Abstract

The diabetic foot interacts with anatomical, vascular, and neurological factors that challenge clinical practice. This study aimed to compile the primary scientific evidence based on a review of the main guidelines, in addition to articles published on the Embase, Lilacs, and PubMed platforms. The European Society of Cardiology system was used to develop recommendation classes and levels of evidence. The themes were divided into six chapters (Chapter 1 - Prevention of foot ulcers in people with diabetes; Chapter 2 - Pressure relief from foot ulcers in people with diabetes; Chapter 3 -Classifications of diabetic foot ulcers; Chapter 4 - Foot and peripheral artery disease; Chapter 5 - Infection and the diabetic foot; Chapter 6 - Charcot's neuroarthropathy). This version of the Diabetic Foot Guidelines presents essential recommendations for the prevention, diagnosis, treatment, and follow-up of patients with diabetic foot, offering an objective guide for medical practice.

Keywords:
diabetic foot; foot ulcer; diabetes mellitus

Resumo

O pé diabético corresponde a uma interação entre fatores anatômicos, vasculares e neurológicos que representam um desafio na prática clínica. O objetivo deste trabalho foi compilar as principais evidências científicas com base em uma revisão das principais diretrizes, além de artigos publicados nas plataformas Embase, Lilacs e PubMed. O sistema da Sociedade Européia de Cardiologia foi utilizado para desenvolver classes de recomendação e níveis de evidência. Os temas foram divididos em seis capítulos (Capítulo 1-Prevenção de úlceras nos pés de pessoas com diabetes; Capítulo 2-Alívio da pressão de úlceras nos pés de pessoas com diabetes; Capítulo 3-Classificações das úlceras do pé diabético; Capítulo 4-Pé diabético e a doença arterial periférica; Capítulo 5-Infecção e o pé diabético; Capítulo 6-Neuroartropatia de Charcot). A versão atual das Diretrizes sobre pé diabético apresenta importantes recomendações para prevenção, diagnóstico, tratamento e seguimento dos pacientes com pé diabético, oferecendo um guia objetivo para prática médica.

Palavras-chave:
pé diabético; úlcera do pé; diabetes mellitus

INTRODUCTION

Guidelines, an organized collection of medical information on a topic that is derived from quality scientific evidence, help doctors with diagnostic, therapeutic, and monitoring decisions for their patients.¹1 Nobre MRC, Bernardo WM. Diretrizes AMB/CFM. Rev Assoc Med Bras. 2002;48(4):275-96. http://doi.org/10.1590/S0104-42302002000400027.
http://doi.org/10.1590/S0104-42302002000... Understanding that such information requires constant updating to maintain its relevance and safety for specialists, in 2023 the Brazilian Society of Angiology and Vascular Surgery updated and incorporated new guidelines into its library. The objective is to provide a tool to assist in clinical decisions while preserving the doctor’s autonomy, as provided for in the Federal Council of Medicine’s Code of Medical Ethics.²2 Migowski A, Stein AT, Santos MS, Fernandes MM, Ferreira DM, Ferreira CB. Diretrizes metodológicas: elaboração de diretrizes clínicas. Brasília: Ministério da Saúde; 2016.

It is estimated that 415 million adults aged 20 to 79 years had diabetes mellitus (DM) worldwide in 2015, approximately 46.5% of whom lived in 3 countries: China (109 million), India (69 million) and the USA (29 million).³3 Zheng Y, Ley S, Hu F. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2018;14(2):88-98. http://doi.org/10.1038/nrendo.2017.151. PMid:29219149.
http://doi.org/10.1038/nrendo.2017.151... Another 10-20 million lived in Brazil, Russia, and Mexico.³3 Zheng Y, Ley S, Hu F. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2018;14(2):88-98. http://doi.org/10.1038/nrendo.2017.151. PMid:29219149.
http://doi.org/10.1038/nrendo.2017.151... According to International Diabetes Federation estimates, 9.1-26.1 million people with DM will develop diabetic foot ulcers (DFU) each year.⁴4 Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med. 2017;376(24):2367-75. http://doi.org/10.1056/NEJMra1615439. PMid:28614678.
http://doi.org/10.1056/NEJMra1615439... Approximately 34% of people with DM will develop DFU at some point in their lives,⁴4 Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med. 2017;376(24):2367-75. http://doi.org/10.1056/NEJMra1615439. PMid:28614678.
http://doi.org/10.1056/NEJMra1615439... with an annual risk of 2.5%-42% within 5 years.⁵5 Stern JR, Wong CK, Yerovinkina M, et al. A meta-analysis of long-term mortality and associated risk factors following lower extremity amputation. Ann Vasc Surg. 2017;42:322-7. http://doi.org/10.1016/j.avsg.2016.12.015. PMid:28389295.
http://doi.org/10.1016/j.avsg.2016.12.01... In addition to functional impairment and reduced quality of life, approximately 20% of patients with foot injuries will not heal 1 year after diagnosis,⁶6 Walsh JW, Hoffstad OJ, Sullivan MO, Margolis DJ. Association of diabetic foot ulcer and death in a population-based cohort from the United Kingdom. Diabet Med. 2016;33(11):1493-8. http://doi.org/10.1111/dme.13054. PMid:26666583.
http://doi.org/10.1111/dme.13054... and the recurrence rate during this period is approximately 40%.⁴4 Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med. 2017;376(24):2367-75. http://doi.org/10.1056/NEJMra1615439. PMid:28614678.
http://doi.org/10.1056/NEJMra1615439...

Having 13 million people diagnosed with DM, Brazil ranks fourth in worldwide prevalence and first in South America (Figure 1).³3 Zheng Y, Ley S, Hu F. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2018;14(2):88-98. http://doi.org/10.1038/nrendo.2017.151. PMid:29219149.
http://doi.org/10.1038/nrendo.2017.151... ,⁷7 Prompers L, Schaper N, Apelqvist J, et al. Prediction of outcome in individuals with diabetic foot ulcers: focus on the differences between individuals with and without peripheral arterial disease. The EURODIALE study. Diabetologia. 2008;51(5):747-55. http://doi.org/10.1007/s00125-008-0940-0. PMid:18297261.
http://doi.org/10.1007/s00125-008-0940-0... Santos et al.⁸8 Mesquita LO, Aquino EC, Gouvea ECD, Oliveira PPV, França GVA. Mortalidade por diabetes mellitus no Brasil, 2010 a 2021. Boletim Epidemiológico. 2022;53(45):17-25. analyzed diabetic foot complications in 27 Brazilian state capitals over a 10-year period (2008-2018), recording 45,095 complications. There was also a significant increase in complications between 2008 (5.68/100,000 inhabitants) and 2018 (17.68/100,000 inhabitants).

BRAZUPA, a cross-sectional study evaluating 1455 patients at 19 Brazilian centers, focused on risk factors for ulcers and amputation in patients with DM. Alarmingly, the mean age of the population with a limb at risk (57 years) was younger than that of either Western Europe or North America. Of the included patients, 18.6% had an active ulcer, 25.3% had a previous ulcer, and 13.7% had undergone an amputation.⁹9 Santos AAA, Gomes AFL, Silva FSS, et al. Tendência temporal das complicações do pé diabético e da cobertura da Atenção Primária à Saúde nas capitais brasileiras, 2008-2018. Rev Bras Med Fam Comunidade. 2022;17(44):3420. http://doi.org/10.5712/rbmfc17(44)3420.
http://doi.org/10.5712/rbmfc17(44)3420...

Diabetic foot corresponds to an interaction between anatomical, vascular (macro- and microangiopathy) and neurological factors, representing a complex challenge in the daily practice of vascular surgeons.³3 Zheng Y, Ley S, Hu F. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2018;14(2):88-98. http://doi.org/10.1038/nrendo.2017.151. PMid:29219149.
http://doi.org/10.1038/nrendo.2017.151... ,¹⁰10 Parisi MC, Moura A No, Menezes FH, et al. Baseline characteristics and risk factors for ulcer, amputation and severe neuropathy in diabetic foot at risk: the BRAZUPA study. Diabetol Metab Syndr. 2016;8:25. http://doi.org/10.1186/s13098-016-0126-8. PMid:26989446.
http://doi.org/10.1186/s13098-016-0126-8...

OBJECTIVES

This study compiles scientific evidence by reviewing the main guidelines and relevant articles, presenting important recommendations for the prevention, diagnosis, treatment, and follow-up of patients with diabetic foot and offering objective guidelines for medical practice.

METHODOLOGY

Previously published guidelines were critically synthesized and the most relevant articles in the Embase, Lilacs, PubMed/MEDLINE, and Cochrane platforms were reviewed, which added important information for decision-making and recommendations. The main revised guidelines were: The management of diabetic foot: A clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine (2016),¹¹11 Hingorani A, LaMuraglia GM, Henke P, et al. The management of diabetic foot: a clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine. J Vasc Surg. 2016;63(2, Suppl):3S-21S. http://doi.org/10.1016/j.jvs.2015.10.003. PMid:26804367.
http://doi.org/10.1016/j.jvs.2015.10.003... Best practice recommendations for the Prevention and Management of Diabetic Foot Ulcers (2017),¹²12 Botros M, Kuhnke J, Embil J, et al. Best practice recommendations for the prevention and management of diabetic foot ulcers. In: Canadian Association of Wound Care, editor. Foundations of best practice for skin and wound management: a supplement of Wound Care Canada. North York, ON: Wounds Canada; 2017. 68 p. Practical Guidelines on the prevention and management of diabetic foot disease (2019),¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... Global vascular guidelines on the management of chronic limb-threatening ischemia (2019),¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334. and Australian evidence-based guidelines for diabetes-related foot disease (2022).¹⁵15 Chuter V, Quigley F, Tosenovsky P, et al. Australian guideline on diagnosis and management of peripheral artery disease: part of the 2021 Australian evidence-based guidelines for diabetes-related foot disease. J Foot Ankle Res. 2022;15(1):51. http://doi.org/10.1186/s13047-022-00550-7. PMid:35787293.
http://doi.org/10.1186/s13047-022-00550-...

Only reviewed publications were included, following the “pyramid of evidence” principle (Tables 1 and 2). Multiple randomized clinical trials or meta-analyses of multiple randomized clinical trials were at the top of the pyramid, followed by single randomized clinical trials or large non-randomized studies (including meta-analyses of large cohorts), meta-analyses of small non-randomized studies, observational studies, and case series. Expert opinion was at the base of the pyramid, and case reports and summaries were excluded.

The European Society of Cardiology system was used to develop recommendation classes and levels of evidence.¹⁶16 European Society of Cardiology. Recommendations for guidelines production [Internet]. 2023 [citado 2023 dez 1]. https://www.escardio.org/static-file/Escardio/Guidelines/Documents/ESC%20Clinical%20Practice%20Guidelines%20-%20Policies%20and%20Procedures-updated.pdf
https://www.escardio.org/static-file/Esc... Strength (class) is graded from I to III, with I being the strongest (Table 1). Recommendations were developed by the authors assigned to each section, and all members approved the text and final classifications.

The main themes were divided into 6 chapters:

• Chapter 1 - Preventing foot ulcers in people with diabetes;

• Chapter 2 – Relieving pressure on foot ulcers in people with diabetes;

• Chapter 3 - Classifying diabetic foot ulcers;

• Chapter 4 – The diabetic foot and peripheral arterial disease;

• Chapter 5 - Infection and the diabetic foot;

• Chapter 6 - Charcot neuroarthropathy.

CHAPTER 1. PREVENTING FOOT ULCERS IN PEOPLE WITH DIABETES

Introduction

Diabetic foot is among the most serious complications of DM. It is a source of great suffering and financial cost, in addition to a considerable burden on the patient’s family, health care professionals and facilities, and society in general.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... It is estimated that in 2015 approximately USD 673 billion (12% of global health expenditure) was spent on treating DM and its complications.³3 Zheng Y, Ley S, Hu F. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2018;14(2):88-98. http://doi.org/10.1038/nrendo.2017.151. PMid:29219149.
http://doi.org/10.1038/nrendo.2017.151...

The frequency of amputation is much higher among people with diabetes than those without it.¹⁷17 Fosse S, Hartemann-Heurtier A, Jacqueminet S, Ha Van G, Grimaldi A, Fagot-Campagna A. Incidence and characteristics of lower limb amputations in people with diabetes. Diabet Med. 2009;26(4):391-6. http://doi.org/10.1111/j.1464-5491.2009.02698.x. PMid:19388969.
http://doi.org/10.1111/j.1464-5491.2009.... This is especially true in developed countries such as Canada, where adults with diabetes are 20 times more likely to be hospitalized for non-traumatic lower limb amputation than adults without diabetes.¹⁸18 Ikonen TS, Sund R, Venermo M, Winell K. Fewer major amputations among individuals with diabetes in Finland in 1997-2007: a population-based study. Diabetes Care. 2010;33(12):2598-603. http://doi.org/10.2337/dc10-0462. PMid:20807872.
http://doi.org/10.2337/dc10-0462... Preventive measures, foot care education, and early aggressive intervention are important components of diabetes treatment.

Pathophysiology

Although the prevalence and spectrum of the diabetic foot vary in different regions of the world, the pathways of ulceration are similar in most patients. Peripheral neuropathy and peripheral arterial disease (PAD) often play a central role in diabetic foot complications, while infection often arises as a secondary phenomenon. However, all 3 components often have a synergistic role in the etiological triad. Peripheral neuropathy occurs in approximately 50% of diabetic patients, who often gradually develop “high pressure” zones in the foot that lead to loss of protective sensation (LPS), which is considered the main cause of DFU.¹⁹19 Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med. 2017;376(24):2367-75. http://doi.org/10.1056/NEJMra1615439. PMid:28614678.
http://doi.org/10.1056/NEJMra1615439... ,²⁰20 Bus SA, Armstrong DG, Gooday C, et al. Guidelines on offloading foot ulcers in persons with diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3274. http://doi.org/10.1002/dmrr.3274. PMid:32176441.
http://doi.org/10.1002/dmrr.3274...

In people with neuropathy, minor trauma (eg, improperly fitting shoes or acute mechanical or thermal injury) may precipitate foot ulceration. LPS, acquired foot deformities, and limited joint mobility can result in abnormal biomechanical loading on the foot. High mechanical stress in certain areas can lead to callus formation. The callus then leads to a further load increase on the foot, usually followed by subcutaneous hemorrhaging and, occasionally, skin ulceration. Finally, regardless of the primary cause of ulceration, continuing to walk with an insensitive foot impairs healing.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,²¹21 Mens MA, Busch-Westbroek TE, Bus SA, et al. The efficacy of flexor tenotomy to prevent recurrent diabetic foot ulcers (DIAFLEX trial): study protocol for a randomized controlled trial. Contemp Clin Trials Commun. 2023;33:101107. http://doi.org/10.1016/j.conctc.2023.101107. PMid:36950303.
http://doi.org/10.1016/j.conctc.2023.101... People with diabetes are also more susceptible to infections due to neuropathy, PAD, microcirculation dysfunction, and immunopathy.¹⁹19 Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med. 2017;376(24):2367-75. http://doi.org/10.1056/NEJMra1615439. PMid:28614678.
http://doi.org/10.1056/NEJMra1615439... Figure 2 shows DFU resulting from biomechanical alterations to the foot, including callus formation and progression to ulcer and infection.

There are 5 pillars to DFU prevention (Figure 3):

1. identifying the foot at risk;

2. regularly inspecting and examining the foot at risk;

3. educating patients, their families, and health care professionals;

4. ensuring the routine use of appropriate footwear;

5. treating risk factors for ulceration.

1. Identifying the foot at risk

A lack of symptoms in people with diabetes does not exclude the disease; they may present asymptomatic neuropathy, PAD, pre-ulcerative signs, or an ulcer.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,²²22 Bus SA, Lavery LA, Monteiro-Soares M, et al. Guidelines on the prevention of foot ulcers in persons with diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3269. http://doi.org/10.1002/dmrr.3269. PMid:32176451.
http://doi.org/10.1002/dmrr.3269... A thorough examination of the feet is important for early disease detection. Screening for peripheral neuropathy and PAD can help identify patients at risk of foot ulcers (recommendation class I, level of evidence B). A history of ulcers or amputation and poor glycemic control increase the risk.²³23 Crawford F, Cezard G, Chappell FM, et al. A systematic review and individual patient data meta-analysis of prognostic factors for foot ulceration in people with diabetes: the international research collaboration for the prediction of diabetic foot ulcerations (PODUS). Health Technol Assess. 2015;19(57):1-210. http://doi.org/10.3310/hta19570. PMid:26211920.
http://doi.org/10.3310/hta19570... ,²⁴24 Mishra SC, Chhatbar KC, Kashikar A, Mehndiratta A. Diabetic foot. BMJ. 2017;359:j5064. http://doi.org/10.1136/bmj.j5064. PMid:29146579.
http://doi.org/10.1136/bmj.j5064... Periodic reassessments are recommended for at-risk patients according to the risk stratification shown in Table 3 (recommendation class I, level of evidence C).

2. Regularly inspecting and examining the foot at risk

The foot should be examined at each follow-up visit for active disease (ulceration or gangrene) (Figure 4A), as well as for lesions that increase the risk of ulceration, such as fungal infection, skin cracks and fissures, deformed nails, skin maceration, calluses and deformities (hammer toe, claw toe, and pes cavus) (Figure 4B and 4C) (recommendation class I, level of evidence B). Cold limb temperature may suggest ischemia, whereas flushing, increased warmth, or swelling may suggest inflammation, such as acute Charcot foot or cellulitis.²³23 Crawford F, Cezard G, Chappell FM, et al. A systematic review and individual patient data meta-analysis of prognostic factors for foot ulceration in people with diabetes: the international research collaboration for the prediction of diabetic foot ulcerations (PODUS). Health Technol Assess. 2015;19(57):1-210. http://doi.org/10.3310/hta19570. PMid:26211920.
http://doi.org/10.3310/hta19570... ,²⁴24 Mishra SC, Chhatbar KC, Kashikar A, Mehndiratta A. Diabetic foot. BMJ. 2017;359:j5064. http://doi.org/10.1136/bmj.j5064. PMid:29146579.
http://doi.org/10.1136/bmj.j5064...

Current American Diabetes Association and Canadian Diabetes Association guidelines recommend screening for diabetic neuropathy in all patients upon diagnosis of type 2 DM and after 5 years in patients with type 1 DM.²⁵25 Feldman EL, Callaghan BC, Pop-Busui R, et al. Diabetic Neuropathy. Nat Rev Dis Primers. 2019;5(1):41. http://doi.org/10.1038/s41572-019-0092-1. PMid:31197153.
http://doi.org/10.1038/s41572-019-0092-1... Subsequent reevaluation should follow the International Working Group on the Diabetic Foot (IWGDF) risk stratification system.²²22 Bus SA, Lavery LA, Monteiro-Soares M, et al. Guidelines on the prevention of foot ulcers in persons with diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3269. http://doi.org/10.1002/dmrr.3269. PMid:32176451.
http://doi.org/10.1002/dmrr.3269...

Risk stratification IWGDF 0

Patients should be assessed annually to identify risk factors for ulceration, such as PAD and neuropathy.²¹21 Mens MA, Busch-Westbroek TE, Bus SA, et al. The efficacy of flexor tenotomy to prevent recurrent diabetic foot ulcers (DIAFLEX trial): study protocol for a randomized controlled trial. Contemp Clin Trials Commun. 2023;33:101107. http://doi.org/10.1016/j.conctc.2023.101107. PMid:36950303.
http://doi.org/10.1016/j.conctc.2023.101... ,²²22 Bus SA, Lavery LA, Monteiro-Soares M, et al. Guidelines on the prevention of foot ulcers in persons with diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3269. http://doi.org/10.1002/dmrr.3269. PMid:32176451.
http://doi.org/10.1002/dmrr.3269... Chart 1 outlines basic clinical examination of these patients. In general, LPS is caused by diabetic neuropathy. If detected, it is generally necessary to obtain more information about the history of the disease and conduct additional tests regarding its causes and consequences (recommendation class I, level of evidence B).

Risk stratification IWGDF ≥ 1

A more comprehensive examination must be performed in patients with PAD, LPS, deformities, a history of ulcer or amputation, or end-stage chronic kidney disease, as shown in Chart 2 (recommendation class I, level of evidence B).

3. Educating patients, their families, and health care professionals

Due to the lack of standardization and high heterogeneity of studies on self-care in foot ulcer prevention, no high-quality evidence on the effect of such interventions is available. However, they allow a person to detect the first signs of DFU, thus contributing to basic foot hygiene.²⁶26 Adiewere P, Gillis RB, Imran Jiwani S, Meal A, Shaw I, Adams GG. A systematic review and meta-analysis of patient education in preventing and reducing the incidence or recurrence of adult diabetes foot ulcers (DFU). Heliyon. 2018;4(5):e00614. http://doi.org/10.1016/j.heliyon.2018.e00614. PMid:29872752.
http://doi.org/10.1016/j.heliyon.2018.e0...

Home monitoring of plantar foot temperature once a day with an infrared thermometer can be considered a preventive intervention, especially when high temperatures are observed for 2 consecutive days (recommendation class IIb, level of evidence B).²⁷27 Skafjeld A, Iversen MM, Holme I, Ribu L, Hvaal K, Kilhovd BK. A pilot study testing the feasibility of skin temperature monitoring to reduce recurrent foot ulcers in patients with diabetes: a randomized controlled trial. BMC Endocr Disord. 2015;15:55. http://doi.org/10.1186/s12902-015-0054-x. PMid:26452544.
http://doi.org/10.1186/s12902-015-0054-x...

28 Wijlens AM, Holloway S, Bus SA, van Netten JJ. An explorative study on the validity of various definitions of a 2·2 °C temperature threshold as warning signal for impending diabetic foot ulceration. Int Wound J. 2017;14(6):1346-51. http://doi.org/10.1111/iwj.12811. PMid:28990362.
http://doi.org/10.1111/iwj.12811... -²⁹29 van Netten JJ, Prijs M, van Baal JG, Liu C, van der Heijden F, Bus SA. Diagnostic values for skin temperature assessment to detect diabetes-related foot complications. Diabetes Technol Ther. 2014;16(11):714-21. http://doi.org/10.1089/dia.2014.0052. PMid:25098361.
http://doi.org/10.1089/dia.2014.0052... However, despite its easy applicability, the results may unnecessarily worry people and lower their confidence, and calibrated equipment is required.²⁷27 Skafjeld A, Iversen MM, Holme I, Ribu L, Hvaal K, Kilhovd BK. A pilot study testing the feasibility of skin temperature monitoring to reduce recurrent foot ulcers in patients with diabetes: a randomized controlled trial. BMC Endocr Disord. 2015;15:55. http://doi.org/10.1186/s12902-015-0054-x. PMid:26452544.
http://doi.org/10.1186/s12902-015-0054-x...

28 Wijlens AM, Holloway S, Bus SA, van Netten JJ. An explorative study on the validity of various definitions of a 2·2 °C temperature threshold as warning signal for impending diabetic foot ulceration. Int Wound J. 2017;14(6):1346-51. http://doi.org/10.1111/iwj.12811. PMid:28990362.
http://doi.org/10.1111/iwj.12811... -²⁹29 van Netten JJ, Prijs M, van Baal JG, Liu C, van der Heijden F, Bus SA. Diagnostic values for skin temperature assessment to detect diabetes-related foot complications. Diabetes Technol Ther. 2014;16(11):714-21. http://doi.org/10.1089/dia.2014.0052. PMid:25098361.
http://doi.org/10.1089/dia.2014.0052...

Pre-ulcerative signs, such as blisters, fissures, or calluses with subcutaneous hemorrhaging, ingrown toenails, or onychomycosis appear to be strong predictors of foot ulceration.³⁰30 Waaijman R, de Haart M, Arts ML, et al. Risk factors for plantar foot ulcer recurrence in neuropathic diabetic patients. Diabetes Care. 2014;37(6):1697-705. http://doi.org/10.2337/dc13-2470. PMid:24705610.
http://doi.org/10.2337/dc13-2470... A health care professional should remove abundant calluses, protect blisters (draining them when necessary), and treat fissures, ingrown toenails, and fungal infections (recommendation class I, level of evidence C).³¹31 Young MJ, Cavanagh PR, Thomas G, Johnson MM, Murray H, Boulton AJ. The effect of callus removal on dynamic plantar foot pressures in diabetic patients. Diabet Med. 1992;9(1):55-7. http://doi.org/10.1111/j.1464-5491.1992.tb01714.x. PMid:1551311.
http://doi.org/10.1111/j.1464-5491.1992.... ,³²32 Pitei DL, Foster A, Edmonds M. The effect of regular callus removal on foot pressures. J Foot Ankle Surg. 1999;38(4):251-5. http://doi.org/10.1016/S1067-2516(99)80066-0. PMid:10464719.
http://doi.org/10.1016/S1067-2516(99)800... Flexor tenotomy may be considered for patients with an ulcer or pre-ulcerative sign in the toe who do not respond to conservative treatment and who require normalization of the foot structure to prevent ulceration (recommendation class IIb, level of evidence C).³³33 Rasmussen A, Bjerre-Christensen U, Almdal TP, Holstein P. Percutaneous flexor tenotomy for preventing and treating toe ulcers in people with diabetes mellitus. J Tissue Viability. 2013;22(3):68-73. http://doi.org/10.1016/j.jtv.2013.04.001. PMid:23809991.
http://doi.org/10.1016/j.jtv.2013.04.001... ,³⁴34 van Netten JJ, Bril A, van Baal JG. The effect of flexor tenotomy on healing and prevention of neuropathic diabetic foot ulcers on the distal end of the toe. J Foot Ankle Res. 2013;6(1):3. http://doi.org/10.1186/1757-1146-6-3. PMid:23347589.
http://doi.org/10.1186/1757-1146-6-3... Because these treatments may cause harm when performed inappropriately, they should only be performed by professional, adequately trained health care providers.³¹31 Young MJ, Cavanagh PR, Thomas G, Johnson MM, Murray H, Boulton AJ. The effect of callus removal on dynamic plantar foot pressures in diabetic patients. Diabet Med. 1992;9(1):55-7. http://doi.org/10.1111/j.1464-5491.1992.tb01714.x. PMid:1551311.
http://doi.org/10.1111/j.1464-5491.1992.... ,³²32 Pitei DL, Foster A, Edmonds M. The effect of regular callus removal on foot pressures. J Foot Ankle Surg. 1999;38(4):251-5. http://doi.org/10.1016/S1067-2516(99)80066-0. PMid:10464719.
http://doi.org/10.1016/S1067-2516(99)800...

Chart 3 lists the main care recommendations for patients with diabetic foot.²²22 Bus SA, Lavery LA, Monteiro-Soares M, et al. Guidelines on the prevention of foot ulcers in persons with diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3269. http://doi.org/10.1002/dmrr.3269. PMid:32176451.
http://doi.org/10.1002/dmrr.3269...

4. Ensuring the use of appropriate footwear

All of the patient’s footwear must be clinically assessed for the following characteristics:¹²12 Botros M, Kuhnke J, Embil J, et al. Best practice recommendations for the prevention and management of diabetic foot ulcers. In: Canadian Association of Wound Care, editor. Foundations of best practice for skin and wound management: a supplement of Wound Care Canada. North York, ON: Wounds Canada; 2017. 68 p.

• fit: the toe space must be large enough to avoid pressure and the heel must be firm, but not too tight;

• structure: shoes must have laces/Velcro fasteners; they must not have seams or structures that could result in friction or pressure;

• cushioning;

• general characteristics: shoes must be made of breathable materials, such as leather, to allow moisture to dissipate;

• movement control: shoes must limit excessive pronation (everted foot and arch flattening);

• other: clinicians must confirm that there are no foreign objects inside the shoe;

• never use footwear that has previously caused ulceration.

The footwear of people at moderate or high risk of ulceration (IWGDF risk 2-3) must be adjusted to protect and accommodate the shape of the toes, including adequate length, width, and depth. This may require custom-made shoes, insoles, or orthotics to reduce the risk of ulceration or recurrence (recommendation class I, level of evidence B).³⁵35 Rizzo L, Tedeschi A, Fallani E, et al. Custom-made orthesis and shoes in a structured follow-up program reduces the incidence of neuropathic ulcers in high-risk diabetic foot patients. Int J Low Extrem Wounds. 2012;11(1):59-64. http://doi.org/10.1177/1534734612438729. PMid:22336901.
http://doi.org/10.1177/1534734612438729...

36 Lavery LA, LaFontaine J, Higgins KR, Lanctot DR, Constantinides G. Shear-reducing insoles to prevent foot ulceration in high-risk diabetic patients. Adv Skin Wound Care. 2012;25(11):519-24. http://doi.org/10.1097/01.ASW.0000422625.17407.93. PMid:23080240.
http://doi.org/10.1097/01.ASW.0000422625... -³⁷37 Scirè V, Leporati E, Teobaldi I, Nobili LA, Rizzo L, Piaggesi A. Effectiveness and safety of using Podikon digital silicone padding in the primary prevention of neuropathic lesions in the forefoot of diabetic patients. J Am Podiatr Med Assoc. 2009;99(1):28-34. http://doi.org/10.7547/0980028. PMid:19141719.
http://doi.org/10.7547/0980028...

The benefit of continuously using custom molded shoes or insoles with proven pressure relief outweigh the potential harm.³⁸38 Bus SA, Waaijman R, Arts M, et al. Effect of custom-made footwear on foot ulcer recurrence in diabetes: a multicenter randomized controlled trial. Diabetes Care. 2013;36(12):4109-16. http://doi.org/10.2337/dc13-0996. PMid:24130357.
http://doi.org/10.2337/dc13-0996... ,³⁹39 Ulbrecht JS, Hurley T, Mauger DT, Cavanagh PR. Prevention of recurrent foot ulcers with plantar pressure- based in- shoe orthoses: the CareFUL prevention multicenter randomized controlled trial. Diabetes Care. 2014;37(7):1982-9. http://doi.org/10.2337/dc13-2956. PMid:24760263.
http://doi.org/10.2337/dc13-2956... However, footwear with inadequate length or width increases the risk of ulceration, so a proper fit must be ensured.¹⁸The characteristics of suitable footwear are summarized in Figure 5. A risk stratification protocol for footwear selection is shown in Chart 4.

5. Treating risk factors for ulceration

Any modifiable risk factor or pre-ulcerative sign must be treated. Treatment must be repeated until these anomalies disappear and do not recur. In patients who have recurrent ulcers due to foot deformities despite adhering to the above mentioned preventive measures, surgical intervention should be considered.²²22 Bus SA, Lavery LA, Monteiro-Soares M, et al. Guidelines on the prevention of foot ulcers in persons with diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3269. http://doi.org/10.1002/dmrr.3269. PMid:32176451.
http://doi.org/10.1002/dmrr.3269... Chart 5 summarizes the main measures for controlling the risk of ulceration. Table 4 summarizes the main recommendations from the latest IWGDF consensus.²²22 Bus SA, Lavery LA, Monteiro-Soares M, et al. Guidelines on the prevention of foot ulcers in persons with diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3269. http://doi.org/10.1002/dmrr.3269. PMid:32176451.
http://doi.org/10.1002/dmrr.3269...

CHAPTER 2. RELIEVING PRESSURE ON FOOT ULCERS IN PEOPLE WITH DIABETES

Pressure relief can be achieved with temporary footwear until the ulcer heals and the foot tissues stabilize. Removable or non-removable pressure relief boots can effectively reduce pressure on ulcers in the plantar surface.²⁰20 Bus SA, Armstrong DG, Gooday C, et al. Guidelines on offloading foot ulcers in persons with diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3274. http://doi.org/10.1002/dmrr.3274. PMid:32176441.
http://doi.org/10.1002/dmrr.3274... ,⁴⁹49 Bus SA, van Deursen RW, Armstrong DG, Lewis JE, Caravaggi CF, Cavanagh PR. Footwear and offloading interventions to prevent and heal foot ulcers and reduce plantar pressure in patients with diabetes: a systematic review. Diabetes Metab Res Rev. 2016;32(Suppl 1):99-118. http://doi.org/10.1002/dmrr.2702. PMid:26342178.
http://doi.org/10.1002/dmrr.2702... ,⁵⁰50 Elraiyah T, Prutsky G, Domecq JP, et al. A systematic review and metaanalysis of off-loading methods for diabetic foot ulcers. J Vasc Surg. 2016;63(2, Suppl):59S-68S.e1-2. http://doi.org/10.1016/j.jvs.2015.10.006. PMid:26804369.
http://doi.org/10.1016/j.jvs.2015.10.006...

Although pressure relief casts effectively support the healing of non-infected nonischemic neuropathic plantar ulcers, it is necessary to carefully select patients and personnel with specialized training to minimize the risk of iatrogenic complications.⁵¹51 Oliveira AL, Moore Z. Treatment of the diabetic foot by offloading: a systematic review. J Wound Care. 2015;24(12):560-70. http://doi.org/10.12968/jowc.2015.24.12.560. PMid:26654736.
http://doi.org/10.12968/jowc.2015.24.12....

When a bony deformity of the foot prevents the use of appropriate footwear or relief of pressure-related ulcers, consultation with a foot and ankle surgeon may be considered to evaluate and treat the deformity.⁵²52 Blume PA, Paragas LK, Sumpio BE, Attinger CE. Single-stage surgical treatment of noninfected diabetic foot ulcers. Plast Reconstr Surg. 2002;109(2):601-9. http://doi.org/10.1097/00006534-200202000-00029. PMid:11818842.
http://doi.org/10.1097/00006534-20020200... ,⁵³53 Sayner LR, Rosenblum BI, Giurini JM. Elective surgery of the diabetic foot. Clin Podiatr Med Surg. 2003;20(4):783-92. http://doi.org/10.1016/S0891-8422(03)00073-9. PMid:14636038.
http://doi.org/10.1016/S0891-8422(03)000... Flowchart 1 summarizes pressure relief treatment. Table 5 summarizes the main recommendations from the latest IWGDF consensus.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266...

CHAPTER 3. CLASSIFYING DIABETIC FOOT ULCERS

Introduction

Due to the complexity of factors involved in DFU, there is still no classification system for routine clinical use that encompasses the diverse populations the world.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,⁷⁶76 Monteiro-Soares M, Boyko EJ, Jeffcoate W, et al. Diabetic foot ulcer classifications: a critical review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3272. http://doi.org/10.1002/dmrr.3272. PMid:32176449.
http://doi.org/10.1002/dmrr.3272... In a review, Monteiro-Soares et al.⁷⁶76 Monteiro-Soares M, Boyko EJ, Jeffcoate W, et al. Diabetic foot ulcer classifications: a critical review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3272. http://doi.org/10.1002/dmrr.3272. PMid:32176449.
http://doi.org/10.1002/dmrr.3272... found 37 classifications for DFU. In part, this wide variety is due to different purposes, eg, clinical care, research, and auditing. Clinical care, which concerns limbs and injuries in individual patients, aims to standardize communication between health professionals, establish prognosis, and guide therapeutic approaches. Research and auditing, however, are concerned with limbs and injuries in groups of patients.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,⁷⁶76 Monteiro-Soares M, Boyko EJ, Jeffcoate W, et al. Diabetic foot ulcer classifications: a critical review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3272. http://doi.org/10.1002/dmrr.3272. PMid:32176449.
http://doi.org/10.1002/dmrr.3272... ,⁷⁷77 Game F. Classification of diabetic foot ulcers. Diabetes Metab Res Rev. 2016;32(1, Suppl 1):186-94. http://doi.org/10.1002/dmrr.2746. PMid:26455509.
http://doi.org/10.1002/dmrr.2746... Currently, there is no classification/scoring system for analyzing individual prognosis in people with DFU.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266...

Clinical practice

A consensus classification, scoring system, and description of foot injuries in routine clinical practice would facilitate decision-making and communication between professionals.⁷⁷77 Game F. Classification of diabetic foot ulcers. Diabetes Metab Res Rev. 2016;32(1, Suppl 1):186-94. http://doi.org/10.1002/dmrr.2746. PMid:26455509.
http://doi.org/10.1002/dmrr.2746... Descriptive classifications separate patients into groups but do not necessarily establish prognoses. Scoring systems assign scores to the factors involved in the disease and generally serve to estimate severity and adverse outcomes.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,⁷⁷77 Game F. Classification of diabetic foot ulcers. Diabetes Metab Res Rev. 2016;32(1, Suppl 1):186-94. http://doi.org/10.1002/dmrr.2746. PMid:26455509.
http://doi.org/10.1002/dmrr.2746...

The system used in routine clinical practice, including communication between multidisciplinary health teams, must be simple enough to easily memorize and apply, and it should not require any specialized equipment.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,⁷⁷77 Game F. Classification of diabetic foot ulcers. Diabetes Metab Res Rev. 2016;32(1, Suppl 1):186-94. http://doi.org/10.1002/dmrr.2746. PMid:26455509.
http://doi.org/10.1002/dmrr.2746... The IWGDF recommends the Site, Ischemia, Neuropathy, Bacterial Infection, and Depth (SINBAD) system (recommendation class I, level of evidence B).¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266...

There are only 2 classification systems to aid clinical decision making: IWGDF/IDSA and the Wound, Ischemia, and foot Infection (WIfI) system. Current guidelines recommend WIfI, although the IWGDF/IDSA can be used alone if the equipment required for the WIfI system is unavailable (recommendation class IIb, level of evidence B).¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334.,⁷⁷77 Game F. Classification of diabetic foot ulcers. Diabetes Metab Res Rev. 2016;32(1, Suppl 1):186-94. http://doi.org/10.1002/dmrr.2746. PMid:26455509.
http://doi.org/10.1002/dmrr.2746...

Clinical research

The purpose of a classification system is to identify clinical characteristics for the inclusion or exclusion of patients in studies. Because this is usually done on an experimental basis, only participating centers must agree on the criteria and descriptions.⁷⁷77 Game F. Classification of diabetic foot ulcers. Diabetes Metab Res Rev. 2016;32(1, Suppl 1):186-94. http://doi.org/10.1002/dmrr.2746. PMid:26455509.
http://doi.org/10.1002/dmrr.2746... The Perfusion, Extent, Depth, Infection and Sensation (PEDIS) classification system has refined definitions for prospective research projects, emphasizing reliance on 5 specified criteria: area; depth; infection; neuropathy; and ischemia.⁷⁷77 Game F. Classification of diabetic foot ulcers. Diabetes Metab Res Rev. 2016;32(1, Suppl 1):186-94. http://doi.org/10.1002/dmrr.2746. PMid:26455509.
http://doi.org/10.1002/dmrr.2746...

Clinical auditing

The reasons for auditing can range from a simple description of patient numbers to a search for associations between diseases and outcomes to comparative results between different institutions. These comparisons are essential for optimized clinical management. Because the groups studied in each case can be large, any classification or scoring system must be simple, unambiguous, easily understood, clearly documented without expensive equipment, and accurate enough to be meaningful.⁷⁷77 Game F. Classification of diabetic foot ulcers. Diabetes Metab Res Rev. 2016;32(1, Suppl 1):186-94. http://doi.org/10.1002/dmrr.2746. PMid:26455509.
http://doi.org/10.1002/dmrr.2746... SINBAD is currently the best validated system for auditing and is recommended by the IWGDF (recommendation class IIa, level of evidence C).¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,⁷⁷77 Game F. Classification of diabetic foot ulcers. Diabetes Metab Res Rev. 2016;32(1, Suppl 1):186-94. http://doi.org/10.1002/dmrr.2746. PMid:26455509.
http://doi.org/10.1002/dmrr.2746... Flowchart 2 summarizes DFU classifications according to study objectives.

Rating systems

SINBAD classification

The SINBAD system (described in Table 6) is simple, quick, and easy to use, requiring no specialized equipment other than clinical examination, and contains the necessary information to allow screening by a specialized team. The total score is obtained by summing the points for all important ulcer-related data (scored as 0 or 1). The 6 DFU domains are: area, depth, presence of sepsis, PAD, denervation, and location. Total scores can reach 6 points. This system has been validated for predicting ulcer healing and amputations.⁷⁸78 Monteiro-Soares M, Martins-Mendes D, Vaz-Carneiro A, Dinis-Ribeiro M. Lower-limb amputation following foot ulcers in patients with diabetes: classification systems, external validation and comparative analysis. Diabetes Metab Res Rev. 2015;31(5):515-29. http://doi.org/10.1002/dmrr.2634. PMid:25529456.
http://doi.org/10.1002/dmrr.2634...

79 Forsythe RO, Ozdemir BA, Chemla ES, Jones KG, Hinchliffe RJ. Interobserver reliability of three validated scoring systems in the assessment of diabetic foot ulcers. Int J Low Extrem Wounds. 2016;15(3):213-9. http://doi.org/10.1177/1534734616654567. PMid:27358037.
http://doi.org/10.1177/1534734616654567... -⁸⁰80 Jeon BJ, Choi HJ, Kang JS, Tak MS, Park ES. Comparison of five systems of classification of diabetic foot ulcers and predictive factors for amputation. Int Wound J. 2017;14(3):537-45. http://doi.org/10.1111/iwj.12642. PMid:27723246.
http://doi.org/10.1111/iwj.12642... SINBAD is the most widely validated system in different research contexts and has broadly consistent results.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266...

Infectious Diseases Society of America classification

The Infectious Diseases Society of America (IDSA) guidelines were developed for scientific purposes as part of the PEDIS classification system and to identify patients in need of hospital admission for antibiotic therapy. They were later validated for assessing the risk of major and minor amputation. The IDSA system consists of 4 severity levels for DFU and infection, as shown in Table 7.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266...

WIfI System

Published in 2014, the WIfI (wound, ischemia, and foot infection) system was designed to classify at-risk limbs. It stratifies the risk of major amputation within 1 year and predicts whether revascularization will be necessary for wound healing and limb salvage.⁸¹81 Mills JL Sr, Conte MS, Armstrong DG, et al. The Society for Vascular Surgery lower extremity threatened limb classification system: risk stratification based on wound, ischemia, and foot infection (WIfI). J Vasc Surg. 2014;59(1):220- 34.e1-2. http://doi.org/10.1016/j.jvs.2013.08.003. PMid:24126108.
http://doi.org/10.1016/j.jvs.2013.08.003... The Global Vascular Guidelines, published in 2019, recommend using the WIfI classification analogously to the Malignant Tumor Classification system for cancer staging to analyze the at-risk limb.¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334. It is the classification of choice for patients with DFU according to the latest IWGDF guidelines, which were also published in 2019.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... WIfI has been validated on several continents, including in specific groups with DFU.⁸²82 Mathioudakis N, Hicks CW, Canner JK, et al. The Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification system predicts wound healing but not major amputation in patients with diabetic foot ulcers treated in a multidisciplinary setting. J Vasc Surg. 2017;65(6):1698-705.e1. http://doi.org/10.1016/j.jvs.2016.12.123. PMid:28274750.
http://doi.org/10.1016/j.jvs.2016.12.123...

83 Hicks CW, Canner JK, Karagozlu H, et al. The Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification system correlates with cost of care for diabetic foot ulcers treated in a multidisciplinary setting. J Vasc Surg. 2018;67(5):1455-62. http://doi.org/10.1016/j.jvs.2017.08.090. PMid:29248237.
http://doi.org/10.1016/j.jvs.2017.08.090... -⁸⁴84 Hicks CW, Canner JK, Mathioudakis N, et al. The Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification independently predicts wound healing in diabetic foot ulcers. J Vasc Surg. 2018;68(4):1096-103. http://doi.org/10.1016/j.jvs.2017.12.079. PMid:29622357.
http://doi.org/10.1016/j.jvs.2017.12.079... It has been used in large multicenter trials, such as BEST-CLI, BEST-CLI2, BASIL-2, and BASIL-3, and has high levels of interobserver and intraobserver reproducibility.⁸⁵85 Tokuda T, Hirano K, Sakamoto Y, et al. Use of the wound, ischemia, foot infection classification system in hemodialysis patients after endovascular treatment for critical limb ischemia. J Vasc Surg. 2018;67(6):1762-8. http://doi.org/10.1016/j.jvs.2017.09.037. PMid:29224944.
http://doi.org/10.1016/j.jvs.2017.09.037...

The system’s purpose is to provide a more accurate description of the main factors that lead to non-healing and limb loss, as well as to assist in decision-making in clinical practice.⁷⁶76 Monteiro-Soares M, Boyko EJ, Jeffcoate W, et al. Diabetic foot ulcer classifications: a critical review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3272. http://doi.org/10.1002/dmrr.3272. PMid:32176449.
http://doi.org/10.1002/dmrr.3272... WIfI does not require quantifying the wound area or determining the presence of neuropathy, but specific equipment is needed to measure pressures and ischemic indices.⁷⁶76 Monteiro-Soares M, Boyko EJ, Jeffcoate W, et al. Diabetic foot ulcer classifications: a critical review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3272. http://doi.org/10.1002/dmrr.3272. PMid:32176449.
http://doi.org/10.1002/dmrr.3272... ,⁷⁷77 Game F. Classification of diabetic foot ulcers. Diabetes Metab Res Rev. 2016;32(1, Suppl 1):186-94. http://doi.org/10.1002/dmrr.2746. PMid:26455509.
http://doi.org/10.1002/dmrr.2746...

The system consists of 3 components: wound extent, the presence of ischemia, and the degree of foot infection. Wound extent is evaluated using improved criteria from the University of Texas classification, which, depending on the degree, also correlates with the expected type of surgery. The foot infection classification system, which is the same as that used by the IDSA, predicts amputation risk and has been validated for DFUs. The degree of ischemia is determined using pressures and indices to objectively assess foot perfusion and healing potential without revascularization.⁸⁰80 Jeon BJ, Choi HJ, Kang JS, Tak MS, Park ES. Comparison of five systems of classification of diabetic foot ulcers and predictive factors for amputation. Int Wound J. 2017;14(3):537-45. http://doi.org/10.1111/iwj.12642. PMid:27723246.
http://doi.org/10.1111/iwj.12642... Through a Delphi consensus, the Society for Vascular Surgery committee responsible for the Global Vascular Guidelines on the Management of Chronic Limb-threatening Ischemia created a score for foot wounds, ischemia, and infection in relation to the 1-year risk of limb amputation (very low, low, moderate, or high), assigning a risk of intervention for each possible combinations of scores.¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334.,⁷⁶76 Monteiro-Soares M, Boyko EJ, Jeffcoate W, et al. Diabetic foot ulcer classifications: a critical review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3272. http://doi.org/10.1002/dmrr.3272. PMid:32176449.
http://doi.org/10.1002/dmrr.3272... Tables 8, 9 and 10 detail the WIfI classification system.

PEDIS classification

PEDIS was developed as a descriptive classification system for research, aiming to define DFU and facilitate communication between health services – but not for prognostic purposes. It does not include patient characteristics or the location or number of ulcers. Although mainly designed for research, its use in clinical practice and auditing is not ruled out. PEDIS classifies diabetic foot ulcers into 5 categories of impairment: perfusion, extension, tissue depth/loss, infection, and sensitivity (described in Table 11).⁷⁶76 Monteiro-Soares M, Boyko EJ, Jeffcoate W, et al. Diabetic foot ulcer classifications: a critical review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3272. http://doi.org/10.1002/dmrr.3272. PMid:32176449.
http://doi.org/10.1002/dmrr.3272... ,⁷⁷77 Game F. Classification of diabetic foot ulcers. Diabetes Metab Res Rev. 2016;32(1, Suppl 1):186-94. http://doi.org/10.1002/dmrr.2746. PMid:26455509.
http://doi.org/10.1002/dmrr.2746...

Table 12 summarizes the recommendations of international guidelines about the use of classification systems.

CHAPTER 4. THE DIABETIC FOOT AND PERIPHERAL ARTERIAL DISEASE

Introduction

Diabetes is a strong risk factor for PAD, including the development of more diffuse, multisegmental, and predominantly distal arterial disease. These factors increase the complexity of treatment and are associated with a worse prognosis.⁹³93 Schönborn M, Łączak P, Pasieka P, Borys S, Płotek A, Maga P. Pro- and anti-angiogenic factors: their relevance in diabetic foot syndrome: a review. Angiology. 2022;73(4):299-311. http://doi.org/10.1177/00033197211042684. PMid:34541892.
http://doi.org/10.1177/00033197211042684...

Epidemiology

PAD is highly prevalent in diabetic patients, affecting approximately 25% of those aged > 60 years.⁹⁴94 Ostchega Y, Paulose-Ram R, Dillon CF, Gu Q, Hughes JP. Prevalence of peripheral arterial disease and risk factors in persons aged 60 and older: data from the National Health and nutrition examination survey 1999-2004. J Am Geriatr Soc. 2007;55(4):583-9. http://doi.org/10.1111/j.1532-5415.2007.01123.x. PMid:17397438.
http://doi.org/10.1111/j.1532-5415.2007.... Stoberock et al.⁹⁵95 Stoberock K, Kaschwich M, Nicolay SS, et al. The interrelationship between diabetes mellitus and peripheral arterial disease. Vasa. 2021;50(5):323-30. http://doi.org/10.1024/0301-1526/a000925. PMid:33175668.
http://doi.org/10.1024/0301-1526/a000925... found that the prevalence of PAD varies from 20%-50% and 10%-26% in people with and without diabetes, respectively. The coexistence of DM and PAD (ankle-brachial index [ABI] < 0.9) is associated with a 2- to 4-fold increase in mortality.⁹⁶96 Aboyans V, Björck M, Brodmann M, et al. Questions and answers on diagnosis and management of patients with Peripheral Arterial Diseases: a companion document of the 2017 ESC Guidelines for the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Endorsed by: the European Stroke Organisation (ESO)The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS). Eur Heart J. 2018;39(9):e35-41. http://doi.org/10.1093/eurheartj/ehx499. PMid:29088383.
http://doi.org/10.1093/eurheartj/ehx499...

PAD affects up to 50% of patients with DFU and is associated with poor prognosis, such as amputation (5-24%), ulcer persistence (10-15%), ulcer recurrence, increased hospital admissions, reduced quality of life, and increased mortality.⁹⁷97 Forsythe RO, Apelqvist J, Boyko EJ, et al. Effectiveness of bedside investigations to diagnose peripheral artery disease among people with diabetes mellitus: a systematic review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3277. http://doi.org/10.1002/dmrr.3277. PMid:32176448.
http://doi.org/10.1002/dmrr.3277...

98 Soyoye DO, Abiodun OO, Ikem RT, Kolawole BA, Akintomide AO. Diabetes and peripheral artery disease: a review. World J Diabetes. 2021;12(6):827-38. http://doi.org/10.4239/wjd.v12.i6.827. PMid:34168731.
http://doi.org/10.4239/wjd.v12.i6.827...

99 Gazzaruso C, Montalcini T, Gallotti P, et al. Impact of microvascular complications on the outcomes of diabetic foot in type 2 diabetic patients with documented peripheral artery disease. Endocrine. 2023;80(1):71-8. http://doi.org/10.1007/s12020-022-03291-6. PMid:36565405.
http://doi.org/10.1007/s12020-022-03291-... -¹⁰⁰100 Jeong D, Lee JH, Lee GB, et al. Application of extracorporeal shockwave therapy to improve microcirculation in diabetic foot ulcers: a prospective study. Medicine. 2023;102(11):e33310. http://doi.org/10.1097/MD.0000000000033310. PMid:36930075.
http://doi.org/10.1097/MD.00000000000333... Patients with DFU and PAD have an estimated 5-year mortality of 50%. This grim prognosis is largely attributable to the systemic nature of arterial disease. Furthermore, patients with ischemic and neuroischemic DFU have a higher risk of all-cause mortality than diabetic patients without DFU or with neuropathic DFU.⁹⁵95 Stoberock K, Kaschwich M, Nicolay SS, et al. The interrelationship between diabetes mellitus and peripheral arterial disease. Vasa. 2021;50(5):323-30. http://doi.org/10.1024/0301-1526/a000925. PMid:33175668.
http://doi.org/10.1024/0301-1526/a000925... ,¹⁰¹101 Forsythe RO, Apelqvist J, Boyko EJ, et al. Effectiveness of revascularisation of the ulcerated foot in patients with diabetes and peripheral artery disease: a systematic review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3279. http://doi.org/10.1002/dmrr.3279. PMid:32176439.
http://doi.org/10.1002/dmrr.3279...

Pathophysiology and risk factors for peripheral arterial disease in diabetic patients

PAD develops in diabetes through a complex interaction of hemodynamic, metabolic, and neurohormonal factors, which, through different mechanisms, produce endothelial and smooth muscle cell dysfunction, abnormalities in hemostasis and blood viscosity, chronic inflammation, accumulation of glycation end-products, and oxidative stress.¹⁰²102 Azhar A, Basheer M, Abdelgawad MS, Roshdi H, Kamel MF. Prevalence of peripheral arterial disease in diabetic foot ulcer patients and its impact in limb salvage. Int J Low Extrem Wounds. 2023;22(3):518-23. PMid:34142882.,¹⁰³103 Spiliopoulos S, Festas G, Paraskevopoulos I, Mariappan M, Brountzos E. Overcoming ischemia in the diabetic foot: minimally invasive treatment options. World J Diabetes. 2021;12(12):2011-26. http://doi.org/10.4239/wjd.v12.i12.2011. PMid:35047116.
http://doi.org/10.4239/wjd.v12.i12.2011... In order of importance, the main risk factors for PAD are smoking, DM, arterial hypertension, and hypercholesterolemia. However, other associations have been described, particularly in DM patients, such as disease duration, high levels of glycosylated hemoglobin, abdominal obesity, male sex, and neuropathy.⁹⁸98 Soyoye DO, Abiodun OO, Ikem RT, Kolawole BA, Akintomide AO. Diabetes and peripheral artery disease: a review. World J Diabetes. 2021;12(6):827-38. http://doi.org/10.4239/wjd.v12.i6.827. PMid:34168731.
http://doi.org/10.4239/wjd.v12.i6.827...

Macro- and microvascular manifestations in diabetic patients

Macrovascular manifestation of atherosclerotic disease in DM is generally bilateral and tends to involve arteries in the infrapopliteal segment. Concomitant femoropopliteal involvement is also common and has the same incidence in the non-diabetic population, while involvement of the iliac segment, especially in isolation, is less frequent.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁰³103 Spiliopoulos S, Festas G, Paraskevopoulos I, Mariappan M, Brountzos E. Overcoming ischemia in the diabetic foot: minimally invasive treatment options. World J Diabetes. 2021;12(12):2011-26. http://doi.org/10.4239/wjd.v12.i12.2011. PMid:35047116.
http://doi.org/10.4239/wjd.v12.i12.2011... It is also common for diabetic patients to have an incomplete plantar arch and a higher risk of PAD, including a palpable tibial pulse, which can evolve into ulcerations and gangrene in the toes.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... The lesions have multisegmental characteristics with long occlusions, a reduced collateral network, and extensive arterial calcification.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁰¹101 Forsythe RO, Apelqvist J, Boyko EJ, et al. Effectiveness of revascularisation of the ulcerated foot in patients with diabetes and peripheral artery disease: a systematic review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3279. http://doi.org/10.1002/dmrr.3279. PMid:32176439.
http://doi.org/10.1002/dmrr.3279... They affect younger individuals, presenting a rapid clinical course with greater tissue loss and risk of amputation, and have a high recurrence rate after revascularization.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁰³103 Spiliopoulos S, Festas G, Paraskevopoulos I, Mariappan M, Brountzos E. Overcoming ischemia in the diabetic foot: minimally invasive treatment options. World J Diabetes. 2021;12(12):2011-26. http://doi.org/10.4239/wjd.v12.i12.2011. PMid:35047116.
http://doi.org/10.4239/wjd.v12.i12.2011... ,¹⁰⁴104 Meloni M, Morosetti D, Giurato L, et al. Foot revascularization avoids major amputation in persons with diabetes and ischaemic foot ulcers. J Clin Med. 2021;10(17):3977. http://doi.org/10.3390/jcm10173977. PMid:34501432.
http://doi.org/10.3390/jcm10173977...

The microvascular system includes capillaries and arterioles (up to ≈100 um) and is essential for maintaining tissue homeostasis, providing oxygen and nutrients for wound healing. It allows angiogenesis and hormonal signaling and participates in the regulation of systemic blood pressure.⁹⁹99 Gazzaruso C, Montalcini T, Gallotti P, et al. Impact of microvascular complications on the outcomes of diabetic foot in type 2 diabetic patients with documented peripheral artery disease. Endocrine. 2023;80(1):71-8. http://doi.org/10.1007/s12020-022-03291-6. PMid:36565405.
http://doi.org/10.1007/s12020-022-03291-... ,¹⁰⁵105 Behroozian A, Beckman JA. Microvascular disease increases amputation in patients with peripheral artery disease. Arterioscler Thromb Vasc Biol. 2020;40(3):534-40. http://doi.org/10.1161/ATVBAHA.119.312859. PMid:32075418.
http://doi.org/10.1161/ATVBAHA.119.31285... Microvascular dysfunction is characterized by an imbalance between blood flow and vascular tone, resulting in compromised oxygen supply to tissue, increased oxidative stress, impaired healing, and target organ damage.¹⁰⁵105 Behroozian A, Beckman JA. Microvascular disease increases amputation in patients with peripheral artery disease. Arterioscler Thromb Vasc Biol. 2020;40(3):534-40. http://doi.org/10.1161/ATVBAHA.119.312859. PMid:32075418.
http://doi.org/10.1161/ATVBAHA.119.31285... Among the main microvascular complications (polyneuropathy, nephropathy, and retinopathy), retinopathy appears to have a greater correlation with wound healing failure, minor amputation, and mortality.⁹⁹99 Gazzaruso C, Montalcini T, Gallotti P, et al. Impact of microvascular complications on the outcomes of diabetic foot in type 2 diabetic patients with documented peripheral artery disease. Endocrine. 2023;80(1):71-8. http://doi.org/10.1007/s12020-022-03291-6. PMid:36565405.
http://doi.org/10.1007/s12020-022-03291-... Thus, microvascular disease has been proposed as a risk factor for both PAD progression and amputation.⁹⁹99 Gazzaruso C, Montalcini T, Gallotti P, et al. Impact of microvascular complications on the outcomes of diabetic foot in type 2 diabetic patients with documented peripheral artery disease. Endocrine. 2023;80(1):71-8. http://doi.org/10.1007/s12020-022-03291-6. PMid:36565405.
http://doi.org/10.1007/s12020-022-03291-...

Although some authors assert that these microangiopathy mechanisms affect healing, no concrete evidence currently supports such a hypothesis, which prevents extrapolation to clinical practice. Therefore, PAD continues to be the most important cause of perfusion deficit in diabetic patients, and microvascular disease should not preclude recommending limb revascularization.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266...

Diagnosis

The diagnosis, prognosis, and treatment of diabetic patients with PAD are markedly different from those without PAD. No clinical signs or symptoms accurately exclude PAD in patients with DM.⁹⁷97 Forsythe RO, Apelqvist J, Boyko EJ, et al. Effectiveness of bedside investigations to diagnose peripheral artery disease among people with diabetes mellitus: a systematic review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3277. http://doi.org/10.1002/dmrr.3277. PMid:32176448.
http://doi.org/10.1002/dmrr.3277... Approximately 50% of patients are asymptomatic,10% have symptoms of intermittent claudication, and PAD can remain subclinical until patients experience severe tissue loss.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,⁹⁷97 Forsythe RO, Apelqvist J, Boyko EJ, et al. Effectiveness of bedside investigations to diagnose peripheral artery disease among people with diabetes mellitus: a systematic review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3277. http://doi.org/10.1002/dmrr.3277. PMid:32176448.
http://doi.org/10.1002/dmrr.3277... The lack of symptoms may be related to polyneuropathy and loss of pain sensitivity.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... Early identification of PAD is essential in patients with DFU, since arterial involvement is associated with a greater risk of ulcers that do not heal, infection, and amputation, as well as increased cardiovascular morbidity and mortality.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... Ischemic ulceration generally affects the forefoot and toes, but other areas may be affected in patients with diabetic neuropathy, altered biomechanics, or foot deformities. Therefore, all patients presenting signs or symptoms of PAD should undergo complete vascular assessment.¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334.

Anamnesis should be directed towards PAD risk factors, such as hypertension, dyslipidemia, smoking, obesity, DM duration, and manifestations of atherosclerotic disease, such as cerebrovascular and coronary disease. Patients who have had diabetes > 10 years are more prone to PAD.⁹⁸98 Soyoye DO, Abiodun OO, Ikem RT, Kolawole BA, Akintomide AO. Diabetes and peripheral artery disease: a review. World J Diabetes. 2021;12(6):827-38. http://doi.org/10.4239/wjd.v12.i6.827. PMid:34168731.
http://doi.org/10.4239/wjd.v12.i6.827... Microvascular disease mainly affects the retinal vessels (eg, amaurosis), glomerular vessels (eg, renal failure), and those that nourish peripheral nerves (vasa nervosarum), causing sensory, motor, and autonomic polyneuropathy.¹⁰⁶106 Ferreira RC. Diabetic foot. Part 1: ulcers and infections. Rev Bras Ortop. 2020;55(4):389-96. PMid:32968329.

Ischemic pain at rest affects the forefoot and often increases with recumbency, although it is relieved when the limb is hanging. It lasts > 2 weeks and must be associated with one or more altered hemodynamic parameters (ABI < 0.4; ankle systolic pressure [ASP] < 50 mmHg; toe systolic pressure [TSP] < 30 mmHg; transcutaneous oxygen pressure [PtcO₂ ] < 30 mmHg and flat or minimal pulse waves). Pressure measurements must be correlated with arterial Doppler waveforms due to medial calcinosis.¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334.

All patients suspected of PAD should undergo a thorough physical examination. Although non-specific, characteristics such as coldness, skin xerosis, muscular atrophy, and rarified or dystrophic nails are frequently observed in patients with PAD.¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334.,⁹⁸98 Soyoye DO, Abiodun OO, Ikem RT, Kolawole BA, Akintomide AO. Diabetes and peripheral artery disease: a review. World J Diabetes. 2021;12(6):827-38. http://doi.org/10.4239/wjd.v12.i6.827. PMid:34168731.
http://doi.org/10.4239/wjd.v12.i6.827... However, autonomic and motor polyneuropathy can manifest with some of these integumentary and muscle changes, respectively. The foot’s temperature may be relatively warm due to dysautonomia or arteriovenous shunts, which mask the signs of an ischemic limb.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... Patients with suspected PAD should not be examined while sitting in a chair with their leg hanging, since this may lead to false interpretations regarding foot perfusion.¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334. Buerger’s sign, pallor in an elevated foot, redness in a hanging one, and a capillary refill time > 5 seconds are also signs of a limb with arterial insufficiency.¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334.

Although foot pulse palpation is part of the initial workup, the results should not be used in isolation to exclude PAD in patients with DM. Even when assessed by experienced professionals, a palpable pulse may be present in limbs with significant ischemia.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... A systematic review demonstrated that foot pulse palpation had a sensitivity of 55% and specificity of 60% for PAD diagnosis.⁹⁷97 Forsythe RO, Apelqvist J, Boyko EJ, et al. Effectiveness of bedside investigations to diagnose peripheral artery disease among people with diabetes mellitus: a systematic review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3277. http://doi.org/10.1002/dmrr.3277. PMid:32176448.
http://doi.org/10.1002/dmrr.3277... Therefore, a more objective assessment should be performed in all patients with DFU.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266...

Bedside diagnostic tests may lose accuracy due to peripheral neuropathy, arterial calcification, or peripheral edema.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... There is still no ideal test or defined cut-off value that safely excludes PAD. It is recommended to use more than 1 test in parallel to increase diagnostic accuracy.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,⁹⁷97 Forsythe RO, Apelqvist J, Boyko EJ, et al. Effectiveness of bedside investigations to diagnose peripheral artery disease among people with diabetes mellitus: a systematic review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3277. http://doi.org/10.1002/dmrr.3277. PMid:32176448.
http://doi.org/10.1002/dmrr.3277... In most patients with DFU, the Doppler wave shape of the distal arteries should be assessed in combination with ASP and ABI or with toe systolic pressure (TSP) measurement and the toe/brachial index (TBI). PAD is less likely with an ABI of 0.9-1.3, TBI ≥ 0.75, and a triphasic Doppler waveform (recommendation class I, level of evidence C). However, if there is uncertainty or an unfavorable clinical course, the investigation should be complemented with imaging exams.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... Alternative tests that may also be useful when investigating DFU include: pulse oximetry, pulse volume, photoplethysmography, transcutaneous oxygen tension, and skin perfusion pressure.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334.

Ankle-brachial index

Peripheral (autonomic) neuropathy associated with calcification of the tunica media (Mönckeberg sclerosis) in the distal arteries makes them rigid and incompressible, and can even result in a falsely elevated ABI (between 0.4 and 1.4). This phenomenon should be suspected when the ABI is near or within normal range, but is associated with abnormal (damped) monophasic waveforms, which can be recognized acoustically or visually on a monitor. False-normal ASP and ABI values have been reported as independent predictors of major amputation.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334. Detection of a triphasic arterial waveform with a handheld Doppler ultrasound device appears to provide stronger evidence for ruling out PAD. Although an ABI < 0.9 is useful for detecting PAD, results > 0.9 do not exclude PAD.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,⁹⁷97 Forsythe RO, Apelqvist J, Boyko EJ, et al. Effectiveness of bedside investigations to diagnose peripheral artery disease among people with diabetes mellitus: a systematic review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3277. http://doi.org/10.1002/dmrr.3277. PMid:32176448.
http://doi.org/10.1002/dmrr.3277...

ABI may be more useful for diagnosing PAD in patients with intact feet, but it is less useful for ruling out PAD in patients with foot neuropathy or DFU (sensitivity 69.5% vs 80.7%; specificity 74% vs 91.5%). Thus, it should not be used in isolation to rule out PAD in DFU patients.⁹⁷97 Forsythe RO, Apelqvist J, Boyko EJ, et al. Effectiveness of bedside investigations to diagnose peripheral artery disease among people with diabetes mellitus: a systematic review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3277. http://doi.org/10.1002/dmrr.3277. PMid:32176448.
http://doi.org/10.1002/dmrr.3277...

Toe systolic pressure and toe/brachial index

Digital arteries are often spared the extensive calcification that occurs in tibial arteries, so their flow measurement more accurately reflects foot perfusion in people with DM.¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334. TSP measurement is recommended whenever falsely elevated ASP or ABI are detected or suspected, especially when the values do not agree with acoustic or visual analysis of the waveform.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334.,⁹⁷97 Forsythe RO, Apelqvist J, Boyko EJ, et al. Effectiveness of bedside investigations to diagnose peripheral artery disease among people with diabetes mellitus: a systematic review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3277. http://doi.org/10.1002/dmrr.3277. PMid:32176448.
http://doi.org/10.1002/dmrr.3277...

TSP is measured using a specific cuff that is placed around the base of the great toe and is connected to a standard pressure gauge. A photoplethysmographic or continuous wave Doppler flow detector is then used to determine the flow return after cuff deflation.¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334. TSP is generally 20-40 mmHg less than ASP. TBI < 0.7 is considered abnormal, and TSP < 30 mm Hg is associated with advanced ischemia.¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334. TSP < 50 mmHg has excellent diagnostic ability in patients with DFU, but normal TSP has not been considered accurate enough to rule out diagnosis.⁹⁷97 Forsythe RO, Apelqvist J, Boyko EJ, et al. Effectiveness of bedside investigations to diagnose peripheral artery disease among people with diabetes mellitus: a systematic review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3277. http://doi.org/10.1002/dmrr.3277. PMid:32176448.
http://doi.org/10.1002/dmrr.3277... PAD is unlikely if the TBI is ≥ 0.75. TBI and waveform analysis in the tibial arteries (measured at the medial malleolus, dorsum of the foot, and mid-calf for the peroneal artery) are the most useful non-invasive screening tests for patients who require additional diagnostic imaging.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266...

Audible handheld Doppler: analysis

A validation study to determine the usefulness of audible handheld Doppler ultrasound¹⁰⁷107 Alavi A, Sibbald RG, Nabavizadeh R, Valaei F, Coutts P, Mayer D. Audible handheld Doppler ultrasound determines reliable and inexpensive exclusion of significant peripheral arterial disease. Vascular. 2015;23(6):622-9. http://doi.org/10.1177/1708538114568703. PMid:25628222.
http://doi.org/10.1177/1708538114568703... examined 200 patients (379 legs). The ABI and TSP of all patients was measured in certified vascular laboratories. Audible handheld Doppler signals were sufficiently sensitive to rule out PAD (98.6% posterior tibial, 97.8% dorsalis pedis), but not sufficiently specific to diagnose it (37.5% posterior tibial, 30.19% dorsalis pedis). The test is simple, quick, and can serve as an alternative to ABI. Audible handheld Doppler results (ABI > 0.9) are identified as biphasic or triphasic. If a monophasic waves or no sound is detected, duplex Doppler ultrasound of the entire limb should be ordered.¹²12 Botros M, Kuhnke J, Embil J, et al. Best practice recommendations for the prevention and management of diabetic foot ulcers. In: Canadian Association of Wound Care, editor. Foundations of best practice for skin and wound management: a supplement of Wound Care Canada. North York, ON: Wounds Canada; 2017. 68 p.

Transcutaneous oxygen pressure

PtcO₂ allows microvascular assessment and can also reflect the perfusion of large and small vessels.¹⁰⁸108 Lv Y, Yang Z, Xiang L, et al. Lower limb arterial ischemia: an independent risk factor of sudomotor dysfunction in type 2 diabetes. Diabetes Metab Syndr Obes. 2023;16:883-91. http://doi.org/10.2147/DMSO.S402797. PMid:37012930.
http://doi.org/10.2147/DMSO.S402797... The sensitivity of PtcO₂ appears to be better than ASP (82% vs 67%) in intact feet.¹⁰⁹109 Faglia E, Clerici G, Caminiti M, Quarantiello A, Curci V, Somalvico F. Evaluation of feasibility of ankle pressure and foot oxymetry values for the detection of critical limb ischemia in diabetic patients. Vasc Endovascular Surg. 2010;44(3):184-9. http://doi.org/10.1177/1538574409359430. PMid:20181612.
http://doi.org/10.1177/1538574409359430... However, the sensitivity of both PtcO₂ and ASP is reduced in patients with DFU (28% vs 47%, respectively), having low diagnostic value in such cases.¹¹⁰110 Vriens B, D’Abate F, Ozdemir BA, et al. Clinical examination and non- invasive screening tests in the diagnosis of peripheral artery disease in people with diabetes-related foot ulceration. Diabet Med. 2018;35(7):895-902. http://doi.org/10.1111/dme.13634. PMid:29633431.
http://doi.org/10.1111/dme.13634... However, it should be noted that PtcO₂ decreases only when reductions in macrovascular arterial perfusion are so critical that they reduce tissue oxygen supply.¹⁰⁸108 Lv Y, Yang Z, Xiang L, et al. Lower limb arterial ischemia: an independent risk factor of sudomotor dysfunction in type 2 diabetes. Diabetes Metab Syndr Obes. 2023;16:883-91. http://doi.org/10.2147/DMSO.S402797. PMid:37012930.
http://doi.org/10.2147/DMSO.S402797... This phenomenon occurs through microvascular compensatory mechanisms of hyperemia in ischemic limbs, maintaining a curvilinear relationship between PtcO₂ values and local perfusion pressures sufficient to maintain normal tissue oxygenation.¹⁰⁸108 Lv Y, Yang Z, Xiang L, et al. Lower limb arterial ischemia: an independent risk factor of sudomotor dysfunction in type 2 diabetes. Diabetes Metab Syndr Obes. 2023;16:883-91. http://doi.org/10.2147/DMSO.S402797. PMid:37012930.
http://doi.org/10.2147/DMSO.S402797...

Pulse oximetry

Pulse oximetry is an attractive technique due to its low cost and device availability in most health care settings, although its applicability is still limited by a lack of scientific evidence about PAD diagnosis in patients with DFU. The measurement considers toe saturation < 2% less than finger saturation or a toe saturation increase > 2% when the leg is elevated 12 inches above the horizontal plane.⁹⁷97 Forsythe RO, Apelqvist J, Boyko EJ, et al. Effectiveness of bedside investigations to diagnose peripheral artery disease among people with diabetes mellitus: a systematic review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3277. http://doi.org/10.1002/dmrr.3277. PMid:32176448.
http://doi.org/10.1002/dmrr.3277...

Overall, there is not yet enough evidence to recommend a single bedside test to reliably rule out PAD in patients with DFU. Normal ABI (or a palpable pulse) cannot reliably rule out PAD. A second test should be performed, such as Doppler waveform assessment, possibly in combination with TSP and TBI measurement. Pulse oximetry could become an attractive alternative if confirmed in future studies.⁹⁷97 Forsythe RO, Apelqvist J, Boyko EJ, et al. Effectiveness of bedside investigations to diagnose peripheral artery disease among people with diabetes mellitus: a systematic review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3277. http://doi.org/10.1002/dmrr.3277. PMid:32176448.
http://doi.org/10.1002/dmrr.3277... Bedside tests for probable PAD in diabetic feet are summarized below:⁹⁷97 Forsythe RO, Apelqvist J, Boyko EJ, et al. Effectiveness of bedside investigations to diagnose peripheral artery disease among people with diabetes mellitus: a systematic review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3277. http://doi.org/10.1002/dmrr.3277. PMid:32176448.
http://doi.org/10.1002/dmrr.3277...

1. ABI < 0.9 can suggest PAD, but values between 0.9 and 1.3 do not exclude PAD, especially in patients with neuropathy and/or DFU;

2. TBI > 0.75 makes PAD diagnosis less likely;

3. Pulse oximetry results (ie, if toe saturation is < 2% less than finger saturation or increased by > 2% when the leg is elevated 12 inches above the horizontal plane) may suggest PAD or make it less likely;

4. Analysis of the tibial waveform (triphasic/monophasic) can be useful in PAD diagnosis.

Several other noninvasive tests, including laser Doppler flowmetry, skin perfusion pressure, and plethysmography, have been used to assess limb perfusion. However, these tests can be influenced by a variety of confounding factors and are not routinely used in most vascular laboratories around the world.¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334.

Assessing prognosis of ischemic diabetic foot ulcers

Due to the scarce literature, comorbidities in patients with DFU, and the complexity of arterial lesions (infrapopliteal predominance, extensive calcification, reduced collateral network, and long lesions), there is still no single measure to consistently predict healing.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... Diagnostic tests, the WIfI system, and disorder duration can help physicians decide about more detailed arterial study and the need for revascularization (recommendation class I, level of evidence B). Above all, decisions must always be considered in light of the patient’s comorbidities.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334.

Prognostic value of bedside tests

Indicators of a greater probability of healing in patients with PAD and DFU include skin perfusion pressure ≥ 40 mmHg, TSP ≥ 30 mmHg, and PtcO₂ ≥ 25 mmHg (recommendation class I, level of evidence B). Any of these findings increases the probability of healing by at least 25%.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... Indicators of a low probability of healing and an increased risk of amputation are ASP < 50 mmHg, ABI < 0.5, TSP < 30 mmHg, and PtcO₂ < 25 mmHg. Although ABI has little value in healing prognosis, subnormal values are associated with a higher risk of amputation. In these patients, imaging tests are recommended and early revascularization should be considered.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,⁹⁷97 Forsythe RO, Apelqvist J, Boyko EJ, et al. Effectiveness of bedside investigations to diagnose peripheral artery disease among people with diabetes mellitus: a systematic review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3277. http://doi.org/10.1002/dmrr.3277. PMid:32176448.
http://doi.org/10.1002/dmrr.3277...

WIfI classification system

The WIfI system was developed through expert consensus and has since been validated in populations with and without diabetes.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334.,⁸¹81 Mills JL Sr, Conte MS, Armstrong DG, et al. The Society for Vascular Surgery lower extremity threatened limb classification system: risk stratification based on wound, ischemia, and foot infection (WIfI). J Vasc Surg. 2014;59(1):220- 34.e1-2. http://doi.org/10.1016/j.jvs.2013.08.003. PMid:24126108.
http://doi.org/10.1016/j.jvs.2013.08.003... This classification system for foot ulcers, ischemia, and infection, which helps estimate the risk of amputation and the potential benefit of limb revascularization, is recommended by international guidelines.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334. The system is detailed in Chapter 3.

Clinical course

Regardless of the diagnostic test results, imaging studies are recommended and revascularization should be considered in all patients with DFU and PAD if the ulcer does not shrink by approximately 50% within 4-6 weeks, even with ideal treatment (adequate infection control, wound care, and offloading) and no other probable cause of poor healing (recommendation class IIa, level of evidence C).¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334.

Comorbidities

Healing is related to the interaction of perfusion deficit with other characteristics of the patient and the foot, such as tissue loss, infection, mechanical load on the ulcer, and comorbidities (eg, heart failure or end-stage renal disease). Clinical stability and metabolic and infection control are fundamental for the regenerative process.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... Imaging exams and urgent treatment should also be considered in patients with PAD (even with higher pressure levels) when there are other predictors of poor prognosis, such as infection or extensive ulceration.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266...

Arterial imaging tests

High-quality arterial imaging is essential for determining the best method of limb revascularization. Anatomical information from the arterial bed must be obtained to assess the severity and distribution of arterial stenoses or occlusions. Detailed study of the infrapopliteal arteries and feet is essential for patients with DFU.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334.

Color duplex ultrasound

It is recommended to begin the investigation with color duplex ultrasound due to its accessibility, non-invasive nature, and low cost, in addition to using no iodinated contrast medium, no ionizing radiation, and the device’s portability.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334. Arterial circulation in the lower limb can be assessed directly and completely, from the abdomen to the foot. This method provides anatomical detail and a physiological assessment of blood flow, determining the location and extent of the disease, as well as providing information about flow speed and volume. Diffuse multisegmental involvement, extensive calcification, edema, and tissue loss can hamper the quality of the examination.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334. Its main disadvantages are the delay required to perform the examination, its high operator dependence, the fact that it does not produce a map of the arterial bed, and its limited estimation of collateral arterial supply.¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334.

Computed tomography angiography and nuclear magnetic resonance imaging

Computed tomography (CT) angiography has high sensitivity and specificity in the aortoiliac (95% and 96%, respectively) and femoropopliteal (97% and 94%, respectively) segments. Its sensitivity and specificity fall slightly near the infrapopliteal region (95% and 91%, respectively), especially in cases of extensive calcification, which can make it difficult to evaluate smaller arteries.¹¹¹111 Met R, Bipat S, Legemate DA, Reekers JA, Koelemay MJ. Diagnostic performance of computed tomography angi- ography in peripheral arterial disease: a systematic review and meta-analysis. JAMA. 2009;301(4):415-24. http://doi.org/10.1001/jama.301.4.415. PMid:19176443.
http://doi.org/10.1001/jama.301.4.415... Other disadvantages include allergic reactions, contrast-induced nephropathy, and the use of ionizing radiation.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334.

One of the main advantages of nuclear magnetic resonance imaging (MRI) angiography is its use of a contrast agent with low nephrotoxicity (gadolinium) and no ionizing radiation. Disadvantages include stenosis overestimation, difficulty assessing in-stent restenosis, compatibility issues with implanted devices (pacemakers and defibrillators), long image acquisition times, and image artifacts. Its use is limited in patients with claustrophobia, as well as those with severe renal failure (creatinine clearance < 30 mL/min) due to the risk of nephrogenic systemic fibrosis. New non-gadolinic agents, such as ultrasmall paramagnetic iron oxide particles, may be safer in patients with compromised renal function.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334.

To assess arterial disease in leg and foot vessels, neither CT nor nuclear MRI angiography produce complete images with sufficient resolution for therapeutic planning. Thus, the 2019 Global Vascular Guidelines on the Management of Chronic Limb-threatening Ischemia, which have been endorsed by the Society for Vascular Surgery, the European Society for Vascular Surgery, and the World Federation of Vascular Societies, do not recommend CT angiography for detailed study of infrapopliteal disease, which must be investigated by complete diagnostic angiography, including the ankle and foot.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334.

Digital subtraction angiography

Digital subtraction angiography is still considered the gold standard for arterial imaging due to its high spatial resolution, especially for the infrapopliteal territory. Its advantages include allowing treatment during the procedure, while its disadvantages include the use of iodinated contrast and its invasiveness, which can result in complications related to arterial puncture.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334. CO₂ angiography can be used in patients allergic to iodinated contrast and in those with severe chronic kidney disease. Its image quality is lower than iodinated angiography and the image progressively degrades along the leg, although it can still provide useful diagnostic images and it reduces the volume of iodinated contrast.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334.Flowchart 3 summarizes the use of imaging tests in patients with a revascularization plan.

Limb revascularization

The indications for PAD treatment are similar in diabetic and non-diabetic patients: limiting claudication, reducing pain at rest, and reducing tissue loss associated with non-healing ulcers and gangrene.¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334. Approximately 25% of patients with ischemic DFU have no revascularization options, and the major amputation rate due to unsuccessful limb revascularization or to being ineligible for revascularization is 25%-50%.¹⁰¹101 Forsythe RO, Apelqvist J, Boyko EJ, et al. Effectiveness of revascularisation of the ulcerated foot in patients with diabetes and peripheral artery disease: a systematic review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3279. http://doi.org/10.1002/dmrr.3279. PMid:32176439.
http://doi.org/10.1002/dmrr.3279... ,¹¹²112 Zou J, Zhang W, Chen X, Su W, Yu D. Data mining reveal the association between diabetic foot ulcer and peripheral artery disease. Front Public Health. 2022;10:963426. http://doi.org/10.3389/fpubh.2022.963426. PMid:36062083.
http://doi.org/10.3389/fpubh.2022.963426... These individuals are generally characterized by multilevel arterial disease, including high involvement of the arteries of the foot (approximately 75% of cases).¹¹²112 Zou J, Zhang W, Chen X, Su W, Yu D. Data mining reveal the association between diabetic foot ulcer and peripheral artery disease. Front Public Health. 2022;10:963426. http://doi.org/10.3389/fpubh.2022.963426. PMid:36062083.
http://doi.org/10.3389/fpubh.2022.963426... Among diabetic patients, Faglia et al.¹¹³113 Faglia E, Clerici G, Clerissi J, et al. When is a technically successful peripheral angioplasty effective in preventing above-the-ankle amputation in diabetic patients with critical limb ischaemia? Diabet Med. 2007;24(8):823-9. http://doi.org/10.1111/j.1464-5491.2007.02167.x. PMid:17559430.
http://doi.org/10.1111/j.1464-5491.2007.... found that the lack of a patent tibial artery at the end of angioplasty resulted in a 62% amputation rate, compared to 1.7% among patients with at least 1 patent artery to the foot.

The goal of revascularization is to restore direct blood flow to at least 1 artery in the foot, preferably one supplying the anatomical region of the ulcer. Perfusion is the main parameter for DFU healing, amputation level selection, and limb salvage. It should be noted that a delay of more than 2 weeks from DFU diagnosis to revascularization substantially increases the risk of limb loss.¹¹⁴114 Noronen K, Saarinen E, Alback A, Venermo M. Analysis of the elective treatment process for critical limb lschaemia with tissue loss: diabetic patients require rapid revascularisation. Eur J Vasc Endovasc Surg. 2017;53(2):206-13. http://doi.org/10.1016/j.ejvs.2016.10.023. PMid:27889202.
http://doi.org/10.1016/j.ejvs.2016.10.02... However, revascularization must be considered on a case-by-case basis, since the ulcers can heal in up to 50% of patients with DFU and PAD who do not undergo revascularization.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266...

Once PAD has been diagnosed, the need for revascularization will be based on the PLAN concept, in which: P = patient risk, L = limb threat severity (WIfI classification), and AN = anatomic pattern of disease, ie, assessing the extent of arterial disease according to the Global Anatomic Staging System. PLAN assists in treatment selection, from primary amputation to revascularization, and helps determine the best revascularization option (open or endovascular surgery).¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334.

A systematic review found that the limb salvage rate ranges from 70-90% for patients who undergo revascularization (either open or endovascular), with more than 60% of ulcers healed within 1 year.¹¹⁵115 Hinchliffe RJ, Brownrigg JR, Andros G, et al. Effectiveness of revascularization of the ulcerated foot in patients with diabetes and peripheral artery disease: a systematic review. Diabetes Metab Res Rev. 2016;32(1, Suppl 1):136-44. http://doi.org/10.1002/dmrr.2705. PMid:26342204.
http://doi.org/10.1002/dmrr.2705... Even in patients with unfavorable arterial anatomy who undergo ultradistal bypass or inframalleolar angioplasty, limb salvage rates at 1 year have been reported at 86% and 77%.¹⁰¹101 Forsythe RO, Apelqvist J, Boyko EJ, et al. Effectiveness of revascularisation of the ulcerated foot in patients with diabetes and peripheral artery disease: a systematic review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3279. http://doi.org/10.1002/dmrr.3279. PMid:32176439.
http://doi.org/10.1002/dmrr.3279...

Based on current evidence, no technique (endovascular, open, or hybrid) can be considered superior to another. Furthermore, no large randomized studies have determined the most appropriate revascularization methods specifically for patients with DFU and PAD.¹⁰¹101 Forsythe RO, Apelqvist J, Boyko EJ, et al. Effectiveness of revascularisation of the ulcerated foot in patients with diabetes and peripheral artery disease: a systematic review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3279. http://doi.org/10.1002/dmrr.3279. PMid:32176439.
http://doi.org/10.1002/dmrr.3279... Decisions must consider individual factors, such as the morphological distribution of PAD, autogenous vein availability, comorbidities, and surgeon expertise (recommendation class I, level of evidence B).¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334.,¹⁰¹101 Forsythe RO, Apelqvist J, Boyko EJ, et al. Effectiveness of revascularisation of the ulcerated foot in patients with diabetes and peripheral artery disease: a systematic review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3279. http://doi.org/10.1002/dmrr.3279. PMid:32176439.
http://doi.org/10.1002/dmrr.3279...

The Bypass vs Angioplasty in Severe Ischemia of the Leg (BASIL)¹¹⁶116 Adam DJ, Beard JD, Cleveland T, et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet. 2005;366(9501):1925-34. http://doi.org/10.1016/S0140-6736(05)67704-5. PMid:16325694.
http://doi.org/10.1016/S0140-6736(05)677... study compared endovascular intervention with open surgery. Perioperative morbidity was higher in the surgery group, but overall and 1-year amputation-free survival were similar between groups. However, at 2 years, the surgery group was associated with a lower risk of amputation and death. It was concluded that angioplasty should be used first for patients with a life expectancy of ≤ 2 years, and that bypass is preferable when a vein graft is available. However, only a minority of the sample (42%) had DM, there was no subgroup analysis, and the study was not focused on patients with ulcers. Therefore, we cannot extrapolate these findings to patients with DFU and PAD.¹¹⁷117 Conte MS. Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) and the (hoped for) dawn of evidence-based treatment for advanced limb ischemia. J Vasc Surg. 2010;51(5, Suppl):69S-75S. http://doi.org/10.1016/j.jvs.2010.02.001. PMid:20435263.
http://doi.org/10.1016/j.jvs.2010.02.001...

Revascularization should not be performed if there is no realistic chance of ulcer healing or when progression to amputation is inexorable (recommendation class III, level of evidence C). Patients with the following characteristics are not candidates for revascularization: significant frailty, low life expectancy, poor functional status, bedridden, large area of tissue destruction that makes the foot functionally unviable, and unable to undergo rehabilitation after revascularization. In these cases, primary amputation or a palliative approach must be decided upon by the patient and a multidisciplinary team.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁴14 Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33. PMid:31182334.

Angiosome-directed revascularization

In 1987, Taylor & Palmer proposed the concept of the angiosome, a three-dimensional unit of tissue nourished by an artery.¹¹⁸118 Taylor GI, Palmer JH. The vascular territories (angiosomes) of the body: experimental study and clinical applications. Br J Plast Surg. 1987;40(2):113-41. http://doi.org/10.1016/0007-1226(87)90185-8. PMid:3567445.
http://doi.org/10.1016/0007-1226(87)9018... The 3 main vessels (posterior tibial, fibular, and anterior tibial) nourish specific areas of the leg and foot (Figure 6). Hence, the aim is to identify and revascularize the artery that nourishes the specific area of tissue loss (direct revascularization), restoring pulsatile flow directly to the ischemic region, which makes healing more likely. Alternatively, non-angiosome targeted therapy (indirect revascularization) uses a “best vessel” approach, which selects the most suitable target artery, regardless of whether it is related to the area of tissue loss, thus restoring blood flow to the area through collateral vessels.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁰¹101 Forsythe RO, Apelqvist J, Boyko EJ, et al. Effectiveness of revascularisation of the ulcerated foot in patients with diabetes and peripheral artery disease: a systematic review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3279. http://doi.org/10.1002/dmrr.3279. PMid:32176439.
http://doi.org/10.1002/dmrr.3279... ,¹¹⁹119 Alexandrescu V, Sinatra T, Maufroy C. Current issues and interrogations in angiosome wound targeted revascularization for chronic limb threatening ischemia: a review. World J Cardiovasc Dis. 2019;9(3):168-92. http://doi.org/10.4236/wjcd.2019.93016.
http://doi.org/10.4236/wjcd.2019.93016...

Given that patients with DM have a poor network of collateral circulation and typically do not have a complete pedal arch or collateral flow from the peroneal artery to the foot, it seems intuitive that angiosome-directed revascularization would be more effective. Thus, the current consensus is that angiosome-directed revascularization should be performed whenever possible (recommendation class IIb, level of evidence C).¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁰¹101 Forsythe RO, Apelqvist J, Boyko EJ, et al. Effectiveness of revascularisation of the ulcerated foot in patients with diabetes and peripheral artery disease: a systematic review. Diabetes Metab Res Rev. 2020;36(1, Suppl 1):e3279. http://doi.org/10.1002/dmrr.3279. PMid:32176439.
http://doi.org/10.1002/dmrr.3279... However, due to the lack of standardized definitions and to methodological errors, the scientific robustness of the angiosome concept in patients with DM is unknown.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266...

Successful angioplasty of ≥ 1 occluded vessels is not the same as a clinically successful procedure, and before the procedure is completed, blood flow to the ulcerated area must be verified. If possible, opening multiple arteries may be useful, as long ≥ 1 feeds the ischemic area directly.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... The effectiveness of a revascularization procedure should be assessed using objective perfusion measurements, such as: blood pressure skin perfusion > 40 mmHg, TSP > 30 mmHg, or PtcO₂ > 25 mmHg. Since skin oxygen tension increases progressively over a period of several weeks after successful percutaneous transluminal angioplasty, PtcO₂ should be measured at least 1-3 weeks after the procedure.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266...

Extensive debridement or partial amputation of the foot should not be performed until the limb has been revascularized in patients with advanced ischemia, severe tissue loss, or no infection. In patients with severe infection, especially those with systemic inflammatory response syndrome, drainage must be performed before revascularization to control sepsis. As soon as sepsis is controlled and the patient is clinically stable, arterial studies and limb revascularization must be performed as soon as possible. After infection has been controlled and blood flow has been restored, definitive surgery can be performed to make the limb functional.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... Revascularization is another step in DFU treatment and, after the procedure, multidisciplinary follow-up must be guaranteed as part of a comprehensive care plan that addresses immediate infection treatment, ulcer debridement, biomechanical unloading, glycemic control, and comorbidity treatment.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266...

Intensive treatment is needed to reduce cardiovascular risk in these patients, including smoking cessation, hypertension treatment, blood glucose control, and therapy with statins and low-dose antiplatelet agents.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁵15 Chuter V, Quigley F, Tosenovsky P, et al. Australian guideline on diagnosis and management of peripheral artery disease: part of the 2021 Australian evidence-based guidelines for diabetes-related foot disease. J Foot Ankle Res. 2022;15(1):51. http://doi.org/10.1186/s13047-022-00550-7. PMid:35787293.
http://doi.org/10.1186/s13047-022-00550-... Young et al.¹²⁰120 Young MJ, McCardle JE, Randall LE, Barclay JI. Improved survival of diabetic foot ulcer patients 1995-2008: possible impact of aggressive cardiovascular risk management. Diabetes Care. 2008;31(11):2143-7. http://doi.org/10.2337/dc08-1242. PMid:18697900.
http://doi.org/10.2337/dc08-1242... found that an aggressive approach to cardiovascular risk management reduced mortality in patients with neuroischemic DFU (5-year mortality decreased from 58% to 36%, with a 38% relative risk reduction). No specific evidence supports a single most appropriate antiplatelet agent or a combination of new direct oral anticoagulants in patients with PAD and DFU.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... Some studies have found that cardiovascular outcomes are lower in patients with PAD who use clopidogrel rather than acetylsalicylic acid.¹²¹121 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348(9038):1329-39. http://doi.org/10.1016/S0140-6736(96)09457-3. PMid:8918275.
http://doi.org/10.1016/S0140-6736(96)094... ,¹²²122 Hiatt WR, Fowkes FG, Heizer G, et al. Ticagrelor versus clopidogrel in symptom- atic peripheral artery disease. N Engl J Med. 2017;376(1):32-40. http://doi.org/10.1056/NEJMoa1611688. PMid:27959717.
http://doi.org/10.1056/NEJMoa1611688... A meta-analysis of the COMPASS and VOYAGER trials found that low-dose rivaroxaban plus aspirin was superior to aspirin alone for reducing cardiovascular and limb outcomes, although it led to a relative increase in non-fatal major bleeding. This review concluded that the combination is beneficial for patients with PAD. However, the number of diabetic patients was limited (40-47%), few had an at-risk limb (2.8-31.8%), no information was provided about ulceration in the limb, and there was no subgroup analysis of patients with DFU and PAD.¹²³123 Anand SS, Hiatt W, Dyal L, et al. Low-dose rivaroxaban and aspirin among patients with peripheral artery disease: a meta-analysis of the COMPASS and VOYAGER trials. Eur J Prev Cardiol. 2022;29(5):e181-9. http://doi.org/10.1093/eurjpc/zwab128. PMid:34463737.
http://doi.org/10.1093/eurjpc/zwab128... Flowchart 4 summarizes the approach to patients with DFU and PAD, and Table 13 summarizes the main recommendations for diabetic patients with PAD.

CHAPTER 5. DIAGNOSING AND TREATING FOOT INFECTIONS IN PEOPLE WITH DIABETES

Introduction

The complication that most often leads to hospitalization in diabetic patients is foot infection, and it is also a leading cause of amputation.¹³⁶136 Lavery LA, Armstrong DG, Murdoch DP, Peters EJG, Lipsky BA. Validation of the Infectious Diseases Society of America’s diabetic foot infection classification system. Clin Infect Dis. 2007;44(4):562-5. http://doi.org/10.1086/511036. PMid:17243061.
http://doi.org/10.1086/511036... ,¹³⁷137 Tan TW, Shih CD, Concha-Moore KC, et al. Disparities in outcomes of patients admitted with diabetic foot infections. PLoS One. 2019;14(2):e0211481. http://doi.org/10.1371/journal.pone.0211481. PMid:30716108.
http://doi.org/10.1371/journal.pone.0211... Up to 17% of patients with an infected DFU progress to amputation within 1 year, while 10% become reinfected after wound healing.¹³⁷137 Tan TW, Shih CD, Concha-Moore KC, et al. Disparities in outcomes of patients admitted with diabetic foot infections. PLoS One. 2019;14(2):e0211481. http://doi.org/10.1371/journal.pone.0211481. PMid:30716108.
http://doi.org/10.1371/journal.pone.0211... Considering only acute infections, the rates of minor amputation required for treatment can reach 40%.¹³⁸138 Wukich DK, Johnson MJ, Raspovic KM. Limb salvage in severe diabetic foot infection. Foot Ankle Clin. 2022;27(3):655-70. http://doi.org/10.1016/j.fcl.2022.02.004. PMid:36096557.
http://doi.org/10.1016/j.fcl.2022.02.004... Therefore, to reduce morbidity and improve outcomes, a precise systematic approach is needed for early diagnosis of diabetic foot infections.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266...

Diagnosis

Diabetic foot infections have been clinically defined by the IWGDF as “an inflammatory process in any tissue below the malleoli in a person with diabetes.” Despite this definition, however, it is possible for there to be no characteristic inflammatory process, especially in patients with associated PAD. Thus, assessment of factors that predispose patients to infection, such as deep, recurrent, long-standing or traumatic ulcers, chronic kidney disease, and diabetes-related immunity changes, can help resolve diagnostic suspicion.¹³⁹139 Lavery LA, Armstrong DG, Wunderlich RP, Mohler MJ, Wendel CS, Lipsky BA. Risk factors for foot infections in individuals with diabetes. Diabetes Care. 2006;29(6):1288-93. http://doi.org/10.2337/dc05-2425. PMid:16732010.
http://doi.org/10.2337/dc05-2425... ,¹⁴⁰140 Hao D, Hu C, Zhang T, Feng G, Chai J, Li T. Contribution of infection and peripheral artery disease to severity of diabetic foot ulcers in Chinese patients. Int J Clin Pract. 2014;68(9):1161-4. http://doi.org/10.1111/ijcp.12440. PMid:24750557.
http://doi.org/10.1111/ijcp.12440... Assessing changes in temperature and edema can also be useful for diagnosis, since they are present in infectious processes and may be the result of underlying cellulitis or inflammatory processes related to Charcot arthropathy.¹⁴¹141 Embil JM, Albalawi Z, Bowering K, Trepman E. Foot care. Can J Diabetes. 2018;42(Suppl 1):S222-7. http://doi.org/10.1016/j.jcjd.2017.10.020. PMid:29650101.
http://doi.org/10.1016/j.jcjd.2017.10.02...

Although most diabetic foot infections are superficial, deep infections have devastating potential, since they can spread upwards through the fascia and tendons of the deep compartments of the foot. In these cases, they can produce rapidly progressive infections, leading to increased internal compartment pressure, compartment syndrome, and necrosis due to tissue perfusion changes.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266...

When evaluating a foot ulcer in a diabetic patient, the presence of infection should be investigated. Clinical differentiation between a soft tissue infection, diabetic neuropathic osteoarthropathy, and osteomyelitis is a diagnostic challenge and requires a detailed work-up. Pain, fever, and elevated inflammatory markers can occur and overlap in all of these conditions.¹⁴²142 Abikhzer G, Le H, Israel O. Hybrid imaging of diabetic foot infections. Semin Nucl Med. 2023;53(1):86-97. http://doi.org/10.1053/j.semnuclmed.2022.08.003. PMid:36089528.
http://doi.org/10.1053/j.semnuclmed.2022... At this point, the ulcer must be classified according to the IWGDF/IDSA system, which has been validated for stratifying infections and has been included in the WIfI system, the most frequently used scale for diabetic foot classification (recommendation class I, level of evidence B).¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹³⁶136 Lavery LA, Armstrong DG, Murdoch DP, Peters EJG, Lipsky BA. Validation of the Infectious Diseases Society of America’s diabetic foot infection classification system. Clin Infect Dis. 2007;44(4):562-5. http://doi.org/10.1086/511036. PMid:17243061.
http://doi.org/10.1086/511036... The classification method is detailed in Chapter 3.

Upon assessing the severity of the infectious process, hospital admission should be considered in severe and complex infections for which surgery is recommended, especially in patients with important comorbidities and PAD. Complementary laboratory assessment can determine severity parameters and help diagnose the infection when the physical examination is inconclusive. Leukocytosis, which is included in the IWGDF/ISDA classification system, is associated with the severity of the infectious process. Laboratory tests for infection markers are also indicated, such as erythrocyte sedimentation rate, C-reactive protein, and procalcitonin level (recommendation class IIb, level of evidence C). C-reactive protein and procalcitonin levels have greater sensitivity to earlier elevation, while an erythrocyte sedimentation rate > 70 mm/h is associated with bone infection.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266...

Additional parameters can be used to determine the presence of osteomyelitis in diabetic foot infections. There are 2 clinical predictors of osteomyelitis: the ulcer’s size/ depth and the probe-to-bone test. A deep ulcer with visual bone exposure has a 100% specificity, but only a 32% sensitivity, for diagnosing osteomyelitis. When the ulcerated area is > 2 cm, sensitivity increases to 52% and the specificity remains high (92%).¹⁴³143 Dinh MT, Abad CL, Safdar N. Diagnostic accuracy of the physical exam- ination and imaging tests for osteomyelitis underlying diabetic foot ulcers: meta-analysis. Clin Infect Dis. 2008;47(4):519-27. http://doi.org/10.1086/590011. PMid:18611152.
http://doi.org/10.1086/590011... The probe-to-bone test involves gently introducing a sterile blunt probe into the wound. If it reaches the bone or joint space, the result is positive. Positive results indicate bone infection with a sensitivity of 87% and specificity of 83%.¹⁴⁴144 Lam K, Van Asten SAV, Nguyen T, La Fontaine J, Lavery LA. Diagnostic accuracy of probe to bone to detect osteomyelitis in the diabetic foot: a systematic review. Clin Infect Dis. 2016;63(7):944-8. http://doi.org/10.1093/cid/ciw445. PMid:27369321.
http://doi.org/10.1093/cid/ciw445... The gold standard for diagnosing osteomyelitis is aseptic bone biopsy (percutaneous or surgical route). A positive culture or histology is the only way to determine the specific pathogen and guide antibiotic therapy. Although feasible, bone biopsy should be considered in cases where there may be resistance, where there has been previous treatment, or where current antimicrobial treatment has failed.¹⁴²142 Abikhzer G, Le H, Israel O. Hybrid imaging of diabetic foot infections. Semin Nucl Med. 2023;53(1):86-97. http://doi.org/10.1053/j.semnuclmed.2022.08.003. PMid:36089528.
http://doi.org/10.1053/j.semnuclmed.2022...

Soft tissue cultures must be collected aseptically from all wounds (curettage or biopsy) to guide treatment. When the culture is obtained from deep tissue and a single pathogen grows, it may suggest the etiology of the associated bone infection, although studies have found a correlation between soft tissue and bone cultures in < 50% of cases, being as low as 17.4% in some cases.¹⁴⁵145 Senneville E, Morant H, Descamps D, et al. Needle puncture and transcutaneous bone biopsy cultures are inconsistent in patients with diabetes and suspected osteomyelitis of the foot. Clin Infect Dis. 2009;48(7):888-93. http://doi.org/10.1086/597263. PMid:19228109.
http://doi.org/10.1086/597263... ,¹⁴⁶146 Dos Santos VP, Alves CAS, Queiroz AB, et al. Is there concordance between bone and tendon cultures in patients with foot tissue loss? J Vasc Bras. 2019;18:e20190063. PMid:31762776. Thus, in most cases material should be collected aseptically, surgically, or percutaneously due to the reliable results.¹⁴⁷147 Al-Balas H, Metwalli ZA, Nagaraj A, Sada DM. Is fluoroscopy-guided percutaneous bone biopsy of diabetic foot with suspected osteomyelitis worthwhile? A retrospective study. J Diabetes. 2023;15(4):332-7. http://doi.org/10.1111/1753-0407.13377. PMid:36905125.
http://doi.org/10.1111/1753-0407.13377... Acute infections of lesser severity that have not undergone previous treatment can be considered for empirical treatment without culture collection, although culture collection should be performed or repeated when the clinical course is unfavorable or when the ulcer is subject to surgical debridement (recommendation class IIa, level of evidence C).¹¹11 Hingorani A, LaMuraglia GM, Henke P, et al. The management of diabetic foot: a clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine. J Vasc Surg. 2016;63(2, Suppl):3S-21S. http://doi.org/10.1016/j.jvs.2015.10.003. PMid:26804367.
http://doi.org/10.1016/j.jvs.2015.10.003... ,¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266...

Imaging exams

Due to its easy access and low cost, radiography should be the initial imaging modality for patients with a DFU and suspected osteomyelitis (recommendation class I, level of evidence B).¹⁴²142 Abikhzer G, Le H, Israel O. Hybrid imaging of diabetic foot infections. Semin Nucl Med. 2023;53(1):86-97. http://doi.org/10.1053/j.semnuclmed.2022.08.003. PMid:36089528.
http://doi.org/10.1053/j.semnuclmed.2022... A meta-analysis found that radiography had a sensitivity of 28% and a specificity of 68%.¹⁴³143 Dinh MT, Abad CL, Safdar N. Diagnostic accuracy of the physical exam- ination and imaging tests for osteomyelitis underlying diabetic foot ulcers: meta-analysis. Clin Infect Dis. 2008;47(4):519-27. http://doi.org/10.1086/590011. PMid:18611152.
http://doi.org/10.1086/590011... However, when combined with the probe-to-bone test, the sensitivity and specificity increase to 97% and 93%, respectively.¹⁴⁸148 Senneville É, Lipsky BA, Abbas ZG, et al. Diagnosis of infection in the foot in diabetes: a systematic review. Diabetes Metab Res Rev. 2020;36(Suppl 1):e3281. http://doi.org/10.1002/dmrr.3281. PMid:32176440.
http://doi.org/10.1002/dmrr.3281... Therefore, these tests should be combined for initial diagnosis.

Radiographic changes are only apparent when bone loss of 30%-50% has occurred, and they may not be visualized in the first 10 days of infection.¹⁴²142 Abikhzer G, Le H, Israel O. Hybrid imaging of diabetic foot infections. Semin Nucl Med. 2023;53(1):86-97. http://doi.org/10.1053/j.semnuclmed.2022.08.003. PMid:36089528.
http://doi.org/10.1053/j.semnuclmed.2022... Chart 6 shows plain radiography parameters that are associated with soft tissue changes and osteomyelitis.¹⁴⁹149 Aragón-Sánchez J, Lipsky BA, Lázaro-Martínez JL. Diagnosing diabetic foot osteomyelitis: Is the combination of probe-to-bone test and plain radiography sufficient for high-risk inpatients? Diabet Med. 2011;28(2):191-4. http://doi.org/10.1111/j.1464-5491.2010.03150.x. PMid:21219428.
http://doi.org/10.1111/j.1464-5491.2010....

CT has high spatial resolution and provides better assessment of bone structures than plain radiography when assessing osteomyelitis. CT can also detect gas and small or deep abscesses that are imperceptible in radiography. It has a sensitivity of 67% and a specificity of 50% for diagnosing osteomyelitis.¹⁴²142 Abikhzer G, Le H, Israel O. Hybrid imaging of diabetic foot infections. Semin Nucl Med. 2023;53(1):86-97. http://doi.org/10.1053/j.semnuclmed.2022.08.003. PMid:36089528.
http://doi.org/10.1053/j.semnuclmed.2022... Nevertheless, MRI is the main diagnostic modality for osteomyelitis in diabetic patients (recommendation class I, level of evidence B). MRI can also show bone marrow signal changes, which may manifest before bone lysis becomes evident in radiography or CT.¹⁴²142 Abikhzer G, Le H, Israel O. Hybrid imaging of diabetic foot infections. Semin Nucl Med. 2023;53(1):86-97. http://doi.org/10.1053/j.semnuclmed.2022.08.003. PMid:36089528.
http://doi.org/10.1053/j.semnuclmed.2022... It has a sensitivity of 93% and a specificity of 75% for diagnosing diabetic foot osteomyelitis.¹⁵⁰150 Lauri C, Tamminga M, Glaudemans A, et al. Detection of osteomyelitis in the diabetic foot by imaging techniques: a systematic review and meta-analysis comparing MRI, white blood cell scintigraphy, and FDG- PET. Diabetes Care. 2017;40(8):1111-20. http://doi.org/10.2337/dc17-0532. PMid:28733376.
http://doi.org/10.2337/dc17-0532... Routine non-contrast MRI with fat-suppressed sequences (T1, T2, and STIR) on multiple orthogonal planes can be used to diagnose osteomyelitis. Contrast is often necessary and may not be feasible in diabetic patients with chronic kidney disease.¹⁴²142 Abikhzer G, Le H, Israel O. Hybrid imaging of diabetic foot infections. Semin Nucl Med. 2023;53(1):86-97. http://doi.org/10.1053/j.semnuclmed.2022.08.003. PMid:36089528.
http://doi.org/10.1053/j.semnuclmed.2022...

When bone marrow is replaced with a low T1 signal (darker than skeletal muscle), it is typically associated with osteomyelitis. This may also be associated with the loss of a normal cortical T1 signal due to bone lysis or the presence of periosteal edema, which increases diagnostic confidence for osteomyelitis. The “ghost” effect of bone structures involved in osteomyelitis is also a useful sign. Bones are imperceptible in T1-weighted sequences due to marrow replacement and cortex loss, becoming readily visible in fluid-sensitive (fat-saturated T2 sequence) or contrast-enhanced sequences. A diagnosis of osteomyelitis is reinforced when bone marrow adjacent to an ulcer (with or without a fistula) is replaced with soft tissue edema.¹⁴²142 Abikhzer G, Le H, Israel O. Hybrid imaging of diabetic foot infections. Semin Nucl Med. 2023;53(1):86-97. http://doi.org/10.1053/j.semnuclmed.2022.08.003. PMid:36089528.
http://doi.org/10.1053/j.semnuclmed.2022...

Although positron emission tomography with fluorodeoxyglucose and scintigraphy with labeled leukocytes can also help clarify the diagnosis, due to their higher cost and more limited availability, they should be reserved for when a conclusion cannot be reached from the initial assessment.¹⁴²142 Abikhzer G, Le H, Israel O. Hybrid imaging of diabetic foot infections. Semin Nucl Med. 2023;53(1):86-97. http://doi.org/10.1053/j.semnuclmed.2022.08.003. PMid:36089528.
http://doi.org/10.1053/j.semnuclmed.2022...

Treatment

Flowchart 5 summarizes diabetic foot infection treatment. Empirical antibiotic therapy must be based on the pathogen’s local susceptibility data, considering availability and possible drug interactions. Virulent pathogens such as Staphylococcus aureus and beta-hemolytic streptococci should be treated, considering that less virulent pathogens only tend appear as local contaminants/colonizers. Additionally, for all tropical countries, the IWGDF recommends including an antibiotic that is effective against Pseudomonas aeruginosa due to its high prevalence, especially when the lesion has been in contact with humid media.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266...

More complex cases should involve consultation with an infectious disease specialist, including individualized discussion of each case.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... Table 14 suggests combinations of empirical antibiotic therapy according to infection severity. According to expert opinion, simple wounds can receive antibiotic therapy for 1 to 2 weeks. The treatment period may be extended to 4 weeks, especially in extensive wounds that are healing and in cases with more severe PAD, comorbidities associated with delayed wound healing, or an increased rate of infection treatment failure (recommendation class IIa, level of evidence C).¹⁵¹151 Waibel FW, Schöni M, Kronberger L, et al. Treatment Failures in diabetic foot osteomyelitis associated with concomitant charcot arthropathy: the role of underlying arteriopathy. Int J Infect Dis. 2022;114:15-20. http://doi.org/10.1016/j.ijid.2021.10.036. PMid:34715357.
http://doi.org/10.1016/j.ijid.2021.10.03... If the infection has not resolved after this period, the possibility of treatment failure must be considered and the treatment should be reassessed.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁵¹151 Waibel FW, Schöni M, Kronberger L, et al. Treatment Failures in diabetic foot osteomyelitis associated with concomitant charcot arthropathy: the role of underlying arteriopathy. Int J Infect Dis. 2022;114:15-20. http://doi.org/10.1016/j.ijid.2021.10.036. PMid:34715357.
http://doi.org/10.1016/j.ijid.2021.10.03...

Using topical antibiotics in the wound or indiscriminate use of systemic/topical antibiotics to prevent infection in non-infected ulcers is not recommended. When wound infection has not been confirmed after detailed evaluation, antibiotics provide no actual benefits and could induce bacterial resistance, which overrides any theoretical benefit they might provide in such scenarios (recommendation class III, level of evidence B).¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266...

Although cases of mild infection occur, most diabetic foot infections will require surgical intervention to resolve. In cases of severe infection with necrosis and deep abscesses, surgical evaluation is essential and drainage/decompression should ideally be performed urgently, in most cases within 24 hours.¹¹11 Hingorani A, LaMuraglia GM, Henke P, et al. The management of diabetic foot: a clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine. J Vasc Surg. 2016;63(2, Suppl):3S-21S. http://doi.org/10.1016/j.jvs.2015.10.003. PMid:26804367.
http://doi.org/10.1016/j.jvs.2015.10.003... In general, urgent cases are associated with soft tissue infection, although this is rare in isolated bone infections. Initially, the surgical procedure must involve resection of devitalized, infected tissue and pressure reduction in deep compartments, maintaining all viable skin coverage, even in non-critical areas, considering its use in future surgeries after the infection has been controlled.¹⁵²152 Michelsson O, Tukiainen E. Minor forefoot amputations in patients with diabetic foot ulcers. Foot Ankle Clin. 2022;27(3):671-85. http://doi.org/10.1016/j.fcl.2022.05.003. PMid:36096558.
http://doi.org/10.1016/j.fcl.2022.05.003...

Although the gold standard treatment for osteomyelitis involves resection of the compromised bone segment, similar success rates have been described for osteomyelitis treatment without bone resection or conservative bone resection, especially when limited to the forefoot, with remission rates in some series reaching 64% in 1 year.¹⁵³153 Nguyen S, Wallard P, Robineau O, et al. Conservative surgical treatment for metatarsal osteomyelitis in diabetic foot: experience of two French centres. Diabetes Metab Res Rev. 2022;38(5):e3534. http://doi.org/10.1002/dmrr.3534. PMid:35486542.
http://doi.org/10.1002/dmrr.3534... ,¹⁵⁴154 Truong DH, Bedimo R, Malone M, et al. Meta-analysis: outcomes of surgical and medical management of diabetic foot osteomyelitis. Open Forum Infect Dis. 2022;9(9):c407. http://doi.org/10.1093/ofid/ofac407. PMid:36147596.
http://doi.org/10.1093/ofid/ofac407... The suggested treatment time in such cases is 6 weeks, with improvement observed ideally in the first 2-4 weeks (recommendation class IIa, level of evidence B). If no resolution occurs during this period, the approach should be changed, including a biopsy to identify the pathogen or resection of the involved structure.¹⁵⁵155 Tone A, Nguyen S, Devemy F, et al. Six-week versus twelve-week antibiotic therapy for nonsurgically treated diabetic foot osteomyelitis: a multicenter open-label controlled randomized study. Diabetes Care. 2015;38(2):302-7. http://doi.org/10.2337/dc14-1514. PMid:25414157.
http://doi.org/10.2337/dc14-1514...

When complete resection of the bone lesion is performed, antibiotic therapy can be reduced to a few days, especially when cultures of bone tissue fragments from the resection edge are negative. When the resection edge yields positive cultures, 6 weeks of treatment is recommended (recommendation class IIb, level of evidence C).¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266...

Similar to serious infections, osteomyelitis treatment can be modified from intravenous to oral, while maintaining an antibiotic regimen with similar coverage and dosage in the upper range. Prolonging treatment beyond 6 weeks has shown no benefits⁸⁸88 Bravo-Molina A, Linares-Palomino JP, Vera-Arroyo B, Salmerón-Febres LM, Ros-Díe E. Inter-observer agreement of the Wagner, University of Texas and PEDIS classification systems for the diabetic foot syndrome. Foot Ankle Surg. 2018;24(1):60-4. PMid:29413776. and, according to the IWGDF, long-term suppressive antibiotic therapy should only be used in cases involving a large amount of necrotic bone tissue that is not amenable to removal or in cases of infected orthopedic material.¹⁵⁵155 Tone A, Nguyen S, Devemy F, et al. Six-week versus twelve-week antibiotic therapy for nonsurgically treated diabetic foot osteomyelitis: a multicenter open-label controlled randomized study. Diabetes Care. 2015;38(2):302-7. http://doi.org/10.2337/dc14-1514. PMid:25414157.
http://doi.org/10.2337/dc14-1514... Follow-up with laboratory monitoring is suggested, including foot X-rays and serial measurement of C-reactive protein and erythrocyte sedimentation rate. The patient can be considered cured after 1 year of follow-up.¹³⁸138 Wukich DK, Johnson MJ, Raspovic KM. Limb salvage in severe diabetic foot infection. Foot Ankle Clin. 2022;27(3):655-70. http://doi.org/10.1016/j.fcl.2022.02.004. PMid:36096557.
http://doi.org/10.1016/j.fcl.2022.02.004...

Regarding adjuvant therapies for infection, there are no high quality recommendations about hyperbaric or topical oxygen therapy, granulocyte colony-stimulating factor, topical antiseptics,⁸⁹89 Lavery LA, Armstrong DG, Harkless LB. Classification of diabetic foot wounds. J Foot Ankle Surg. 1996;35(6):528-31. http://doi.org/10.1016/S1067-2516(96)80125-6. PMid:8986890.
http://doi.org/10.1016/S1067-2516(96)801... silver compounds⁹⁰90 Ince P, Abbas ZG, Lutale JK, et al. Use of the SINBAD classification system and score in comparing outcome of foot ulcer management on three continents. Diabetes Care. 2008;31(5):964-7. http://doi.org/10.2337/dc07-2367. PMid:18299441.
http://doi.org/10.2337/dc07-2367... or negative pressure therapy for diabetic foot infection (recommendation class III, level of evidence B).¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... ,¹⁵⁶156 Soldevila-Boixader L, Fernández AP, Laguna JM, Uçkay I. Local antibiotics in the treatment of diabetic foot infections: a narrative review. Antibiotics. 2023;12(1):124. http://doi.org/10.3390/antibiotics12010124. PMid:36671326.
http://doi.org/10.3390/antibiotics120101... ,¹⁵⁷157 Lafontaine N, Jolley J, Kyi M, et al. Prospective randomised placebo-controlled trial assessing the efficacy of silver dressings to enhance healing of acute diabetes-related foot ulcers. Diabetologia. 2023;66(4):768-76. http://doi.org/10.1007/s00125-022-05855-7. PMid:36629877.
http://doi.org/10.1007/s00125-022-05855-... To date, trials regarding these adjuvant therapies have been low quality and do not substantially support their use in light of the cost and potential adverse effects.¹³13 Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(Suppl 1):e3266. http://doi.org/10.1002/dmrr.3266. PMid:32176447.
http://doi.org/10.1002/dmrr.3266... Table 15 summarizes the main recommendations for treating diabetic foot infections.

CHAPTER 6. CHARCOT ARTHROPATHY

Introduction

Although Charcot arthropathy was first described in1868, its pathophysiology remains undefined. It is associated with conditions that cause neuropathy of the lower limbs, and diabetes is its main cause.²¹⁶216 Galhoum AE, Trivedi V, Askar M, et al. Management of ankle charcot neuroarthropathy: a systematic review. J Clin Med. 2021;10(24):5923. http://doi.org/10.3390/jcm10245923. PMid:34945220.
http://doi.org/10.3390/jcm10245923... Its incidence among people with DM can vary from 0.1% to 13%, reaching up to 29% in patients who already have neuropathy.²¹⁷217 Vopat ML, Nentwig MJ, Chong ACM, Agan JL, Shields NN, Yang SY. Initial diagnosis and management for acute charcot neuroarthropathy. Kans J Med. 2018;11(4):114-9. http://doi.org/10.17161/kjm.v11i4.8709. PMid:30937152.
http://doi.org/10.17161/kjm.v11i4.8709... ,²¹⁸218 Cates NK, Wagler EC, Bunka TJ, et al. Charcot reconstruction: outcomes in patients with and without diabetes. J Foot Ankle Surg. 2020;59(6):1229-33. http://doi.org/10.1053/j.jfas.2020.05.019. PMid:32921562.
http://doi.org/10.1053/j.jfas.2020.05.01... Since deformities resulting from Charcot arthropathy lead to inadequate pressure distribution in the foot, they are an important cause of foot ulcers in diabetic patients.²¹⁷217 Vopat ML, Nentwig MJ, Chong ACM, Agan JL, Shields NN, Yang SY. Initial diagnosis and management for acute charcot neuroarthropathy. Kans J Med. 2018;11(4):114-9. http://doi.org/10.17161/kjm.v11i4.8709. PMid:30937152.
http://doi.org/10.17161/kjm.v11i4.8709...

Diagnosis

Charcot arthropathy is defined as a non-infectious neuro-osteoarthropathy of the bones and joints that leads to changes in sensitivity and destruction of foot architecture.²¹⁹219 Güven MF, Karabiber A, Kaynak G, Oğüt T. Conservative and surgical treatment of the chronic Charcot foot and ankle. Diabet Foot Ankle. 2013;4(1):1-10. http://doi.org/10.3402/dfa.v4i0.21177. PMid:23919114.
http://doi.org/10.3402/dfa.v4i0.21177... It usually involves the midfoot, hindfoot, and ankle, and 2 mechanisms for its development have been described.²¹⁶216 Galhoum AE, Trivedi V, Askar M, et al. Management of ankle charcot neuroarthropathy: a systematic review. J Clin Med. 2021;10(24):5923. http://doi.org/10.3390/jcm10245923. PMid:34945220.
http://doi.org/10.3390/jcm10245923... ,²¹⁷217 Vopat ML, Nentwig MJ, Chong ACM, Agan JL, Shields NN, Yang SY. Initial diagnosis and management for acute charcot neuroarthropathy. Kans J Med. 2018;11(4):114-9. http://doi.org/10.17161/kjm.v11i4.8709. PMid:30937152.
http://doi.org/10.17161/kjm.v11i4.8709... According to neurovascular theory, its development can be explained through dysautonomia caused by neuropathy: increased vascularization and the stimulation of osteoclastic activity is the cause of the deformities. According to neurotraumatic theory, multiple joint and bone injuries develop due to a lack of protective sensitivity and inadequate injury healing, resulting in the development of arthropathy.²¹⁶216 Galhoum AE, Trivedi V, Askar M, et al. Management of ankle charcot neuroarthropathy: a systematic review. J Clin Med. 2021;10(24):5923. http://doi.org/10.3390/jcm10245923. PMid:34945220.
http://doi.org/10.3390/jcm10245923... ,²²⁰220 Hester T, Kavarthapu V. Etiology, epidemiology, and outcomes of managing charcot arthropathy. Foot Ankle Clin. 2022;27(3):583-94. http://doi.org/10.1016/j.fcl.2022.03.002. PMid:36096553.
http://doi.org/10.1016/j.fcl.2022.03.002...

Although early diagnosis is decisive for preserving the limb, in up to 79% of cases error leads to delayed diagnosis by as much as 7 months.²¹⁷217 Vopat ML, Nentwig MJ, Chong ACM, Agan JL, Shields NN, Yang SY. Initial diagnosis and management for acute charcot neuroarthropathy. Kans J Med. 2018;11(4):114-9. http://doi.org/10.17161/kjm.v11i4.8709. PMid:30937152.
http://doi.org/10.17161/kjm.v11i4.8709... Both acute and chronic presentations are possible, and diagnosis is still essentially clinical. The acute form presents with erythema, edema, pain, and increased foot temperature and is often confused with other diseases, such as cellulitis, gout, sprains, or deep vein thrombosis. The chronic form is the most characteristic, including plantar arch loss and a ‘rocker bottom’ deformity.²²¹221 Yousaf S, Dawe EJC, Saleh A, Gill IR, Wee A. The acute Charcot foot in diabetics: Diagnosis and management. EFORT Open Rev. 2018;3(10):568-73. http://doi.org/10.1302/2058-5241.3.180003. PMid:30662765.
http://doi.org/10.1302/2058-5241.3.18000... Acute Charcot arthropathy should be considered for presentations involving edema, pain, and erythema of the foot without evident skin lesions (good clinical practice).

In suspected Charcot arthropathy patients with intact skin, infrared skin temperature can be measured at the highest sites on the foot or ankle and compared with the contralateral limb at the same anatomical point (recommendation class IIb, level of evidence C). A 2 °C increase in skin temperature compared to the contralateral foot has been used as a threshold for diagnosing active Charcot arthropathy.²²²222 Jones PJ, Davies MJ, Webb D, Berrington R, Frykberg RG. Contralateral foot temperature monitoring during Charcot immo- bilisation: a systematic review. Diabetes Metab Res Rev. 2023;39(4):e3619. http://doi.org/10.1002/dmrr.3619. PMid:36728905.
http://doi.org/10.1002/dmrr.3619... In the absence of other signs or symptoms of inflammation (ie, redness or swelling), an isolated increase in foot temperature may not always be indicative of active Charcot neuropathic osteoarthropathy and should be interpreted in the context of other clinical findings.²²³223 Macdonald A, Petrova N, Ainarkar S, et al. Thermal symmetry of healthy feet: a precursor to a thermal study of diabetic feet prior to skin breakdown. Physiol Meas. 2017;38(1):33-44. http://doi.org/10.1088/1361-6579/38/1/33. PMid:27941234.
http://doi.org/10.1088/1361-6579/38/1/33... ,²²⁴224 Macdonald A, Petrova N, Ainarker S, et al. Between visit variability of thermal imaging of feet in people attending podiatric clinics with diabetic neuropathy at high risk of developing foot ulcers. Physiol Meas. 2019;40(8):084004. http://doi.org/10.1088/1361-6579/ab36d7. PMid:31362275.
http://doi.org/10.1088/1361-6579/ab36d7... Although an essential part of the diagnostic evaluation, an isolated elevation in foot skin temperature is insufficient to either diagnose or rule out active disease. Consequently, asymmetric temperature elevation is sensitive but not specific in active Charcot arthropathy diagnosis.

Ideally, plain bilateral radiography should be performed for comparison in patients with diabetes and suspected active Charcot arthropathy (recommendation class IIa, level of evidence B). Radiography should include anteroposterior, medial oblique, and lateral views in a diabetic patient with suspected active Charcot neuropathic osteoarthropathy. Views of the ankle and foot should include anteroposterior and lateral projections. Ideally, standing (ie, “weight bearing”) X-rays should be taken. If a patient is unable to stand up, non-weight bearing X-rays are an alternative but may not show misalignments, which are more apparent in the standing position.²²⁵225 De Bruijn J, Hagemeijer NC, Rikken QGH, et al. Lisfranc injury: refined diagnostic methodology using weightbearing and non‐ weightbearing radiographs. Injury. 2022;53(6):2318-25. http://doi.org/10.1016/j.injury.2022.02.040. PMid:35227511.
http://doi.org/10.1016/j.injury.2022.02....

Since non-weight-bearing X-rays may not show changes, weigh-bearing X-rays should always be requested. If the X-ray shows no changes, the diagnosis should not be discarded, since such changes are not expected at the beginning of the process.²²¹221 Yousaf S, Dawe EJC, Saleh A, Gill IR, Wee A. The acute Charcot foot in diabetics: Diagnosis and management. EFORT Open Rev. 2018;3(10):568-73. http://doi.org/10.1302/2058-5241.3.180003. PMid:30662765.
http://doi.org/10.1302/2058-5241.3.18000... MRI can be used for diagnosis, but changes may be indistinguishable from osteomyelitis and must be correlated with clinical and laboratory tests, biopsies, and bone cultures.²²¹221 Yousaf S, Dawe EJC, Saleh A, Gill IR, Wee A. The acute Charcot foot in diabetics: Diagnosis and management. EFORT Open Rev. 2018;3(10):568-73. http://doi.org/10.1302/2058-5241.3.180003. PMid:30662765.
http://doi.org/10.1302/2058-5241.3.18000... If MRI is unavailable or contraindicated, scintigraphy, CT, or single-photon emission CT may be considered to complement diagnosis of active Charcot neuropathic osteoarthropathy.²²⁶226 Ahluwalia R, Bilal A, Petrova N, et al. The role of bone scintigraphy with SPECT/CT in the characterization and early diagnosis of stage 0 charcot neuroarthropathy. J Clin Med. 2020;9(12):1-14. http://doi.org/10.3390/jcm9124123. PMid:33371286.
http://doi.org/10.3390/jcm9124123... ,²²⁷227 Fosbøl M, Reving S, Petersen EH, Rossing P, Lajer M, Zerahn B. Three‐phase bone scintigraphy for diagnosis of Charcot neuro- pathic osteoarthropathy in the diabetic foot ‐ does quantitative data improve diagnostic value? Clin Physiol Funct Imaging. 2017;37(1):30-6. http://doi.org/10.1111/cpf.12264. PMid:26147681.
http://doi.org/10.1111/cpf.12264...

Biochemical markers are generally unaltered in Charcot arthropathy, although C-reactive protein and erythrocyte sedimentation rate levels can be used for differential diagnosis of a lesion due to infection.²¹⁶216 Galhoum AE, Trivedi V, Askar M, et al. Management of ankle charcot neuroarthropathy: a systematic review. J Clin Med. 2021;10(24):5923. http://doi.org/10.3390/jcm10245923. PMid:34945220.
http://doi.org/10.3390/jcm10245923... ,²¹⁷217 Vopat ML, Nentwig MJ, Chong ACM, Agan JL, Shields NN, Yang SY. Initial diagnosis and management for acute charcot neuroarthropathy. Kans J Med. 2018;11(4):114-9. http://doi.org/10.17161/kjm.v11i4.8709. PMid:30937152.
http://doi.org/10.17161/kjm.v11i4.8709... ,²¹⁹219 Güven MF, Karabiber A, Kaynak G, Oğüt T. Conservative and surgical treatment of the chronic Charcot foot and ankle. Diabet Foot Ankle. 2013;4(1):1-10. http://doi.org/10.3402/dfa.v4i0.21177. PMid:23919114.
http://doi.org/10.3402/dfa.v4i0.21177... Eichenholtz divided acute Charcot arthropathy into 4 stages, as described in Table 16.²¹⁸218 Cates NK, Wagler EC, Bunka TJ, et al. Charcot reconstruction: outcomes in patients with and without diabetes. J Foot Ankle Surg. 2020;59(6):1229-33. http://doi.org/10.1053/j.jfas.2020.05.019. PMid:32921562.
http://doi.org/10.1053/j.jfas.2020.05.01...

Treatment

Patients with Charcot arthropathy should be referred to a multidisciplinary team for monitoring and care. Initial treatment is based on load relief through full cast immobilization, which has been successfully used to treat the acute phase.²²⁹229 Christensen TM, Gade-Rasmussen B, Pedersen LW, Hommel E, Holstein PE, Svendsen OL. Duration of off-loading and recurrence rate in Charcot osteo-arthropathy treated with less restrictive regimen with removable walker. J Diabetes Complications. 2012;26(5):430-4. http://doi.org/10.1016/j.jdiacomp.2012.05.006. PMid:22699112.
http://doi.org/10.1016/j.jdiacomp.2012.0... Immobilization to knee height should be begin immediately when active Charcot arthropathy is suspected in a diabetic patient with intact skin (recommendation class IIa, level of evidence C). Early detection, immobilization, and load reduction for the diseased foot have been shown to minimize development of the deformity.²³⁰230 Chantelau E. The perils of procrastination: effects of early vs. delayed detection and treatment of incipient Charcot fracture. Diabet Med. 2005;22(12):1707-12. http://doi.org/10.1111/j.1464-5491.2005.01677.x. PMid:16401316.
http://doi.org/10.1111/j.1464-5491.2005.... ,²³¹231 Wukich DK, Sung W, Wipf SA, Armstrong DG. The consequences of complacency: managing the effects of unrecognized Charcot feet. Diabet Med. 2011;28(2):195-8. http://doi.org/10.1111/j.1464-5491.2010.03141.x. PMid:21219429.
http://doi.org/10.1111/j.1464-5491.2010.... Immobilization should continue until symptoms remit, and patients should be followed up with serial radiographs and clinical examination of the limb. A difference of < 2 °C in skin temperature between the limbs and the consolidation of bone changes in radiography are associated with resolution of the process.²¹⁷217 Vopat ML, Nentwig MJ, Chong ACM, Agan JL, Shields NN, Yang SY. Initial diagnosis and management for acute charcot neuroarthropathy. Kans J Med. 2018;11(4):114-9. http://doi.org/10.17161/kjm.v11i4.8709. PMid:30937152.
http://doi.org/10.17161/kjm.v11i4.8709... ,²²⁹229 Christensen TM, Gade-Rasmussen B, Pedersen LW, Hommel E, Holstein PE, Svendsen OL. Duration of off-loading and recurrence rate in Charcot osteo-arthropathy treated with less restrictive regimen with removable walker. J Diabetes Complications. 2012;26(5):430-4. http://doi.org/10.1016/j.jdiacomp.2012.05.006. PMid:22699112.
http://doi.org/10.1016/j.jdiacomp.2012.0...

Contraindications to full cast immobilization should be considered in patients with actively infected ulcers. Patients undergoing treatment must be monitored on a weekly basis. After remission of the initial phase, orthopedic shoes are recommended to prevent recurrence, ulcerations and deformities (recommendation class IIa, level of evidence C).²¹⁷217 Vopat ML, Nentwig MJ, Chong ACM, Agan JL, Shields NN, Yang SY. Initial diagnosis and management for acute charcot neuroarthropathy. Kans J Med. 2018;11(4):114-9. http://doi.org/10.17161/kjm.v11i4.8709. PMid:30937152.
http://doi.org/10.17161/kjm.v11i4.8709...

In addition to orthopedic shoes, chronic phase Charcot arthropathy treatment may involve surgery. These patients should be referred to a multidisciplinary team with an orthopedic surgeon to evaluate possible surgical recommendations for preventing ulcerations or disease recurrence.²³²232 Miller R. NEMISIS: Neuropathic Minimally Invasive Surgeries. Charcot midfoot reconstruction, surgical technique, pearls and pitfalls. Foot Ankle Clin. 2022;27(3):567-81. http://doi.org/10.1016/j.fcl.2022.05.001. PMid:36096552.
http://doi.org/10.1016/j.fcl.2022.05.001... ,²³³233 Milne TE, Rogers JR, Kinnear EM, et al. Developing an evidence-based clinical pathway for the assessment, diagnosis and management of acute Charcot Neuro-Arthropathy: a systematic review. J Foot Ankle Res. 2013;6(1):30. http://doi.org/10.1186/1757-1146-6-30. PMid:23898912.
http://doi.org/10.1186/1757-1146-6-30... Flowchart 6 outlines an approach to diabetic patients with suspected Charcot arthropathy, while Table 17 summarizes the main recommendations.

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