green Templeton College, University of Oxford, Oxford, U.K. 73% of emergency room admissions for minor amputations. Because 9University of Washington College of most amputations in diabetes are preceded by foot ulceration, a Medicine, Seattle, WA thorough understanding of the causes and management of ulceration 10Baylor College of Medicine, Houston, TX is essential. Address correspondence to The annual incidence of foot ulcers in diabetes is approximately 2% Andrew J.M. Boulton, in most Western countries, although higher rates have been reported [email protected], in certain populations with diabetes, including Medicare beneficia- and David G. Armstrong, ries (6%) and U.S. veterans (5%) (1). Although the lifetime risk of foot [email protected]. ulcers until recently was generally believed to be 15–25%, recent data suggest that the figure may be as high as 34% (1). It was the famous di- ©2018 by the American Diabetes abetes physician Elliott P. Joslin who, having observed many clinical Association, Inc. cases of diabetic foot disease, re- The Scottish poet Thomas bination of infection, foot ul- marked that “diabetic gangrene Campbell wrote, “Coming events ceration, and peripheral artery is not heaven-sent, but earth- cast their shadows before.” Al- disease (PAD) often results in born.” Thus, foot ulceration is though he was not referring to amputation, additional sections not an inevitable consequence foot ulcers at the time, these cover these pivotal areas of man- of having diabetes; rather, ul- words can usefully be applied to agement. cers develop as a consequence of the breakdown of the diabetic The number of available topi- an interaction between specific foot. Ulcers do not occur spon- cal treatments for foot ulcers has lower-limb pathologies and envi- taneously, but rather as a con- rapidly increased in recent years. ronmental hazards. sequence of a combination of We explore these options in de- This treatise will therefore fo- factors. These contributory fac- tail, including growth factors, cus on the pathways that result in tors are summarized in the next skin substitutes, stem cells, and foot ulcer development, the im- section. This is followed by a dis- other biologics. portance of regular screening to cussion of foot screening to iden- No treatise on the diabetic foot identify members of the at-risk tify individuals who are at risk would be complete without men- population, and multiple aspects of ulceration. We then describe tion of Charcot neuroarthropa- of novel treatment approaches. the importance of wound classi- thy, so our next section is devot- Care of the foot in diabetes often fication systems and answer the ed to the differential diagnosis of falls between specialties, and a questions of when and where to the hot, swollen foot in diabetes. team approach is required. Thus, refer diabetic foot problems. It is increasingly recognized we have assembled a team of It is often stated that what you that foot ulcer recurrence is com- experts in the care of diabetes- take off a foot ulcer is as important mon, occurring in up to 50% of related foot conditions from a as what is placed on the wound. cases, and using the term “in re- variety of specialties, including Therefore, we also include dis- mission” has been deemed more endocrinology; dermatology and cussions of various methods for appropriate than describing an wound healing; infectious dis- off-loading foot lesions and the ulcer as “healed.” Thus, in our eases; and podiatric, plastic, and importance of aggressive wound penultimate section, we describe vascular surgery. debridement. Because the com- methods to maintain a foot in

DIABETES Peripheral artery disease

Somatic sensory Somatic motor Autonomic neuropathy neuropathy neuropathy

Decreased pain, Small-muscle Foot Decreased Altered temperature, and wasting deformities Dry skin sweating blood flow proprioception

Increased Distended foot veins: foot pressures Callus “warm feet”

FOOT AT RISK Repetitive trauma (e.g., ill-fitting shoes, barefoot gait, or foreign body in shoe) FOOT ULCERS

FIGURE 1 Pathways to diabetic foot ulceration.

2 | DIAGNOSIS AND MANAGEMENT OF DIABETIC FOOT COMPLICATIONS remission. A brief look into po- sweating (i.e., dry foot skin, ⊲⊲ Other microvascular compli- tential future developments in increasing the risk of callus cations. Several other condi- the care of the foot in diabetes formation) and, in the absence tions are known to be associ- brings the monograph to a close. of PAD, warm feet due to the ated with an increased risk of We hope this succinct mono- release of vasoconstriction. foot ulceration. Visual impair- graph will aid health care provid- Plantar callus in the neuro- ment as a result of retinopathy ers in their efforts to prevent, di- pathic foot is associated with a is an established risk factor for agnose, and manage diabetic foot marked increase in ulcer risk. foot lesions. Perhaps the most problems. ⊲⊲ PAD. A major risk factor for high-risk group for ulceration foot lesions in diabetes, PAD is is the dialysis population. It discussed in detail beginning can be safely presumed that pa- on p. 11. Neuropathy and PAD Pathways to Diabetic tients at all stages of nephrop- often co-exist and may lead to athy have increased risk of ul- neuroischemic ulceration. Foot Complications ceration. Dialysis treatment is ⊲⊲ Deformity. Any deformity oc- an independent risk factor for Although evidence is weak that curring in a foot with other risk foot ulceration. foot care education reduces the factors increases ulcer risk. ⊲⊲ People with risk of first ulceration (2), a thor- Clawing of the toes is common, Transplantation. ough understanding of the etio- leading to increased metatar- diabetes remain at high risk of pathogenesis of ulceration is sal head pressures that, in neu- foot lesions even after success- essential if we are to succeed in ropathic patients, may result ful kidney, pancreas, or com- reducing the incidence of foot in breakdown due to repetitive bined pancreas-kidney trans- lesions and ultimately amputa- moderate stress to an insen- plantation. tions. The pathways to foot ulcer- sate area. Other examples in- ation are summarized in Figure 1, clude Charcot deformities and PATHWAY TO ULCERATION with key contributory factors also hallux valgus. The combination of two or more listed below. ⊲⊲ Age, sex, and duration of di- of the above risk factors com- ⊲⊲ Distal sensorimotor periph- abetes. The risk of ulcers and monly results in ulceration. (See This con- eral neuropathy. amputations increases two- to Figure 1.) Examples include: dition is common in diabetes, fourfold with both age and du- ⊲⊲ Neuropathy, deformity, and affecting up to 50% of older ration of disease. In Western trauma. Inappropriate foot- people with type 2 diabetes. countries, male sex is associ- wear is the most common Small-fiber nerve dysfunction ated with a 1.6-fold increase in cause of trauma in Western results in loss of pain and tem- foot ulcer risk (3). countries. perature perception; patients ⊲⊲ Ethnicity. In the United States, ⊲⊲ Neuropathy plus chemical literally lose the “gift of pain” ulceration is more common trauma. Inappropriate use of that normally protects us from among Hispanics, Native Amer- over-the-counter corn treat- tissue damage. Large-fiber dys- icans, and individuals of Afri- function results in unsteadi- can-Caribbean descent. ments on a neuropathic foot can lead to ulceration. ness, increasing the risk of trips ⊲⊲ Repetitive minor trauma. and falls; recurrent unnoticed Such trauma can occur as a Understanding the many risk minor injuries might increase consequence of high pressures factors that increase the chance the risk of Charcot neuroar- under a neuropathic foot or of foot lesions developing will thropathy. Motor neuropathy from an ill-fitting shoe or a help to prevent many episodes of contributes to small-muscle foreign body inside a shoe. foot ulceration if the screening wasting and a potential im- ⊲⊲ Past foot ulceration or am- process outlined in the next sec- balance of flexor and extensor putation. Both are major risk tion is followed. Further details function in the foot. factors. The annual incidence on the pathways to ulceration, to- ⊲⊲ Autonomic neuropathy. Pe- of ulceration may be as high as gether with supporting referenc- ripheral sympathetic dys- 30–50% in people with a histo- es, are provided in a forthcoming function results in decreased ry of foot ulcers (1). publication on this topic (4).

DIAGNOSIS AND MANAGEMENT OF DIABETIC FOOT COMPLICATIONS | 3 TABLE 1 Modified ADA Diabetic Foot Risk Classification

Suggested Priority Indications Timeline Follow-up URGENT ⊲⊲ Open wound or ulcerative area, with or without signs Immediate referral/ As determined by (active pathology) of infection consultation specialist ⊲⊲ New neuropathic pain or pain at rest ⊲⊲ Signs of active Charcot deformity (red, hot, swollen midfoot or ankle) ⊲⊲ Vascular compromise (sudden absent DP/PT pulses or gangrene) HIGH ⊲⊲ Presence of diabetes with a previous history of ulcer Immediate or “next Every 1–2 months (ADA risk category 3: or lower-extremity amputation available” outpatient the diabetic foot in ⊲⊲ Chronic venous insufficiency (skin color change or referral remission) temperature difference) MODERATE ⊲⊲ PAD ± LOPS Referral within 1–3 Every 2–3 months (ADA risk category 2) ⊲⊲ DP/PT pulses diminished weeks (if not already ⊲⊲ Presence of swelling or edema receiving regular care) LOW ⊲⊲ LOPS ± longstanding, nonchanging deformity Referral within 1 month Every 4–6 months (ADA risk category 1) ⊲⊲ Patient requires prescriptive or accommodative footwear VERY LOW ⊲⊲ No LOPS or PAD Referral within 1–3 At least annually (ADA risk category 0) ⊲⊲ Patient seeks education on topics such as routine foot months for all people with care, athletic training, appropriate footwear, or injury diabetes prevention DP, dorsalis pedis; LOPS, loss of protective sensation; PT, posterior tibial. Modified from Diabetes Care 2008;31:1679–1685 (ref. 6), with permission from the American Diabetes Association, ©2008.

er risk category. In such cases, Screening for Foot the overall degree of limb threat When and Where to Complications Risk should be assessed. The three key factors associat- Refer Diabetic Foot It is important to assess the neu- ed with limb loss include degree Problems rological, vascular, dermatolog- of tissue loss (wound severity), Appropriate patient referral is ical, and musculoskeletal status severity of ischemia, and severi- predicated on a complete history of people with diabetes at least ty of foot infection. The acronym and foot examination. Patients annually. The American Diabe- WIfI can be used as short-hand tes Association (ADA) developed with diabetic foot complications for these factors, which can as- should be referred for preventive a Comprehensive Foot Examina- sist the health care team in de- tion and Risk Assessment that services and when acute pathol- scribing patients’ overall limb ogy is identified. can be performed rapidly with threat status (Figure 2) (7,8). minimal equipment (5,6). The risk categories shown in Using the Society for Vascular After assessment of the foot, Table 1 were adapted from the Surgery (SVS) Threatened Limb Table 1 outlines suggested in- four-tiered diabetic foot risk clas- Classification System (7), pa- dications, priorities, and time- sification system recommended lines for referral based on ADA tients’ wounds, ischemia, and by the International Working guidelines (6). The table shows foot infections are graded on a Group on the Diabetic Foot (9). ADA patient risk categories (i.e., numerical scale from 0 (none) to Patients at the highest risk for ul- very low, low, moderate, and high 3 (severe), and these grades are ceration are those who have a his- risk) and follow-up recommen- then translated into an overall tory of ulceration, amputation, dations. “WIfI score” (discussed in more peripheral vascular surgery, or Patients who present with tis- detail in the section on Recogniz- Charcot neuroarthropathy. These sue loss are assigned to a high- ing and Treating PAD on p. 11). patients are easy to identify from

4 | DIAGNOSIS AND MANAGEMENT OF DIABETIC FOOT COMPLICATIONS FIGURE 2 SVS WIfI classification system. TcPO2, transcutaneous oxygen pressure. eral perfusion and provide a pre- scription for specific elements of custom insoles and shoes. The prescription will then be sent to a pedorthist or orthotist, who will fabricate the custom insoles and fit the shoes appropriately. Shoes and insoles should be re- placed on a regular basis, so eval- uation of shoes, insoles, and the feet of high-risk patients should be a routine part of clinic exam- inations. Patients with foot ulcers, puncture wounds, ingrown toe- nails, or infections need prompt referral to a local podiatrist who is experienced in diabetic foot com- plications or a wound care center with expertise in DFUs. These patients generally re- quire imaging to evaluate bone infection and vascular testing to history alone and have a very high foot complication, diabetes care determine whether there is ad- rate of developing ulceration (9). providers should find an educator equate perfusion to heal a foot Of patients who have had an ul- who has a strong understanding wound. Patients with signs of cer, 58–83% will develop another of and education program spe- ischemia or gangrene should be ulcer within 1 year if no preven- cifically focused on diabetic foot referred to a vascular surgeon, tive services are provided (10,11). complications. Patients need in- interventional cardiologist, or in- When therapeutic shoes and in- depth education about sensory terventional radiologist for eval- soles are provided, the incidence neuropathy, the etiology of ulcers uation and treatment. These pa- of ulcer recurrence decreases by and infections, warning signs, tients will need arterial Doppler 50% to 30–50% annually (1,9). and preventive measures. Pro- studies and, if these are abnor- The next risk tier includes viding a “tear sheet” with a vague mal, angiography and possibly patients with sensory neuropa- list of things to do and things to vascular intervention. thy and foot deformity or PAD. avoid without explaining the ra- Evaluation of these patients tionale behind such recommen- requires simple sensory testing dations is probably not especially with a 128-Hz tuning fork or a helpful to high-risk patients. Off-Loading the 10-g Semmes-Weinstein mono- Therapeutic shoes and insoles Diabetic Foot Wound filament and clinical assessment are mainstays of preventing of limited joint mobility, ham- recurrent diabetic foot ulcers Off-loading refers to the use of mertoes, hallux valgus, and pe- (DFUs). Providers should part- devices or surgeries that remove ripheral perfusion. ner with a podiatrist in their pressure or reduce the “load” at High-risk patients need re- community who is interested the site of ulceration to improve ferrals for diabetes education, in diabetic foot complications. healing. DFUs often occur on the therapeutic shoes and insoles, A podiatrist can help evaluate sole of the foot at sites of repeti- and regular foot evaluation and and monitor high-risk patients. tive injury that are unrecognized care. Unfortunately, only a small They can evaluate patients’ bio- by patients with diabetic sensory minority of patients receive pre- mechanics, structural foot de- neuropathy. The ulcers are usu- ventive services (12,13). formities, joint range of motion, ally at a pressure point on the For patients with a previous sensory neuropathy, and periph- bottom of the foot where a callus

DIAGNOSIS AND MANAGEMENT OF DIABETIC FOOT COMPLICATIONS | 5 has formed. If a neuropathic pa- reduce motion of the joints of controlled trials (RCTs) of the tient continues to walk on an the foot, and they are usually as- various off-loading methods are ulcer, every step “crushes” new sociated with reduced activity. summarized in Table 2, and read- tissue that is attempting to orga- Reducing pressure and shear ers are referred to a review by nize and fill the soft-tissue void. forces and decreasing the number Health Quality Ontario (14) for People without sensory neurop- of steps or loading cycles per day details on the individual studies athy find it painful to walk on allows healing tissue to bridge the discussed here. an open wound and will instinc- wound without continual dam- TCCs involve a casting tech- tively avoid any weight-bearing age. Off-loading is one of the most nique that uses a minimal amount forces on a wounded foot; they important interventions to facili- of cast padding. Plaster of paris or alter their gait or limp to pro- tate the healing of foot ulcers. plaster cast material is molded to tect the injured site. However, There are a variety of ap- conform closely to the anatomic in people with sensory neuropa- proaches to protecting the site of structures of the foot and ankle thy, ulcers are painless and often ulceration from repetitive injury and to limit movement within the unrecognized unless they leave by off-loading the diabetic foot. cast. Fiberglass cast material is a stain on socks or blood on the These include the use of thera- then applied as an outer layer, so floor. Because neuropathy blocks peutic shoes and custom insoles the patient can walk on the cast the pain response, these patients (often referred to as “diabetic within 30 minutes. continue to fully bear weight on shoes”), postoperative shoes or The use of TCCs is one of the the site of injury. sandals, padded dressings, re- most frequently studied tech- Off-loading devices facilitate movable cast boots (RCBs), and niques for healing DFUs and is healing in several ways. The most casting to protect the foot and regarded by many as the “gold effective off-loading strategies re- immobilize the joints of the foot, standard” for protecting and duce pressure and shear forces often referred to as “total con- off-loading DFUs (15). Numer- at the site of ulceration. They tact casts” (TCCs). Randomized ous RCTs have evaluated TCCs, other casting techniques, mod- TABLE 2 Results of Selected RCTs Evaluating Different Off-Loading Approaches: ifications of TCCs, and RCBs. Proportion of Ulcers That Heal and Time to Healing (2) Descriptive retrospective cohort studies and RCTs have reported MUELLER, et al. TCC 90%, Shoes 32%, Diabetes Care, 1989 42 days (n = 21) 65 days (n = 9) that a high proportion of DFUs (70–100%) heal with an average CARAVAGGI, et al. Fiberglass 50%, Shoes 21%, healing time of approximately 6 Diabetes Care, 2000 healing time NS healing time NS (n = 26) (n = 24) weeks (14). There are challenges involved ARMSTRONG, et al. TCC 90%, RCB 65%, Half shoe 58%, Diabetes Care, 2001 35 days (n = 21) 50 days (n = 21) 61 days (n = 21) in using TCCs, and thus the tech- nique is not widely used. The KATZ, et al. TCC 74%, iTCC 80%, casting technique requires train- Diabetes Care, 2005 38 days (n = 21) 36 days (n = 22) ing, and many clinics do not have ARMSTRONG, et al. RCB 52%, iTCC 83%, the skill, staff, or facilities to use Diabetes Care, 2005 58 days (n = 27) 42 days (n = 23) the technique effectively. In ad- PIAGGESI, et al. TCC 95%, iTCC 85%, dition, wearing a TCC may not be Diabetes Care, 2007 46 days (n = 21) 47 days (n = 20) well accepted by patients, espe- CARAVAGGI, et al. Cast 82%, RCB 79%, cially if it impedes driving or in Diabetes Care, 2007 48 days (n = 29) 71 days (n = 29) patients with postural instabili- ty. TCCs are hot, and they make FAGLIA, et al. TCC 74%, RCB 73%, Diabetes Care, 2010 35 days (n = 24) 40 days (n = 24) daily activities such as bathing and walking difficult. LAVERY, et al. TCC 70%, RCB 22%, Int Wound J, 2014 38 days (n = 23) 47 days (n = 27) Alternative therapies include RCBs, which were initially de- NS, not stated.

6 | DIAGNOSIS AND MANAGEMENT OF DIABETIC FOOT COMPLICATIONS signed to immobilize the foot and clude therapeutic shoes and in- ADDITIONAL ankle to treat fractures. RCBs are soles, padded dressings, and post- CONSIDERATIONS FOR safe, easy to use, and require lit- operative sandals. These have the WOUND HEALING tle training or expertise. Patients advantage of being widely accept- Debridement is merely one like them because they can be ed by patients. They do not re- factor, albeit a vital one, in removed to bathe, clean the foot, quire expertise, special training, modern wound bed prepara- and apply new dressings. How- or special equipment. Insurance tion. The fundamental tenets ever, they can be expensive, and will often pay for therapeutic in the management of most often insurance will not pay for shoes and insoles, and postop- lower-extremity wounds in- RCBs to off-load diabetic foot ul- erative sandals and padding are clude eradication of infection, cers. Moreover, because these are relatively inexpensive. These op- optimization of tissue perfu- not custom-molded devices, they tions do not interfere with nor- sion, and adequate off-loading. may not fit patients well, and they mal walking, driving, or bathing. Diabetic foot wounds in partic- may need to be replaced every few Unfortunately, they are the least ular require adherence to a mul- months. effective off-loading strategies. tifactorial algorithm that affords Several companies have de- Mueller and Caravaggi reported the greatest healing potential signed modifications of RCBs to that only 21–32% of DFUs healed while mitigating costs and min- meet the needs of patients with with these techniques during 12- imizing recurrence. foot ulcers. Although not all of week RCTs (14). Consideration of a variety of these products are equally ef- Off-loading is one of the most factors other than appropriate fective, several companies have important treatments for healing debridement is essential to ob- designed boots that have been DFUs. The evidence clearly in- taining and preserving a healthy shown in RCTs to be as effec- dicates that there are significant wound bed. These factors include tive as a TCC in healing DFUs differences in the proportion a patient’s comorbidities, nutri- (16,17). However, other studies of ulcers that heal and the rate tion, glycemic control, smoking have shown much lower heal- of healing based on the type of status, ambulatory status, wound ing rates with RCBs than TCCs off-loading employed. Referral to etiology, access to resources, ad- (22–52%) (14). a center that has experience with herence, and, perhaps most im- One of the reasons RCBs may TCCs should be considered for portantly, wound location and not be as effective as TCCs is patients with chronic non-heal- topography. Once the patient and that patients can remove them ing ulcers if optimal off-loading wound have been optimized, sev- and walk with their injured foot is not otherwise available. eral options on the reconstructive unprotected. Several studies ladder are available for definitive have evaluated boots that can be closure, including secondary in- “locked” on and thus have been Wound Debridement: tention, primary closure, skin deemed “instant TCCs” (iTCCs) grafting, local tissue transfers, (18). The rationale for this ap- Surgical or Otherwise regional tissue transfers, and free proach is that iTCCs, like RBCs, tissue transfers (21). can provide the advantages of DEBRIDEMENT DEFINED Wound Etiology easy application without the Debridement is the excision of Determining the etiology of a need for special training or fa- dead, damaged, or infected tis- patient’s wound is of utmost cilities while offering the same sues to optimize the healing importance to guide decisions pressure reduction and “forced potential of the remaining via- regarding the most appropriate compliance” of TCCs. RCTs by ble tissues. It is performed in a course of wound optimization, Piaggesi et al. (16) and Katz et variety of ways and settings in including the type of debride- al. (19) reported similar healing preparation for closure within ment performed. It is impera- rates with this approach com- the steps of the reconstructive tive, however, to understand that pared to TCCs. ladder ranging from primary clo- debridement type, like wound Other off-loading options in- sure to flaps and grafts (20). character, may evolve over time,

DIAGNOSIS AND MANAGEMENT OF DIABETIC FOOT COMPLICATIONS | 7 especially in the comorbid pop- dead and devitalized tissue over can quite effectively debride a ulation, including individuals time by allowing wound fluids wound in a matter of just a few with diabetes. Consequently, a to maintain constant contact in days. The larvae derive nutrients thoughtful understanding and the wound bed to hydrate, soften, by secreting a broad spectrum careful consideration of the pa- and liquefy necrotic tissue and of enzymes that liquefy necrot- tient, wound, and possible meth- eschar. This method is achieved ic tissue for consumption. In an ods of debridement are vital to a with the use of occlusive or optimum environment, maggots successful outcome (22). semi-occlusive dressings with molt twice, increasing in overall or without the supplementation size and leaving a clean wound TYPES OF DEBRIDEMENT of hydrocolloids, hydrogels, and free of necrotic tissue when they transparent films and is suitable are removed. Mechanical for cases in which the amount of This method has gained popu- Mechanical debridement is dead tissue is not extensive and larity over time, but some patients perhaps the oldest form of de- there is no infection. find it painful, and some patients’ bridement and involves the use Autolytic debridement is selec- aversion to maggots being placed of moist or wet flushes or dress- tive for necrotic tissues, easy to on their body may impede its use. ings, which are subsequent- perform, and virtually painless to That said, this method has the ad- ly removed. This removal and patients. However, it is by far the vantage of being non-surgical in physical wound base disruption slowest type of debridement, and nature and works faster than au- causes non-selective debride- the wound must be rigorously tolytic or enzymatic debridement ment of loose tissues and slough. monitored for signs of infection. with little risk to healthy tissues. Examples include direct wound For these reasons, this method is Surgical irrigation with saline, wet-to- usually reserved for patients with dry dressings, and hydrotherapy, Surgical debridement is arguably poor access to resources or those including bath and whirlpool. the most common and varied requiring a break from other Dressing changes are simple and type of debridement (Figure 3). debridement methods. can be performed independently A myriad of instrumentation and by patients in many cases. How- Biologic adjuncts are used to physically ever, mechanical debridement Biologic debridement employs excise non-viable tissue from the is considered non-selective in medical maggots that have been wound bed, either at the bedside, nature and thus may remove or grown in a sterile environment. in the clinic, or in an operating damage healthy tissues if not Several young larvae of the green room. The surgeon will debride performed meticulously. bottle fly Lucilia( sericata) are tissue to viability, as determined introduced into a wound bed by tissue character and the pres- Enzymatic and secured with a dressing. The ence of vascularity in healthy Enzymatic debridement involves maggots feed selectively on the tissues, using any combination of using chemical agents to slough necrotic tissue of the host with- instruments, such as rongeur, cu- necrotic wound tissue. Collec- out injuring living tissue and rette, blade, scissors, and forceps. tively, these enzymes are derived from microorganisms such as Clostridium histolyticum or from FIGURE 3 Progression of a diabetic foot ulcer from necrotic wound base (A), to surgical debridement (B), to complete healing (C). plants, including collagenase, varidase, papain, and bromelain. This method is most useful for de- bridement of wounds with a large amount of necrotic tissue and poses little risk to healthy tissues. Autolytic Autolytic debridement uses the body’s own enzymatic processes to debride necrotic tissues and slough. This process interrupts A B C

8 | DIAGNOSIS AND MANAGEMENT OF DIABETIC FOOT COMPLICATIONS Adjuncts such as the micro water a break in the skin envelope and tions suggest osteomyelitis (24). jet device have been developed frequently spreads to deeper soft Definitively diagnosing bone in- for even more meticulous and se- tissues (often including bone), is fection requires collecting a bone lective debridement. a sentinel event. For people with specimen that has a positive cul- A novel method used by the au- diabetes, DFIs are the most com- ture or histological evidence of thors to ensure a more thorough mon diabetes-related reason for inflammation and necrosis, and debridement of wounds, espe- hospitalizations and for lower- preferably both. cially those pending closure, is extremity amputations. Recent to completely paint the wound studies have shown, however, CULTURES that rapid recognition and ap- with methylene blue immediate- It is not necessary to obtain a propriate management of DFIs ly before debridement. Sharp de- wound specimen for culture of can usually avert these adverse bridement sufficient to remove clinically uninfected diabetic outcomes (23). all of the blue-stained tissue pro- foot wounds (because they do vides a clear delineation between not require antimicrobial ther- more superficial exposed tissues DEFINING INFECTION apy), but cultures are indicated that may harbor bioburden and Because all open wounds will be for all DFIs. Tissue specimens the healthy tissues below. colonized with microorganisms, collected by curettage or biopsy Surgical debridement is best we define DFIs by the presence of provide more specific and sensi- suited for progressive or recalci- classic signs and symptoms of in- tive culture results than swabs. trant wounds; larger-sized wounds; flammation. Because these find- For osteomyelitis, cultures of those in abnormal or precarious ings may be altered in patients bone (percutaneous or surgical) locations; grossly infected wounds; with peripheral neuropathy or more accurately reveal the patho- and wounds considered to be of PAD (present in most cases), gens than those of soft tissue. an unknown etiology, which ne- some clinicians accept “second- Only collect blood cultures for cessitate surgical biopsy or re- ary” signs, such as friable granu- patients with sepsis syndrome. section. Surgical debridement is lation tissue or wound undermin- Studies conducted in the past considered the fastest method of ing, as evidence of infection. decade using molecular microbi- debridement because it is very Classifying the severity of in- ological (genotypic) techniques selective and limited only by the fection using standardized crite- demonstrate that there are many skill and experience of the sur- ria helps to define the approach more microorganisms, of many geon. Overall, surgical debride- to treatment and the prognosis. more species (especially anaer- ment affords superior control Clinicians should probe foot obes), than identified by standard over which tissues and how much wounds to establish their depth microbiology (phenotypic) (25). and extent and to seek palpable of them are removed, is the fastest But, it remains unclear whether bone, which is highly suggestive way to achieve a clean wound bed, it is clinically beneficial to direct of osteomyelitis. The presence of and can speed the healing process antimicrobial therapy to all of findings of systemic inflamma- in most patients with diabetic these identified organisms. foot wounds. tory response, especially fever or leukocytosis, defines a severe infection. TREATMENT For all but the mildest DFIs, While awaiting the results of cul- Management of clinicians should obtain a com- tures (and any additional diag- Infection plete blood count, as well as plain nostic studies), clinicians should X-rays to look for foreign bodies, initiate empiric antibiotic therapy Among patients with diabetes tissue gas, or bone abnormalities. for DFIs. Base the choice of a regi- presenting with a foot wound, Advanced imaging techniques men on the clinical characteristics about half have clinical evidence such as magnetic resonance im- and severity of the infection, any of infection (23). The develop- aging or radiolabeled scintigra- clues to the likely pathogens, any ment of a diabetic foot infection phy may be appropriate for some history of recent antibiotic thera- (DFI), which typically begins in patients in whom initial evalua- py, and knowledge of local antibi-

DIAGNOSIS AND MANAGEMENT OF DIABETIC FOOT COMPLICATIONS | 9 otic resistance patterns. In West- to the difficulty in eradicating that appear to decrease the likeli- ern countries, the most common infections and healing wounds. hood of successful treatment in- DFI pathogens are aerobic gram- That said, it is not clear wheth- clude isolating antibiotic-resistant positive cocci, especially Staph- er any of the currently available pathogens (especially methicillin- ylococcus aureus. For non-severe agents promoted for their ability resistant S. aureus, Pseudomonas infections, in the absence of risk to eradicate biofilm are clinically aeruginosa, and gram-negative factors for gram-negative patho- effective. bacilli with extended-spectrum gens (e.g., previous antibiotic ther- In addition to antimicrobial beta-lactamases), the presence of apy or hospitalization) or obligate therapy, most patients with a DFI severe PAD, and end-stage renal anaerobes (ischemia, gangrene), require some type of surgical pro- disease. relatively narrow-spectrum (anti- cedure; these range from bedside Despite the difficulties in diag- staphylococcal) therapy often suf- sharp debridement to more ex- nosing and treating DFIs, with fices. For severe infections, it is tensive operative soft-tissue and proper management, clinicians safer to initially prescribe a broad- bone resection. The operating can expect to achieve resolu- er-spectrum regimen (26). surgeon must have a thorough un- tion of such infections in more Topical antimicrobial therapy derstanding of how to drain infec- than 90% of mild and moderate may be appropriate for some mild tions that may involve several of soft-tissue infections. Appropri- infections, but most DFIs require the compartments in the foot. In ate treatment can also resolve systemic antibiotic therapy (27). general, it is best to perform sur- infections in more than 75% of For severe infections, initial par- gical drainage of deep soft-tissue osteomyelitis cases (often with enteral therapy (usually for a few infection, especially abscesses, minor bone resection) and se- days) is often best; otherwise, as soon as practical, rather than vere infections (usually with sur- oral antibiotic agents with good waiting for the infectious process gical debridement). Eliminating bioavailability are sufficient. to “cool off” with medical thera- the clinical manifestations of Clinicians should review the py. Because most cases of diabet- infection is the key first step in selected empiric treatment reg- ic foot osteomyelitis are chronic managing patients with a DFI, imen and adjust it within a few and accompanied by necrotic but these patients will also need days, after reviewing the clinical bone, surgical resection is usu- appropriate wound care, often response and the culture and sen- ally the preferred treatment ap- including pressure off-loading, sitivity results. Select the defini- proach. Most surgical resections wound healing, and revascu- tive antibiotic regimen based on can and should be “conservative,” larization of an ischemic limb. principles of antimicrobial stew- removing only necrotic bone The best predictor of the de- ardship: treat with the narrowest- and soft tissue, while attempting velopment of a DFI is a history spectrum regimen possible for to spare as much of the foot as of a previous DFI, so clinicians the shortest duration necessary. A possible. should also teach patients opti- key point is that antibiotics treat Some cases of osteomyelitis, mal prevention techniques. infections but do not heal wounds such as limited forefoot infec- or prevent infections (28). Thus, tions, respond to antibiotic ther- although a foot wound may take apy alone. Because bone infec- months to heal, antibiotic treat- tion recurs in about one-third Recognizing and ment of 10–14 days is sufficient of patients, often months after Treating Peripheral apparently successful treatment, for most soft-tissue infections, Artery Disease and treatment for 4–6 weeks is clinicians should consider osteo- adequate for bone infections. myelitis to be “in remission” until Although it has been repeated- There is no evidence to sup- 1 year after treatment, after which ly demonstrated that creation of port recommending any adjunc- it may be considered “cured.” well-organized diabetic foot care tive treatments (e.g., hyperbaric teams is a highly effective means oxygen therapy) for DFIs. Pro- OUTCOME of reducing major limb amputa- duction of biofilm by causative In addition to the involvement tions associated with DFUs and pathogens appears to contribute of bone in an infection, factors PAD, such teams are not the norm

10 | DIAGNOSIS AND MANAGEMENT OF DIABETIC FOOT COMPLICATIONS in many parts of the world, in- Failure to diagnose and ade- ing mandates measurement of cluding the United States, where quately treat underlying PAD is perfusion/hemodynamic status management of DFUs is often a major cause of amputations in of the threatened limb. Because fragmented. For example, a re- people with diabetes. The prev- of the issue with falsely elevated cently published cross-section- alence of PAD among people ankle brachial index measure- al analysis of approximately 6.7 with diabetes has risen steadily ments due to underlying medial million patients with DFUs seen throughout the past three de- calcinosis of the arterial wall, toe in ambulatory care settings from cades, and PAD is estimated to be waveforms and pressures are the 2007 to 2013 across the United present in as many as 50–60% of preferred measurements in pa- States reported that, compared patients with DFUs (1). tients with DFUs. The WIfI clas- to ambulatory visits of patients To improve vascular care for sification is intended to stage the without DFUs, DFU visits were such patients, the Society for limb, much as the American Joint associated with a 3.4 times higher Vascular Surgery (SVS) devel- Committee on Cancer/Union for odds of direct emergency depart- oped and published in 2014 a International Cancer Control ment or inpatient admission; dou- Threatened Limb Classification TNM (Tumor, Nodes, and Me- ble the number of previous visits System based on grading the tastases) classification is used to during the past 12 months; dou- three major limb factors associat- stage cancer. Data accumulated ble the odds of referral to anoth- ed with amputation risk: Wound, to date, as recently summarized er physician; and an outpatient Ischemia, and foot Infection in a detailed review of 19 stud- visit length 1.4 times longer (29). (WIfI) (7). As briefly described in ies that correlated WIfI clinical In another study of more than 1 the section on Screening for Foot stage with clinically meaningful million patients presenting with Complications Risk (p. 4), each of outcomes such as major-limb DFUs to emergency departments these three factors is graded on a amputation, wound-healing time, in the United States from 2006 to scale from 0 to 3, and the resultant hospital costs, and lengths of stay, 2010, more than 80% were admit- grades are used to classify a giv- have confirmed the utility of WIfI ted to the hospital. Among those en limb into four clinical stages staging (31). admitted, annual estimated costs of amputation risk ranging from One of the principles of WIfI is were $8.78 billion. Clinical out- Stage 1 (very low) to Stage 4 (high) that limb threat is a spectrum, and comes included a sobering 2.0% (Table 3). Readers are referred the use of an absolute critical lev- mortality rate, 9.6% rate of sepsis, to the original publication for el of perfusion or cut-off measure and 10.5% rate of minor or ma- details regarding grading and that mandates revascularization jor amputations (30). Outcomes classification (7). is not appropriate. The use of the were significantly worse for pa- Although the presence of clear- term “chronic limb-threatening tients residing in rural locations, ly palpable pedal pulses is reas- ischemia” (CLTI), has been sug- Medicaid beneficiaries, and those suring, pulse palpation alone is gested to avoid confusion and residing in regions in the lowest unreliable to assess ischemia, missed opportunities to identi- quartile for income. and the application of WIfI grad- fy ischemia associated with the

TABLE 3 SVS Threatened Limb Classification System, With Clinical Stages 1–4 Based on Severity of Wound, Ischemia, and foot Infection (WIfI)

ISCHEMIA: 0 ISCHEMIA: 1 ISCHEMIA: 2 ISCHEMIA: 3 WOUND: 0 1 1 2 3 1 2 3 4 2 2 3 4 2 3 3 4 WOUND: 1 1 1 2 3 1 2 3 4 2 3 4 4 3 3 4 4 WOUND: 2 2 2 3 4 3 3 4 4 3 4 4 4 4 4 4 4 WOUND: 3 3 3 4 4 4 4 4 4 4 4 4 4 4 4 4 4 fI: 0 fI: 1 fI: 2 fI: 3 fI: 0 fI: 1 fI: 2 fI: 3 fI: 0 fI: 1 fI: 2 fI: 3 fI: 0 fI: 1 fI: 2 fI: 3 Each of the three WIfI components is graded from 0 to 3. Based on Delphi consensus, the 64 possible combinations were placed into one of four clinical stages based on the estimated baseline risk of amputation. For example, a limb scoring Wound: 1, Ischemia: 3, and foot Infection (fI): 2 would be at high risk for amputation, or clinical Stage 4. Adapted from ref. 7.

DIAGNOSIS AND MANAGEMENT OF DIABETIC FOOT COMPLICATIONS | 11 anachronistic term “critical limb to improve the classification in ischemia” (CLI). intermediate-risk patients. Evidence-Based The level of perfusion required Increasingly, revascularization Adjunctive to heal a foot ulcer is complicat- may be carried out by an endovas- ed and depends on a number of cular approach, including more Therapies for factors that include ulcer size, complex techniques such as sub- Diabetic Foot Ulcers location, and depth; presence and intimal angioplasty or retrograde extent of infection; and nutrition- pedal access, as well as surgical DFUs are common and costly al status. The amount of blood bypass. Because patients with di- (34–36). One of six patients with flow improvement required to abetes often have PAD below the a DFU undergoes an amputation, heal a small, shallow, non-infect- level of the knee, interventions accounting for nearly 100,000 am- ed ulcer in a compliant patient are frequently required to the tib- putations each year in the United with well-controlled diabetes ial arteries and even the pedal lev- States and making diabetes the and a toe pressure of 36 mmHg leading cause of non-traumatic el. To date, no prospective trials is likely to be less than that in amputation. Patients with a DFU have been conducted randomiz- a patient with diabetes in poor or history of a DFU have an in- ing patients to open versus endo- control who requires open am- creased risk of 5- and 10-year mor- putation of multiple toes for wet vascular revascularization based tality, but it is not yet proven that gangrene and who has an identi- on WIfI clinical stage. However, healing DFUs improves longevi- cal toe pressure. In general, most in functional patients with avail- ty. DFUs and their complications patients with foot ulcers and an able vein conduit presenting with exact a financial cost as well; es- ischemia grade of 3 (severe) will Stage 4 limbs, open bypass may be timated costs of hospitalizations require revascularization, but the more effective and durable than due to DFUs range from $9 to $13 decision regarding revasculariza- endovascular therapy (32), which billion, and $43.5 billion is spent tion also depends on the wound has been associated with higher on lower-extremity complications stage, the presence or absence of rates of failure of wound healing, of diabetes each year (37,38). infection, and a variety of patient the need for repeat revasculariza- Standard care includes ensur- factors such as functional status, tion, and limb amputation (33). ing good vascular supply, pre- advanced age (>80 years), and In summary, studies have venting and treating soft-tissue oxygen-dependent chronic ob- shown that identification of PAD and bone infection, performing structive lung disease. Impor- in patients with DFUs and ag- initial excisional debridement tantly, patients with moderate gressive, timely revasculariza- and maintenance debridement ischemia who do not meet the tion reduces amputation rates. as indicted, and, of crucial impor- traditional definition of CLI may WIfI is a systematic classifica- tance, adhering to high-quality also benefit from revasculariza- tion to aid in the identification off-loading. Even in optimal sit- tion, particularly as wound and of PAD and impaired perfusion. uations, at least 25% of patients foot infection grades increase. fail to heal. Instituting adjunc- Patients with threatened limbs WIfI Stage 4 patients uniformly tive therapy early improves out- in whom significant ischemia is have a higher risk of amputation, comes. Typically, standard care detected (ischemia grades 2 and even with aggressive revascular- is provided for a 4-week period ization, with a mean 1-year am- 3) and any patient with failure to because wounds that do not re- putation rate of 23.8% (median progress after 4 weeks of prop- duce in size by more than 50% 32.5%) based on a compilation of er wound care and off-loading after 4 weeks have a decreased 2,939 patients treated at 10 cen- should be referred to a vascular likelihood of healing by 12 weeks. ters (32). In contrast, the mean limb salvage specialist for further Referral to a wound center, where amputation rate in Stage 1 patients evaluation and consideration clinical expertise and access to was 3.8% (median 0). Patients at for revascularization. Preferably, advanced therapies are available, Stages 2 and 3 exhibit intermedi- vascular specialists should serve is often indicated. ate amputation rates of 10–11% at as integral components of and Numerous therapies can be ap- 1 year, suggesting some overlap routinely participate in diabetic plied for these recalcitrant ulcers; in these stages and opportunities foot and limb salvage teams. however, few have been proven to

12 | DIAGNOSIS AND MANAGEMENT OF DIABETIC FOOT COMPLICATIONS improve complete ulcer healing EVIDENCE-BASED platelet-rich concentrate, auto- in RCTs and fewer still in high- TREATMENT OF logous platelet gel, and platelet quality trials. Evidence-based ad- UNCOMPLICATED releasate), the portion of the junctive therapies include cell- REFRACTORY DFUS plasma fraction of autologous and tissue-based products (CTPs) Growth Factors blood having a platelet concen- such as bioengineered cell-based One recombinant growth factor, tration above baseline, has also therapies, acellular matrices, and recombinant human platelet– been shown to improve healing placental-derived membranes; re- derived growth factor (rhPDGF; of DFUs. Platelet gels and releas- combinant growth factors; plate- becaplermin [Regranex], Smith ates are prepared from PRP. The let-rich plasma; negative pressure & Nephew, Largo, FL) is FDA- benefit of PRP is supported by a wound therapy; and possibly hy- approved and is the only drug ap- prospective, double-blind, multi- perbaric oxygen, all of which can proved for the treatment of DFUs. center RCT of 72 DFUs using a improve complete healing and per-protocol (as opposed to an some of which may treat biofilm, Produced by incorporation of the gene for the B-chain of human intention-to-treat) analysis of 35 prevent bone infection and limb patients. This analysis revealed loss, and improve patients’ qual- PDGF into the yeast Saccharo- myces cerevisiae, becaplermin that DFUs treated with PRP ity of life (Table 4). The highest- gel healed significantly more quality evidence exists for prod- has biological activities similar to endogenous PDGF. Pivotal trials (81.3 vs. 42.1%) than similar- ucts that have undergone the sized DFUs in a control group us- rigorous approval process of the that led to approval have shown ing an inert gel (P = 0.036) (42). U.S. Food and Drug Administra- that, at week 20, one-third more tion (FDA) (as opposed to those ulcers healed in the active group CTPs: Cell-Based Products that have been “cleared” by the receiving daily rhPDGF than in Two cellular constructs are FDA- FDA) (39,40). Direct compari- a placebo control group (41). Ef- approved class III devices to treat son of the clinical trial results fectiveness data support benefit DFUs. The first, allogeneic bi- (efficacy data) is not possible of rhPDGF, and in clinical prac- layered human skin equivalent because of the varying rigor of tice its use appears to reduce the (HSE; [Apligraf], Organogenesis, trial design and analysis, inclu- risk of amputation. Autologous Canton, MA), consists of a bovine sion and exclusion criteria, and platelet-rich plasma (PRP; also collagen matrix with neonatal sample sizes. called platelet-enriched plasma, fibroblasts overlaid by a stratified

TABLE 4 Comparison of Evidence-Based Treatments for Refractory Ulcers

rhPDGF PRP HSE DSS IDRT SIS HADWM hVWM dHACM NPWT HBOT (41) (42) (43) (45) (46) (47) (48) (38) (49) (50) (52) n = 382 n = 35 n = 208 n = 245 n = 307 n = 82 n = 86 n = 97 n = 40 n = 162 n = 94 50 vs. 81 vs. 56 vs. 30 vs. 51 vs. 54 vs. 70 vs. 62 vs. 95 vs. 56 vs. 52 vs. HEALED, % 35 at 20 42 at 12 38 at 12 18 at 12 32 at 16 32 at 12 46 at 12 21 at 12 35 at 6 39 at 16 29 at 1 weeks weeks weeks weeks weeks weeks weeks weeks weeks weeks year TIME TO CLOSURE, 86 vs. 43 vs. 65 vs. Not 43 vs. 78 63 vs. 40 vs. 42 vs. 24 vs. N/A N/A DAYS 127 47 90 stated 77 48 70 57 FDA- APPROVED + + + + STUDY QUALITY +++ + +++ +++ +++ ++ ++ ++ + ++ ++

ADDITIONAL + RCTs + + + + + EFFECTIVE- NESS DATA + + + + Because of differences in study design and quality, caution is warranted regarding direct comparisons. Numbers in parentheses after therapy abbreviations are reference citations. N/A, not applicable.

DIAGNOSIS AND MANAGEMENT OF DIABETIC FOOT COMPLICATIONS | 13 epithelium containing neonatal dimensional matrix of colla- Among these, the highest-quality keratinocytes. In an RCT, up to gen and the glycosaminoglycan evidence exists for human viable five weekly applications of HSE chondroitin-6-sulfate. The tem- wound matrix (hVWM [Grafix], in patients with chronic plantar porary epidermal layer is made Osiris Therapeutics, Columbia, DFUs resulted in a significantly of silicone to provide mechanical MD), which is designed to pre- higher healing rate (P = 0.0042) protection and act as a barrier serve the native components of and shorter time to complete clo- against bacterial contamination. the human placental membrane sure (P = 0.0026) than in individ- A large RCT demonstrated that in a cryopreserved product. The uals receiving standard care (43). complete DFU closure was sig- proportion of patients achiev- A second RCT confirmed those nificantly greater with a single ing complete wound closure was results, making HSE the best- application of IDRT (51%) than significantly higher among those studied of all CTP therapies (44). with a control treatment (32%, who received hVWM compared The second cellular construct, P <0.001) at 16 weeks. Time to to control subjects (62 vs. 21%, dermal skin substitute (DSS; closure was 35 days faster for P = 0.0001), and those in the [Dermagraft], Organogenesis, IDRT-treated patients compared hVWM group had a faster median Canton, MA), consists of human to control subjects (46). Use of the time to healing (42 vs. 69.5 days in fibroblasts grown in a bioabsorb- second acellular construct, the control subjects, P = 0.019). Addi- able polyglactin mesh scaffold. tri-layer porcine small intestine tionally, fewer adverse events (44 A large RCT found that weekly submucosa (SIS [Oasis], Smith & vs. 66%, P = 0.031) were noted (38). application produced signifi- Nephew, Largo FL), led to a sig- Dehydrated human amnion/ cantly higher healing rates than nificantly greater proportion of chorion membrane (dHACM in control subjects in patients wounds closed by 12 weeks than [EpiFix], MiMedx Group, Mar- with DFUs of more than 6 weeks’ in a control group (54 vs. 32%, ietta, GA) was tested in a small duration (P = 0.023) with signifi- P = 0.021) and faster time to closure study in which 20 patients re- cantly faster time to complete for ulcers (2 weeks earlier) (47). ceived the product applied, on wound healing (P = 0.04). Treat- The third product, human acellu- average, 2–3 times during a 12- ed patients were 1.7 times more lar dermal wound matrix (HAD- week period. Ninety-five per- likely to have complete wound WM; [Graftjacket], KCI USA, San cent of dHACM-treated patients closure at any given time than Antonio, TX), is processed from healed in 6 weeks compared to were control subjects, and ulcer- screened donated human skin 35% of individuals in a control related adverse events were sig- and regulated by the FDA as hu- group (49). Effectiveness data nificantly lower (45). The effica- man tissue for transplantation. have not demonstrated such dra- cy results of clinical trials have Epidermal and dermal cells are matic results. been confirmed by effectiveness removed while dermal structure Many other acellular matrices results in clinical practice; these is preserved, including an intact and placental/amnionic/chorionic- later data suggest that use of DSS basement membrane complex. derived products have been may produce the best results in A multicenter RCT compared a cleared by the FDA, with clinical clinical practice. single application HADWM to experience suggesting yet-to-be- CTPs: Acellular Products advanced moist wound therapy proven benefits. Three acellular constructs have (AMWT). At 12 weeks, signifi- been shown to improve DFU cantly more HADWM patients EVIDENCE-BASED healing. The highest-quality ev- (P = 0.0289) achieved complete TREATMENT OF idence exists for Integra Dermal healing than did AMWT patients COMPLICATED Regenerative Template (IDRT; (70 vs. 46%) (48). REFRACTORY DFUS Integra Life Sciences, Plainsboro, CTPs: Placental/Amnionic/ For complicated (i.e., deeper, in- NJ), which consists of a dermal Chorionic-Derived Products fected) wounds, RCTs suggest replacement layer designed with Two placental/amnionic/chorionic- that two treatments may be help- a controlled porosity and degra- derived products have been ful. Negative pressure wound dation rate made up of a three- shown in RCTs to heal DFUs. therapy (NPWT; VAC Therapy

14 | DIAGNOSIS AND MANAGEMENT OF DIABETIC FOOT COMPLICATIONS System, KCI USA, San Antonio, Patients sometimes comment TX) has been shown beneficial in The Acute Hot, that what brought them to see two large studies using different Swollen Foot: the doctor was that they could no study designs. In one, patients longer fit their foot into a shoe or with DFUs undergoing large sur- Charcot or Infection? that the shape of their foot had changed, rather than that they gical debridement or amputations Primary care providers need healed better with application of were in pain. to have a high index of suspi- Diagnosis of Charcot neuro- NPWT after surgery than those cion that a red, hot, swollen arthropathy is based on medical who did not (50). A second study foot is Charcot neuroarthropa- history, physical examination, of more than 300 patients found thy, especially in patients with and plain radiographs (54,55). that NPWT plus investigators’ sensory neuropathy. Charcot The differential diagnosis in- choice of other closure techniques neuroarthropathy is a fracture cludes cellulitis, deep venous led to improved healing of DFUs; dislocation process that affects thrombosis, and trauma. Often, 43% of those using NPWT healed the bones, joints, and ligaments patients are treated with anti- of the foot and ankle in people compared to 29% of those not us- biotics, surgery, or amputation with peripheral sensory neurop- ing NPWT throughout 16 weeks for infection, or they have multi- athy (54). of treatment (P <0.007) (51). ple ultrasound examinations for The disease process was orig- The second treatment, hyper- deep vein thrombosis before the inally described in patients with baric oxygen therapy (HBOT), is correct diagnosis is made. often used for DFUs complicated tertiary syphilis and usually presents as a unilateral red, hot, The duration of the swelling by osteomyelitis. Data regarding swollen foot and ankle (55). The and redness is important to as- HBOT use are mixed, and a de- diagnosis for the hot, swollen certain in attempting to pinpoint finitive positive study has not yet diabetic foot is often delayed by the timing of the injury. Musculo- been performed. The best study weeks or months or missed en- skeletal deformity may be absent, to date involved 94 patients with tirely, resulting in severe defor- or there can be severe deformity Wagner grade 2–4 ulcers and re- mity, loss of function, ulceration, at initial presentation (56). Pa- ported 52% healing with HBOT infection, and lower-extremity tients with an early presentation versus 29% healing in the place- amputation. often have normal X-rays and a bo group (P = 0.03) (52). The best Perhaps the easiest screening normal musculoskeletal clinical results were observed in patients tool is to ask whether a patient examination. Untreated injuries completing more than 35 sessions has symptoms of neuropathy of longer duration have more se- of HBOT. Other studies have not (i.e., numbness, tingling, formi- vere bone and joint destruction yet confirmed these results (53). cation, and burning) and then to and dislocation. Patients who seek medical care later in the dis- Chronic DFUs are a growing test for sensory neuropathy. ease process on inspection may global health concern given the The classic presentation is of a have loss of the medial longitudi- implied high associated morbid- patient with painless unilateral nal arch of the foot compared to ity and mortality. Standard care swelling without a history of trau- ma. Sometimes, the patient will the contralateral foot, or their feet is not sufficient for some ulcers, recall an incidental injury such as do not appear to be symmetrical. and adjunctive therapy should be making a misstep when stepping The classic “rocker-bottom” foot considered no later than 4 weeks down from a curb or a slight in- deformity is an example of end- after standard care fails to re- version of the ankle. The foot and stage disease with severe frac- duce wound size. Many products ankle are usually swollen, red, ture dislocation, collapse of the may work, but many fewer have and warm to the touch compared midfoot, dorsal dislocation of the been proven to do so. The use of to the contralateral foot. The uni- metatarsals, and plantar disloca- evidence-based adjunctive ther- lateral swelling could have lasted tion of the tarsal bones. apies may speed healing, save for days, weeks, or even months Patients will have a history of limbs, and potentially save lives. by the time of presentation. neuropathy symptoms with a

DIAGNOSIS AND MANAGEMENT OF DIABETIC FOOT COMPLICATIONS | 15 symmetrical distribution. Oc- is purulence from the wound or Specifically, integrated foot casionally, patients will say that exposed bone when the wound care focuses on regular visits to they feel as if they have a thick is examined with a sterile probe, podiatrists and other members of stocking on their feet when they there is infection (54,56). the diabetes foot care team as de- are barefoot or that their feet Treatment of Charcot neuro- scribed earlier in this monograph. feel cold when they are not. Sim- arthropathy requires prompt Self-management involves daily ply put, if you ask these patients referral to a podiatric or ortho- evaluation by patients, family whether they have symptoms of pedic surgeon with experience members, or caregivers and the neuropathy, they will often help in treating this complication. use of thermometry. Therapeutic to make the diagnosis before you Early treatment requires immo- footwear that off-loads the foot by do a physical examination (57). bilization and non-weight-bear- at least 30% appears to be asso- Clinical examination often ing in a cast or wheelchair until ciated with lower risks of recur- shows good peripheral pulses the acute inflammatory process rence (62). If these non-surgical and severe sensory loss. Sensory subsides, which may take weeks methods are problematic, foot testing can be quickly accom- or months. Late treatment re- surgery appears to provide ben- plished with a 128-Hz tuning quires reconstructive surgery to efit in reducing the severity of fork or a 10-g monofilament or repair the deformity and obtain deformity and plantar pressure by testing light-touch percep- a plantar-grade foot (54,57). and therefore reduces the risk of tion. Examination of the joints recurrence (63–65). of the foot and ankle can show abnormal alignment, joint effu- sion, and dislocations that are How to Maintain the painless when examined. Plain Foot in Remission Conclusions and X-rays maybe appear normal ear- Future Directions ly in the Charcot process, or the The overall risk for developing a radiographic signs can be sub- wound in people with diabetes is Diabetic foot complications are, tle. Dislocation at the Lis Franc ~2% per year. This risk increases as has often been said, common, joint in the midfoot is a common to 7.5% for patients with neurop- complex, and costly. Demograph- presentation that can be missed athy. However, the risk jumps ic trends suggest that these com- even by experienced radiologists to 40% in people with a history plications, including ulcers, in- unless concerns regarding pos- of ulceration (1). The risk fur- fections, PAD, and amputations, sible Charcot neuroarthropathy ther increases to nearly 60% at 3 will continue to be highly preva- are voiced when imaging is or- years and up to 75% at 5 years (1). lent (29). dered (54,55). In fact, re-ulceration is not only Future directions should focus It is uncommon for adults to common, it is likely. We there- not only on the promising thera- have infections without a wound. fore use the term “in remission” peutic advances discussed in this Inspect the skin for ulceration. to refer to this population (58). monograph, but also on novel Charcot patients sometimes Our goal is not necessarily to pre- monitoring systems (59,66–71). also have ulcerations. If there is vent every wound, but to maxi- For example, efforts designed to a wound, fractures and disloca- mize ulcer-free, hospital-free, identify pre-ulcerative inflam- tions, and cellulitis, the patient and activity-rich days (59–61) by mation through the past gener- may have both disease process- making each wound recurrence ation have now culminated in es. Many people with diabetes as uncomplicated as possible. home-based monitors that can who have cellulitis do not have There are currently four key alert patients up to several weeks leukocytosis, so using this in the strategies associated with maxi- in advance of a potential com- decision process will be helpful mizing ulcer-free days: integrat- plication (69). Similarly, smart to confirm infection when there ed foot care, self-management, insoles paired with smart watch- are both leukocytosis and oth- therapeutic footwear, and, as es may be able to identify poten- er systemic signs of infection. If necessary, reconstructive foot tially damaging pressure, which there is no leukocytosis, you have surgery. These are summarized over time can cause blistering not ruled infection out. If there in Table 5. or callusing and tissue loss (67).

16 | DIAGNOSIS AND MANAGEMENT OF DIABETIC FOOT COMPLICATIONS TABLE 5 Effect Sizes in Studies of Interventions to Reduce the Risk of Foot Ulcer Recurrence

EFFECT OF THE EFFECT OF ADHERENCE INTERVENTION TO TREATMENT INTERVENTION Number of Mean Sample Mean Effect Size,* % Number of Mean Effect CATEGORY Studies Size, n (Range) (Range) Studies Size,† % INTEGRATED FOOT CARE 4‡ 179 (53–549) 30.9 (9.1 to 100) 2 76.7 SELF-MANAGEMENT 4 138 (70–225) 54.3 (−5.4 to 90.0) 1 98.0 PATIENT EDUCATION 2 152 (131–172) −13.4 (−26.3 to −0.5) 2 85.5 THERAPEUTIC FOOTWEAR 9 181 (46–400) 47.2 (−14.6 to 92.9) 2 58.1 FOOT SURGERY 7 73 (40–207) 61.8 (10.4 to 100) 0 — Adapted from ref. 1, to which readers are referred for details about the individual studies summarized here, as well as a 2015 systematic review of ulcer prevention performed by the International Working Group on the Diabetic Foot that assessed the five categories of preventive interventions. All studies were controlled prospective or retrospective studies (randomized trial, cohort study, or case-control study). Information about the quality of the studies can be obtained from the systematic review. *The mean effect size is expressed as the percentage reduction in the risk of recurrent foot ulcer in the intervention group compared to the group receiving usual care (control group). Therefore, negative percentages indicate an increase in the risk of recurrent foot ulcer in the intervention group as compared with the control group. †The mean effect size is expressed as the percentage reduction in the risk of recurrent foot ulcer among patients who adhered to the study treatment compared to those who did not adhere to the study treatment. ‡Studies of integrated foot care include one study that is ongoing; see ref. 1 for details.

Combining the evidence-based ment: Surgical or Otherwise.” R.S.K. MedTech, and Medline Industries. and common-sense therapies de- wrote “Evidence-Based Adjunctive B.A.L. is a consultant for Medimmune, scribed here with emerging tech- Therapies for Diabetic Foot Ulcers.” Microbion, and Debiopharm. J.S.S. is nologies has the potential to help L.A.L. wrote “When and Where to a consultant for Integra and Syntactx. us maximize ulcer-free, hospi- Refer Diabetic Foot Problems” and REFERENCES tal-free, and activity-rich days for “Off-Loading the Diabetic Foot 1. Armstrong DG, Boulton AJM, our patients. Wound” and co-wrote “The Acute Hot, Swollen Foot: Charcot or Infec- Bus SA. Diabetic foot ulcers and ACKNOWLEDGMENTS tion?” B.A.L. wrote “Management of their recurrence. N Engl J Med The authors acknowledge Jayson N. Infection.” J.L.M. wrote “Recogniz- 2017;376:2367–2375 Atves, DPM, CO, for contributions to ing and Treating Peripheral Artery 2. Jeffcoate WJ, Vileikyte L, Boyko the section on debridement. Disease.” J.S.S. co-wrote “Wound EJ, Armstrong DG, Boulton AJM. Editorial and project management ser- Debridement: Surgical or Otherwise.” Current challenges and opportunities vices were provided by Debbie Kendall A.J.M.B. and D.G.A. are the guaran- in the prevention and management of Kendall Editorial in Richmond, VA. tors of this work. of diabetic foot ulcers. Diabetes Care 2018;41:645–652 AUTHOR CONTRIBUTIONS DUALITIES OF INTEREST A.J.M.B. and D.G.A. served as A.J.M.B., D.G.A., and J.L.M. have 3. Abbott CA, Carrington AL, Ashe H, co-editors and, as such, co-wrote the no relevant dualities of interest to et al; North-West Diabetes Foot Care introduction and conclusion and disclose. C.E.A. is a consultant for Study. The North-West Diabetes Foot reviewed and edited the entire Acelity and Integra. R.S.K. has re- Care Study: incidence of, and risk fac- manuscript. A.J.M.B. also wrote ceived honoraria for participation in tors for, new diabetic foot ulceration “Pathways to Diabetic Foot Compli- educational programs for Healogics. in a community-based patient cohort. cations,” and D.G.A. wrote “Screen- L.A.L. has received research grants Diabet Med 2002;19:377–384 ing for Foot Complications Risk” and from Cardinal Health; serves on 4. Boulton AJM. The pathway to ul- “How to Maintain the Foot in Remis- speakers bureaus for Integra, Osiris, ceration. In The Foot in Diabetes, 5th sion” and co-wrote “The Acute Hot, and Smith & Nephew; and is a con- ed. Boulton AJM, Rayman G, Wukich Swollen Foot: Charcot or Infection?” sultant or advisor to Apilon Medical DK, Eds. Chichester, U.K., John Wiley C.E.A. co-wrote “Wound Debride- Users, Boehringer Ingelheim, Harbor & Sons, 2019. In press

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DIAGNOSIS AND MANAGEMENT OF DIABETIC FOOT COMPLICATIONS | 19 50. Armstrong DG, Lavery LA; Diabet- arthropathy in a diabetic foot specialty Working Group on the Diabetic Foot. ic Foot Study Consortium. Negative clinic. Diabet Med 1997;14:357–363 IWGDF guidance on footwear and pressure wound therapy after partial 58. Armstrong DG, Mills JL. Toward a offloading interventions to prevent diabetic foot amputation: a multi- change in syntax in diabetic foot care: and heal foot ulcers in patients with centre, randomised controlled trial. prevention equals remission. J Am diabetes. Diabetes Metab Res Rev Lancet. 2005;366:1704–1710. Podiatr Med Assoc 2013;103:161–162 2016;32(Suppl. 1):25–36 51. Blume PA, Walters J, Payne W, 59. Khan T, Armstrong DG. Ulcer-free, 66. Basatneh R, Najafi B, Armstrong Ayala J, Lantis J. Comparison of hospital-free and activity-rich days: DG. Health sensors, smart home negative pressure wound therapy three key metrics for the diabetic devices, and the Internet of Medical using vacuum-assisted closure with foot in remission. J Wound Care Things: an opportunity for dramatic advanced moist wound therapy in 2018;27(Suppl. 4):S3–S4 improvement in care for the lower the treatment of diabetic foot ulcers: extremity complications of diabetes. J a multicenter randomized controlled 60. Miller JD, Salloum M, Button A, Diabetes Sci Technol 2018;12:577–586 trial. Diabetes Care 2008;31:631–636 Giovinco NA, Armstrong DG. How can I 67. Najafi B, Ron E, Enriquez A, maintain my patient with diabetes and 52. Löndahl M, Katzman P, Nilsson A, Marin I, Razjouyan J, Armstrong DG. history of foot ulcer in remission? Int J Hammarlund C. Hyperbaric oxygen Smarter sole survival: will neuropath- Low Extrem Wounds 2014;13:371–377 therapy facilitates healing of chronic ic patients at high risk for ulceration foot ulcers in patients with diabetes. 61. Boghossian J, Miller J, Armstrong use a smart insole-based foot protec- Diabetes Care 2010;33:998–1003 D. Offloading the diabetic foot: toward tion system? J Diabetes Sci Technol 53. Santema KTB, Stoekenbroek RM, healing wounds and extending 2017;11:702–713 ulcer-free days in remission. Chronic Koelemay MJW, et al.; DAMO2CLES 68. Roser MC, Canavan PK, Najafi B, Wound Care Management and Study Group. Hyperbaric oxygen ther- Cooper Watchman M, Vaishnav K, Research 2017;4:83–88 apy in the treatment of ischemic low- Armstrong DG. Novel in-shoe exo- er-extremity ulcers in patients with 62. van Netten JJ, Lazzarini PA, skeleton for offloading of forefoot diabetes: results of the DAMO2CLES Armstrong DG, et al. Diabetic Foot pressure for individuals with diabetic multicenter randomized clinical trial. Australia guideline on footwear for foot pathology. J Diabetes Sci Technol Diabetes Care 2018;41:112–119 people with diabetes. J Foot Ankle 2017;11:874–882 Res 2018;11:2 54. Rogers LC, Frykberg RG, Armstrong 69. Frykberg RG, Gordon IL, Reyzelman DG, et al. The Charcot foot in diabetes. 63. Finestone AS, Tamir E, Ron G, AM, et al. Feasibility and efficacy of a Diabetes Care 2011;34:2123–2129 Wiser I, Agar G. Surgical offloading smart mat technology to predict de- 55. Konarzewska A, Korzon-Burakowska procedures for diabetic foot ulcers velopment of diabetic plantar ulcers. A, Rzepecka-Wejs L, Sudoł-Szopińska compared to best non-surgical Diabetes Care 2017;40:973–980 I, Szurowska E, Studniarek M. Diabetic treatment: a study protocol for a 70. Armstrong DG, Holtz-Neiderer K, foot syndrome: Charcot arthropathy randomized controlled trial. J Foot Wendel C, Mohler MJ, Kimbriel HR, or osteomyelitis? Part I: Clinical Ankle Res 2018;11:6 Lavery LA. Skin temperature monitor- picture and radiography. J Ultrason 64. Armstrong DG, Lavery LA, Stern S, ing reduces the risk for diabetic foot 2018;18:42–49 Harkless LB. Is prophylactic diabetic ulceration in high-risk patients. Am J 56. Jeffcoate WJ. Charcot foot syn- foot surgery dangerous? J Foot Ankle Med 2007;120:1042–1046 drome. Diabet Med 2015;32:760–770 Surg 1996;35:585–589 71. Yap MH, Chatwin KE, Ng CC, et al. 57. Armstrong DG, Todd WF, Lavery 65. Bus SA, Armstrong DG, van A new mobile application for standard- LA, Harkless LB, Bushman TR. The Deursen RW, Lewis JE, Caravaggi izing diabetic foot images. J Diabetes natural history of acute Charcot’s CF, Cavanagh PR; International Sci Technol 2018;12:169–173

20 | DIAGNOSIS AND MANAGEMENT OF DIABETIC FOOT COMPLICATIONS Suggested citation: Boulton AJM, Armstrong DG, Kirsner RS, et al. Diagnosis and Management of Diabetic Foot Complications. Arlington, Va., American Diabetes Association, 2018