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1362557110 diabetic foot an overview

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diabetic foot an overview

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1362557110 diabetic foot an overview

  1. 1. THE DIABETIC FOOT: AN OVERVIEW September 2004 Andrew J M Boulton MD, DSc (Hon), FRCP Professor of Medicine, University of Manchester Consultant Physician, Manchester Royal Infirmary, Manchester, UK. Professor of Medicine, University of Miami, Miami, Fl, USA
  2. 2. AN EXPERT ‘An expert is someone who comes a long way - and brings slides’ Henry Miller
  3. 3. A SPECIALIST ‘A Specialist is a man who knows more and more about less and less’ William Mayo
  4. 4. ‘Mind like parachute – Does not work if not open.’ Charlie Chan
  5. 5. Diabetic foot care is the PITS:- Prevention Identification Treatment Service
  6. 6. THE DIABETIC FOOT: Two decades of progress 1986: First Malvern Diabetic Foot Meeting 1987: Foot Council of ADA formed 1991: First International Diabetic Foot Meeting 1998: Diabetic Foot Study Group of EASD founded 1998: Japanese and Alfadiem symposia on the foot 1999: International Consensus group publishes Guidelines on management
  7. 7. THE DIABETIC FOOT: no longer the Cinderella of diabetic complications Publications listed on Medline on the diabetic foot / total diabetes publications 1979-1988: 0.7% 1989-1996: 1.4% 1997-2003: 2.7%
  8. 8. INTERNATIONAL MEETINGS ON THE DIABETIC FOOT 1991 First meeting – 250 delegates 1995 Second meeting – 450 delegates 1999 Third meeting – 600 delegates 2003 Fourth meeting – 700 delegates
  9. 9. ‘Diabetes itself may play an active part in the causation of perforating ulcers……. ..And it is abundantly evident that the actual cause of the perforating ulcers was a peripheral nerve degeneration
  10. 10. Paul Brand CBE, MD, FRCS 1914-2003 • The Gift of Pain • Pain: the Gift nobody wants • Surgeon and missionary: worked in leprosy and diabetes • He took the foot from art to science
  11. 11. Paul BrandPaul Brand
  12. 12. Paul Brand CBE, MD, FRCS 1914-2003 • THE ART: ‘Remove the patient’s shoes and socks and look at the feet’ • THE SCIENCE Classic studies of the relationship between pressure, time and ulceration in the canine hind-limb
  13. 13. The Diabetic Foot • Epidemiology • Causal pathways • Reducing foot pressures • Charcot Foot • Wound healing • International perspective
  14. 14. AMPUTATIONS IN DIABETES: TRENDS 1995-2000 • US data: steady increase in major amputations • UK: 50% increase in one health care district • Germany: no evidence of decrease • Sweden: 78% decrease in amputations CDC, 1997 Anonymous, 1997 Stiegler et al, 1998 Larrson et al, 1995 Trautner et al, 2001
  15. 15. Prevalence of Foot Ulcers and Amputations in Diabetes Prevalence Author Yr Country Ulceration Amputation Borssen 1990 Sweden 0.75% Moss 1992 USA 3.6% Kumar 1994 UK 1.4% Carrington 1996 UK 4.8% 1.4% Vozar 1997 Slovakia 2.5% 0.9% Pendsey 1994 India 3.6% - Van Rensbe 1995 S. Africa 11.2% - U-Roven 1998 Slovenia 7.1% - Belhadj 1998 Algeria 11.9% 6.7%
  16. 16. The Diabetic Foot • Epidemiology • Causal pathways • Reducing foot pressures • Charcot Foot • Wound healing • International perspective
  17. 17. THE PAIN OF NEUROPATHY ‘Of a burning and unremitting character’ F W Pavy, 1887
  18. 18. PAINFUL NEUROPATHY ‘I don’t like peripheral neuritis - it interferes with work’ R D Lawrence, 1923
  19. 19. DIABETIC NEUROPATHY: PREVALENCE. • UKPDS showed that >10% of patients had neuropathy at the diagnosis of Type 2 diabetes • Neuropathy may be asymptomatic in over 50% of subjects. • UK Community study of Type 2 patients (n=811), mean age 65 yrs. * 41.6% clinical evidence of neuropathy * 11% peripheral vascular disease • Over 50% of older Type 2 patients have risk factors for foot ulceration Kumar at al: 1994 UKPDS, 1998
  20. 20. Risk Factors for Neuropathy in UKPDS Irene M Stratton, Rury R Holman, Andrew JM Boulton for the UKPDS group
  21. 21. Background to UKPDS • A multicentre, randomised clinical trial of therapies in patients with newly diagnosed Type 2 diabetes • 5,102 subjects, mean age 53 years • Trial period 1977-1997 • Recruitment ended in 1991 with main study results in 1998 • No sustained difference was seen in indices of neuropathy between allocated treatment policies
  22. 22. Measures of neuropathy • Patients were assessed at entry to the study, and then every three years for:- • vibration perception threshold (VPT) • absence of one or both ankle reflexes • erectile dysfunction (ED)
  23. 23. Aims • To examine prevalence and incidence of new neuropathy we examined:- • Age • Gender • HbA1c • Height • Waist circumference • Alcohol consumption • Smoking status • Weight
  24. 24. Vibration Perception Threshold • Biothesiometer used to assess VPT at the lateral malleoli and at apex of great toes • Abnormal VPT defined here as mean value for great toes >25 volts
  25. 25. Relative risk for VPT in great toes >25 12.8% prevalence at diagnosis ______________________________________________________________________________________________________________________________________________________ __________ Age (per 5 years) 1.89 (1.73 to 2.07) Height (per 5 cm) 1.40 (1.32 to 1.50) Waist (per 5 cm) 1.05 (1.01 to 1.10) 13.3% incidence at 12 years ______________________________________________________________________________________________________________________________________________________ __________ Age (per 5 years) 1.58 (1.44 to 1.73) Female 0.56 (0.44 to 0.70) HbA1c (per 1%) 1.07 (1.01 to 1.14)
  26. 26. Years from entry Age at entry VPT in great toes >25 by age 0 10 20 30 40 50 60 70 0 3 6 9 12 Proportionwithevent(%) <50 50-59 60+ Point prevalence at 12 years 37%
  27. 27. Conclusions • The risk factors for these 3 indices of neuropathy were similar for prevalent cases at diagnosis and for subsequent incident cases • For prevalence the most important risk factor was age, but HbA1c, height, waist circumference and alcohol were also significant • For incidence age was the most important factor, again height, HbA1c and measures of obesity were important • Twelve years from diagnosis 71% of men and 51% of women have at least one of these indices of neuropathy
  28. 28. Does Neuropathy Lead to Ulceration? A Prospective Study –469 diabetic patients screened in 1988 –Vibration perception assessed by biothesiometry –All foot ulcers recorded Young et al, Diabetes Care 1994;17:557
  29. 29. Biothesiometer
  30. 30. Prospective Foot Ulcer Study Results — Foot Ulcers VPT<15 VPT 16-24 VPT>25 Total ulcers 1988-92 6 2 41 Risk per patient 2.9% 3.4% 19.6% Risk/patient/year 0.7% 0.9% 4.9%
  31. 31. Causal Pathways for Foot Ulceration • Neuropathy most important component cause (78%) • Critical triad: neuropathy, deformity, and trauma present in 63% • Ischemia component cause in 35% • >80% of ulcers potentially preventable Reiber, Vileikyte et al, 1999.
  32. 32. The Most Common Causal Pathway to Incident Diabetic Foot Ulcers
  33. 33. FOOTWEAR • Controlled evidence for reduction of recurrent ulceration • evidence for footwear as part of multidisciplinary approach Uccioli et al, D.Care 1995; 18: 1376 Dargis et al, D. Care 1999; 22: 1428 Faglia et al, D. Care 2001; 245: 78
  34. 34. Predicting Neuropathic Foot Ulcer Risk • North West Diabetes Foot Care Study (NWDFCS) • Population-based prospective study in NW UK – 6 health-care districts • 16,000 patients included in total • First study on 9,710 diabetic patients Abbott et al, Diabetic Med 2002;19:377
  35. 35. NWDFCS: THE NDS • 3 sensory modalities Vibration (128 Hz tuning fork – hallux) Pin-prick (Neurotip): dorsal distal hallux Hot/cold rods : dorsal distal hallux ALL: normal = 0, abnormal = 1 Ankle reflex: normal = 0, absent = 2, reinforcement = 1 MAX TOTAL 5 each leg: =10 Abbott et al, 2002
  36. 36. NWDFCS: Results • 9710 diabetic patients followed for 2 years • 291 ulcers developed: male to female: 1.6:1.0 • NDS best baseline predictor NDS < 6: 1.1% annual ulcer incidence NDS > 6: 6.3% annual ulcer incidence Abbott et al, 2002
  37. 37. Foot Pressure Studies in Diabetic Neuropathy • High foot pressures associated with first and recurrent plantar neuropathic ulcers • Foot Pressure abnormalities precede the appearance of neuropathy • High foot pressures predict ulcers • Plantar callus associated with high pressure and predicts ulcer formation Boulton et al, 1983, 1984, 1985,1986. Veves et al, 1992. Murray et al, 1996
  38. 38. Semi-Quantitative Foot Pressure Assessment • Podotrack (PressureStat): a dynamic pressure print map system • Inexpensive, easy to use in clinic or at home • Validated by comparison with optical pedobarograph • All high pressure sites correctly identified by trained observers Van Schie et al: Diabetic Med 1999;16:154
  39. 39. ‘Coming Events cast their shadows before.’ Thomas Campbell
  40. 40. The Diabetic Foot • Epidemiology • Causal pathways • Reducing foot pressures • Charcot Foot • Wound healing • International perspective
  41. 41. Reducing Foot Pressures • Orthoses • Padded Hosiery • Removing callus • Footwear • Surgery • Injected liquid silicone Lavery et al, 1998 Veves et al, 1989, 1990 Young et al, 1992 Murray et al, 1996 Van Schie et al, 2001, 2002
  42. 42. Diabetic Foot 2000 • First randomized controlled trial • Podosil/saline injected under callus at high pressure areas • Podosil: Increased plantar tissue thickness: reduced pressures • This treatment may reduce ulcer rates in high risk patients Van Schie et al, Diabetes Care 2000;23:634 New Treatment Does injected liquid silicone reduce ulcer risk?
  43. 43. Silicone Injection in the High Risk Diabetic Foot
  44. 44. Diabetic Foot Ulcer Prevention • Who responds best to silicone? • Podosil: Increased plantar tissue thickness greatest in those with highest baseline foot pressure • Those at highest risk of foot ulceration most likely to benefit from silicone injection. Van Schie et al, Wounds 2002;14:26 Potential New Treatment Does injected liquid silicone reduce ulcer risk?
  45. 45. Diabetic Foot 2002 • Two year follow-up study • Podosil/saline injected under callus at high pressure areas • Two year fu: pressure reduction effects of ILS reduced: plantar tissue thickness remained increased • This suggests that booster injections may periodically be required. Van Schie et al, Arch Phys Med Rehabil 2002;83:919-923 Injected Liquid Silicone (ILS) Does silicone’s pressure reducing effect last?
  46. 46. Classification of Diabetic Foot Ulcers • Wagner Grades: 0-5: classical, most frequently quoted • San Antonio: Wagner Grades and staging for ischaemia/infection • Nottingham S(AD), SAD system • King’s College SSS: Stages 1-6 Armstrong et al, 1998 Jeffcoate et al, 1999 Foster et al, 2000
  47. 47. UT Diabetic Wound Classification System 0 1 2 3 A Pre or postulcerative lesion (epithelialized) Superficial, not involving tendon, capsule or bone Penetrates to tendon or capsule Penetrates to Bone B INFECTION INFECTION INFECTION INFECTION C ISCHEMIA ISCHEMIA ISCHEMIA ISCHEMIA D INFECTION and ISCHEMIA INFECTION and ISCHEMIA INFECTION and ISCHEMIA INFECTION and ISCHEMIA Armstrong, et al, Diabetes Care, 1998Armstrong, et al, Diabetes Care, 1998
  48. 48. • 2 centre prospective observational study • 194 patients followed for 6 months • Inclusion of stage (ischaemic and/or infection) made San Antonio (UT) system a better predictor of outcome Oyibo et al, Diabetes Care 2001;24:84 San Antonio vs Wagner classifications in wound healing prediction
  49. 49. The Diabetic Foot • Epidemiology • Causal pathways • Reducing foot pressures • Charcot Foot • Wound healing • International perspective
  50. 50. Factors Affecting Wound Healing
  51. 51. Some Factors That May Influence Wound Healing • Albumin concentration • TCpO2 concentration • Infection • Hyperglycaemia • Cytokine imbalance • Protease and inhibitor imbalance • Psychological stress
  52. 52. TGF-β distribution in Diabetic Foot Ulcers • TGF-β 1,2 and 3 and TGF-β receptor distribution in foot ulcers compared with diabetic and non-diabetic skin • TGF-β 3 expression was increased in foot ulcer biopsies • TGF-β 1 expression not increased in foot ulcers • Lack of TGF-β1 upregulation may explain the chronicity and retarded wound healing Jude et al, Diabet Med 2002;19:440
  53. 53. NS DS DFU AG TGF β1 TGF β2 TGF β3 Transforming growth factors in diabetic foot ulcers
  54. 54. Lack of IGF1 in Diabetic Foot Ulcers • IGF 1 & 2 distribution in foot ulcers compared with diabetic and non-diabetic skin • IGF 2 found throughout epidermis in all three groups • IGF 1: absent in basal layer at ulcer edge and in fibroblasts • Lack of expression of IGF1 may contribute to retarded wound healing Blakytny et al, J. Pathol 2000;190:606
  55. 55. Matrix metalloproteinases in Diabetic Foot Ulcers • Punch biopsies from 20 DFUs and 12 non- diabetic traumatic wounds • MMPs 1 (x65), 2 (x6), 8(x2) and 9(x14) all increased in chronic DFUs compared to controls • Expression of TIMP-2 decreased twofold in DFU • These findings suggest that the increased proteolytic environment may be contributory to the chronicity of DFUs. Lobmann et al, Diabetologia 2002;45:1011
  56. 56. Psychological stress and wound healing • Anxiety/depression more common in DN: may impact adherence to off-loading Vileikyte et al, 2003 • Psychological stress slows healing of acute wounds Kiecolt-Glaser et al 1995 • Chronic stress can lead to increased IL-6 and altered MMP levels Yang et al 2002,, Kiecolt-Glaser et al 2003
  57. 57. Wound Care
  58. 58. Factors That Enhance Wound Healing Correct underlying condition • Control infection • Vascular reconstruction for patients with severely compromised peripheral circulation • Adequate glycaemic control for patients with diabetes • Off-load pressure • Maintain moist wound healing environment
  59. 59. Factors That Enhance Wound Healing (continued) Adequate debridement – Removes infected and non-viable tissue – May stimulate release of endogenous growth factors
  60. 60. Effect of Debridement on Healing of Diabetic Foot Ulcers Steed, et al.Steed, et al. J Am Coll SurgJ Am Coll Surg 1996;183:61-64.1996;183:61-64. 100 80 60 40 20 0 20 40 60 10080 PatientsHealed(%)PatientsHealed(%) *100 µg rhPDGF-BB per gram sodium*100 µg rhPDGF-BB per gram sodium carboxymethylcellulose gel.carboxymethylcellulose gel. Office Visits at which debridementOffice Visits at which debridement was performed (%)was performed (%) rhPDGF-BB*rhPDGF-BB* PlaceboPlacebo
  61. 61. Common Methods toCommon Methods to “Off-Load” the Foot“Off-Load” the Foot • Bed Rest • Wheel Chair • Crutch Assisted Gait • Total Contact Casts • Felted Foam • “Half Shoes” • Therapeutic Shoes • Custom Splints • Removable Cast Walkers
  62. 62. Total Contact CastTotal Contact Cast Advantages • Forced compliance • Shortens stride length • Decrease cadence • Reduces activity • Reduces peak pressures
  63. 63. Offloading the DM Wound Week of therapy 121086420 CumulativeSurvival 1.2 1.0 .8 .6 .4 .2 0.0 Device TCC Half Shoe Aircast Armstrong, et al, Diabetes Care, 2001Armstrong, et al, Diabetes Care, 2001
  64. 64. Activity Patterns of Persons with Diabetic Foot Ulceration: Persons with Active Ulceration may not Adhere to a Standard Pressure-Offloading Regimen DG Armstrong LA Lavery HR Kimbriel BP Nixon AJM Boulton From the Department of Surgery, Southern Arizona Veterans Affairs Medical Center, Tucson, AZ, USA, the Department of Medicine, Manchester Royal Infirmary, Manchester, United Kingdom, the Department of Surgery, Texas A&M University, and the Department of Medicine, University of Miami, Miami, FL, USA
  65. 65. Introduction • Pressure-offloading is a critical component in treating plantar diabetic foot wounds • Gait lab plantar pressure analysis demonstrated total contact casts (TCC) equivalent to removable cast walkers (RCW) • Yet TCCs have been shown to be clinically superior to RCWs Armstrong, et al, Diabetes Care, 2001 Frykberg, et al, J Foot Ankle Surg, 2000 Lavery et al, Diabetes Care, 1996
  66. 66. Purpose • To evaluate the activity of persons with diabetic foot ulcerations and their adherence to their pressure offloading device.
  67. 67. Methods • 20 persons were treated for UT Grade 1A neuropathic diabetic foot wounds • All were offloaded utilizing a removable cast walker (RCW) • Total activity was recorded (measured in activity units or steps per day) taken on a waist- worn computerized accelerometer • We subsequently correlated this to activity recorded on a RCW- mounted accelerometer, which was not readily accessible to the patient
  68. 68. Results • There were a mean 1219.1 ± 821.2 activity units (steps) taken per patient per day • Patients logged significantly more daily activity units with the protective removable cast walker off than with it on (873.7 ± 828.0 vs. 345.3 ± 219.1, p = 0.01) • This amounts to only 28% of total daily activity recorded while patients were wearing their removable cast walker * p = 0.01
  69. 69. Activity Data: Waist vs. RCW
  70. 70. Conclusion Armstrong, et al, J Amer Podiatr Med Assn, 2002Armstrong, et al, J Amer Podiatr Med Assn, 2002 • Modify RCW to make it less easily removable – “Instant” total contact cast
  71. 71. ‘Instant Total-Contact Cast’ vs TCC: controlled trial • TCC ‘gold standard’ but labor-intensive, expensive and time-consuming • 2 trials in progress • a): TCC vs Instant TCC • b): Instant TCC vs Cast walker Boulton and Armstrong , 2003
  72. 72. ‘Instant Total-Contact Cast’ vs TCC: controlled trial • Randomized controlled trial: 38 plantar neuropathic ulcer patients randomized to instant or regular TCC • No differences in healing times observed • Instant TCC quicker to apply and cheaper for the duration of treatment • Any center can apply instant TCC without casting experience • This treatment could revolutionize the management of plantar neuropathic ulcers Katz et al , Diabetes 2004 (In
  73. 73. Studies of new therapies for neuropathic foot ulcers: time for a paradigm shift? • Why have so many trials of dressings and other new therapies failed? • Few if any have attended to offloading • Conclusions: we propose that all future trials of therapies for plantar neuropathic ulcers should have standardized offloading in all treatment groups Boulton and Jude, 2002, Boulton and Armstrong, 2003, 2004
  74. 74. The effect of pressure relief on the histopathology of diabetic foot ulcers • Randomized trial of patients with chronic plantar diabetic neuropathic ulcers • Group A: TCC for 20 days then ulcerectomy Group B: Ulcerectomy • Histological changes compared between the two groups Piaggesi et al, 2002, 2003
  75. 75. Histological Results Hyperkeratosis 1.8 2.8 p<0.002 Fibrosis 1.8 2.8 p<0.007 Capillaries 2.5 0.5 p<0.001 Inflammation 1.1 3.0 P<0.001 Granulating 2.8 0.2 p<0.001
  76. 76. Effective offloading: histologic evidence Piaggesi, et al, Diabetes Care, 2003Piaggesi, et al, Diabetes Care, 2003 Removable offloadingRemovable offloading Irremovable offloadingIrremovable offloading
  77. 77. The effect of pressure relief on the histopathology of diabetic foot ulcers: Conclusions • Pressure not only has a direct effect on the ulcer but also supports the chronic inflammation • After pressure relief, the diabetic foot ulcer in many ways resembles an acute wound • Prolonged repetitive pressure contributes to the chronicity of diabetic neuropathic foot ulcers Piaggesi et al, 2002, 2003
  78. 78. Summary • Wound healing in diabetes is impaired • Multiple factors are impaired in diabetic wound healing • Cellular differences noted between acute and chronic wound healing • Failure to offload pressure from plantar neuropathic ulcers is a major contributory factor in ulcer chronicity
  79. 79. The future…. • Better understanding of the wound healing process in diabetes is needed • Possibly cocktail of GFs / TIMPs? • Gene expression in chronic wound healing • Gene therapy of wound healing in the not too distant future?
  80. 80. The future…. • Role of bone marrow-derived cells? Preliminary evidence suggests that they can lead to dermal rebuilding Badiavas & Falanga, 2003 • Role of Oestrogen? Oestrogen can enhance wound healing, possibly through down-regulation of macrophage MIF Ashcroft et al 2003 • Role of Androgens? Testosterone inhibits cutaneous wound healing response in males Ashcroft & Mills 2002
  81. 81. The Diabetic Foot • Epidemiology • Causal pathways • Reducing foot pressures • Charcot Foot • Wound healing • International perspective
  82. 82. ‘To live in one land is captivity’ J. Donne
  83. 83. S. America
  84. 84. Save the diabetic foot project Brasília, Brazil 1992-2002 (A ten year educational approach to make professionals concerned about foot problems and motivate the implementation of foot clinics)
  85. 85. Diabetic Foot Clinics: Implementation in Brazil - 1992 Brasília
  86. 86. Diabetic Foot Clinics* 1992/2001 Implemented - 34 In implementation – 10 Total = 44 * outpatient basis
  87. 87. 0 1 2 3 4 5 6 7 8 1992 1993 1994 1995 1996 1997 1998 1999 2000 DM - Female DM - Male Major amputation (1992/2000) Female: 2.67± 1.72 Male: 1.11 ± 0.71 ns Rate reduction (92-94 / 98-00) Female = 71,42% Male = 50%
  88. 88. For one mistake made for not knowing, ten mistakes are made for not looking. J A Lindsay
  89. 89. “Before I came to this lecture, I was confused. After hearing it I am still confused, but on a higher level” Enrico Fermi
  90. 90. “...It ought, however, to be remembered, that more credit is due to the surgeon who saves one limb, than to he who amputates twenty.” Edinburgh Med Surg J. 1805;1:187-193.
  91. 91. Who Rules the World?
  92. 92. ‘ Do not follow where the path may lead, go instead where there is no path, and leave a trail ’ Anon
  93. 93. Inferior physicians treat the full-blown disease Good physicians treat the disease before it appears Superior physicians prevent the disease Chinese proverb
  94. 94. I hear and I forget I see and I remember I do and I understand Chinese proverb
  95. 95. ‘The surest way not to fail is to be determined to succeed’ R. Sheridan
  96. 96. ‘If you always do what you always did.. You will always get what you always got Liam Donaldson
  97. 97. Success consists of going from failure to failure – without loss of enthusiasm Winston Churchill
  98. 98. ‘Prediction is always difficult – especially when it concerns the future.’ Wilde
  99. 99. The old believe everything The middle-aged suspect everything The young know everything Oscar Wilde
  100. 100. The truth is rarely pure and never simple Oscar Wilde
  101. 101. An ulcer is only a symptom of an underlying diathesis Swartz, 1910
  102. 102. www.DiabeticFootOnline.com
  103. 103. International Guidelines on the Outpatient Management of Patients with Peripheral Neuropathy
  104. 104. Annual Review of the Diabetic Patient • Should include: – Patient history • Age diabetes, lifestyle, social circumstances symptoms – Foot examination • Skin status, sweating, infection, blistering, joint mobility, gait, shoes • Tests – Pin prick test – Light touch – Vibration test – Pressure perception – Ankle reflex
  105. 105. I marvel that society would pay a surgeon a large sum of money to remove a person’s leg — but nothing to save it. George Bernard Shaw
  106. 106. ConclusionConclusion “If you don’t know where you’re going, you’ll end up someplace else.” -Yogi Berra
  107. 107. “The art of life is the art of avoiding pain; and he is the best pilot, who steers clearest of the rocks and shoals with which it is beset.” Thomas Jefferson
  108. 108. Use of Apligraf (Graftskin) in diabetic foot ulcers • Randomized trial in 208 patients • Graftskin vs saline gauze + standard treatment • 56% (Graftskin) vs 38% (control) healing (p=0.004) • Time to closure 65 vs 90 days • Graftskin is a useful adjunct to best standard care Veves, Falanga, Armstrong, Sabolinski, Diabetes Care, 2001
  109. 109. A Study of Promogran in Diabetic foot ulceration • Randomized, 11 centre trial: 276 subjects, neuropathic plantar ulcers, 12 week study • Promogran vs. moistened gauze • Offloading constant in each centre, but technique ‘left to individual’ • Results: 37% Promogran healed vs 28%: ns • Conclusions: Promogran safe and may be useful for neuropathic ulcers! Veves et al, Arch Surg 2002;137:822
  110. 110. Results • 30% of the patients in the study recorded more daily activity units while wearing the device (best behaved) – still only wore the device for a total of 60% of their total daily activity
  111. 111. Camillo Golgi, 1898 • On the structure of nerve cells • On the structure of the nerve cells of the spinal ganglia Golgi, Arch Ital Biol, 1898
  112. 112. PAIN ‘I shall never be free until I can feel pain’ Leprosy patient in Madras: cited by Dr Paul Brand
  113. 113. ‘If I were to choose between pain and nothing ….. I would choose pain’ William Faulkner
  114. 114. InflammationInflammation Proliferation/Proliferation/ RegenerationRegeneration RemodellingRemodelling WoundWound HealingHealing Phases of Wound Healing
  115. 115. Inflammation Phase InjuryInjury Clot FormationClot Formation (platelet aggregation)(platelet aggregation) Release of chemotactic agentsRelease of chemotactic agents (platelet degranulation)(platelet degranulation) Orderly recruitment of cellsOrderly recruitment of cells into wound siteinto wound site
  116. 116. Cell Influx Into Wound Site1 1. Pierce, et al1. Pierce, et al J Cell BiochemJ Cell Biochem 1991;45:319-1991;45:319- NeutrophilsNeutrophils MacrophagesMacrophages FibroblastsFibroblasts 00 22 44 66 1414 2828 4242 Days Post-InjuryDays Post-Injury 88 1010
  117. 117. Wound Healing Cascade Early CascadeEarly Cascade Late CascadeLate Cascade PMNsPMNs MacrophagesMacrophages FibroblastsFibroblasts Granulation TissueGranulation Tissue Wound StrengthWound Strength AutocrineAutocrine AutocrineAutocrine GFs PDGF TGF-ß1GFs PDGF TGF-ß1 PDGF-AA TGF-ß1PDGF-AA TGF-ß1 Procollagen 1Procollagen 1 Extracellular MatrixExtracellular Matrix 55 1010 151500 WoundingWounding ((DaysDays))
  118. 118. CONCLUSIONS • Possible future studies with higher doses • Use of oral bisphosphonates? • Earlier diagnosis essential • Better diagnostic markers • Do not forget the words of Dr Jean- Martin Charcot ……………………….
  119. 119. CHARCOT NEUROARTHROPATHY How often have I seen persons, not yet familiar with this arthropathy, misunderstand its real nature, and wholly preoccupied with the local affection, even absolutely forget that behind the disease of the joint there was a disease far more important in character and which really dominated the situation J M Charcot 1881
  120. 120. Chronic Non-healing Wounds • Chronic non-healing wounds occur when the normal healing process is compromised • Ultimately, chronic wounds may fail to heal because of decreased growth factor activity or increased protease activity, or both
  121. 121. Roles of Growth Factors in Wound Healing • All three phases of wound healing • Chemotaxis • Mitogenesis • Stimulate angiogenesis • Influence synthesis and degradation of extracellular matrix • Influence synthesis of other cytokines and growth factors
  122. 122. Nitric oxide in wound healing • NO is important in the wound healing Moncada 1991, Schaffer 1997 • Reduced NO production may impair wound healing Schaffer 1997, Boykin 1999 • NO and other nitrogenous free radicals (superoxide, peroxynitrite) cause tissue destruction Radi 1991, Beckman 1990
  123. 123. Nitric Oxide Synthase and Arginase in Diabetic Foot Ulcers • L Arginine metabolized by NO synthase or Arginase • Enzyme activity measured in foot ulcers, diabetic and normal skin • NO synthase and Arginase activities increased in foot ulcers. TGF beta 1 decreased in foot ulcers • These findings could explain impaired healing: ? Arginase effect on callus Jude et al, Diabetologia 1999;42:748
  124. 124. Adjunctive Wound Healing Modalities • Bioengineered Tissue • Growth Factors • Hyperbaric Oxygen • Vacuum-assisted therapy • Larvatherapy • Antibiotic-impregnated beads
  125. 125. “In God we trust. …all others must show data” anon
  126. 126. Cultured Human Dermis (Dermagraft) 31.7 38.5 50.8 0 10 20 30 40 50 60 Control (n = 126) Cultured Human Dermis (n = 109) Cultured Human Dermis TR (n = 61) %Healedin12Weeks%Healedin12Weeks Pollack,et. al. Wounds, 1997Pollack,et. al. Wounds, 1997
  127. 127. MANCHESTER Loretta Vileikyte Caroline Abbott Frag Abouaesha Gillian Ashcroft Anne Carrington Peter Cavanagh Cuong Dang Mark Ferguson Devaka Fernando Nicky Jackson Ed Jude Evangelos Katoulis Ann Knowles Sudhesh Kumar Rayaz Malik Ewan Masson Sam Oyibo Y Prasad Anne Roscoe Peter Selby Nick Tentolouris David Tomlinson Steve Tomlinson Carine Van Schie Aris Veves Matthew Young
  128. 128. United Kingdom SHEFFIELD John Ward Bill Armstrong Rick Betts Chris Franks Colin Hardisty Graham Knight Paul Newrick John Scarpello Solomon Tesfaye ELSEWHERE Paul Baker Nish Chaturvedi Henry Connor Mollie Donohoe Mike Edmonds Ali Foster Simon Page PK Thomas Bob Young
  129. 129. USA MIAMI Jay Skyler John Bowker Rick Cutfield F Collado-Mesa B Miranda-Palma Mark Mizel Jay Sosenko ELSEWHERE David Armstrong Peter Cavanagh Larry Harkless Larry Lavery Ben Lipsky Mark Peyrot Gary Pittenger Gayle Reiber Richard Rubin Jan Ulbrecht Arthur Vinik
  130. 130. THE WORLD BELGIUM Kristien Van Acker BRAZIL Hermelinda Pedrosa GERMANY Dan Ziegler GREECE Nicolas Katsilambros Evangelos Katoulis Christos Manes Nicolas Tentolouris Dimitris Voyatzaglou ITALY Guido Menzinger Luigi Uccioli LITHUANIA Vytas Dargis Vladimir Petrenko NETHERLANDS Karel Bakker AUSTRALIA Jonathan Shaw
  131. 131. DifferenDifferencesces in cellular infiltratein cellular infiltrate between acute and chronicbetween acute and chronic wounds?wounds? • Cross-sectional study in acute wounds vs. venous and diabetic ulcers • ECM molecules and cellular infiltrates compared • Prolonged presence of ECM molecules noted in dermis of chronic ulcers • Decreased CD4 T cells, increased B cells and macrophages in chronic ulcers Loots et al, J. Invest Dermatol, 1998;111:850
  132. 132. ““EpidemiologyEpidemiology is what you dois what you do when you run outwhen you run out of ideas”of ideas” J.D.WardJ.D.Ward
  133. 133. Ethnicity and foot ulceration and amputations • Diabetic foot ulcers much less common amongst Indian sub-continent Asians in the Manchester area Toledano et al, 1995 • Amputations 4x more common in Europids compared to Asians in NW UK Chaturvedi, Abbott et al, Diab Med 2002;19:99 • Ethnicity and Diabetic Neuropathy Ongoing study in NW UK supported by Diabetes UK Abbott, Chaturvedi et al, 2004
  134. 134. DIABETIC NEUROPATHY ‘PAIN – God’s greatest gift to mankind’ Paul Brand
  135. 135. Future MeetingsFuture Meetings 2nd International Meeting on Chronic Wounds: WUWHS meeting, Paris, France, July 8 – 13th 2004 Cleveland Clinic International Meeting on the Diabetic Foot, 2005 11th Malvern Diabetic Foot Meeting, May 2006
  136. 136. The Diabetic Foot • Epidemiology • Causal pathways • Reducing foot pressures • Charcot Foot • Wound healing • International perspective
  137. 137. Charcot Foot • Common in neuropathic patients • frequently mis-diagnosed • treatable if diagnosed early • suspect in neuropathic patient with warm, swollen foot • AN UPDATE 2004
  138. 138. • Neuropathy - sensory/autonomic • Increased blood flow • Arteriovenous shunting • Reduced BMD / Osteoporosis • ?Osteoclast activation/bone resorption Pathogenesis • Trauma
  139. 139. 1. To reduce disease activity 2. To achieve a stable joint 3. To reduce deformity Treatment Goals
  140. 140. Treatment • Casting • Non-steroidals • Immobilisation • Radiotherapy • Extra-depth shoes • Pharmacotherapy • Surgery
  141. 141. Pamidronate in Charcot • Open-labelled trial • 6 patients with acute CNA • Pamidronate 60 mg 2-weekly x6 • At each time point: - Skin temps measured (Mikron infrared thermometer) - Alkaline phosphatase Selby Diabetic Med 1994
  142. 142. 0 1 2 3 4 Temperaturedifference(°C) Temperature difference between affected and intact foot 2 4 10 126 8Basal * * * * * Weeks of therapy Selby Diabetic Med 1994
  143. 143. -30 -25 -20 -15 -10 -5 0 5 Basal 2 4 6 8 10 12 Weeks of therapy %agechangeinAP Percentage change in plasma alkaline phosphatase Selby Diabetic Med 1994
  144. 144. Randomised double-blind trial of Pamidronate in Diabetic Charcot Arthropathy Jude et al Diabetologia 2001;44:2032
  145. 145. Exeter London Nottingham Manchester
  146. 146. -3 -2 -1 0 1 0 2 4 6 8 10 12 24 36 52 Weeks Temperaturedifference(°C) Active ♦ Placebo Effect of Pamidronate on disease activity
  147. 147. 0 5 10 15 20 25 2 4 6 8 10 12 24 36 52 Weeks BSAP(u/l)Effect of Pamidronate on Bone Specific Alkaline Phosphatase Active ♦ Placebo * * * * *
  148. 148. 0 2 4 6 8 0 2 4 6 8 10 12 24 36 52 Weeks DPD(nM/mM) * * Active ♦ Placebo Effect of Pamidronate on DPD crosslinks
  149. 149. Discussion • Bone turnover markers are increased in Charcot arthropathy • Immobilisation is effective in reducing Charcot activity • Pamidronate is effective in reducing both disease activity and bone turnover markers
  150. 150. Peak pressure 2nd MTH 0 2 4 6 8 10 12 14 0 500 1000 1500 2000 Peak plantar pressure (kPa) Plantartissuethickness(mm) r = - 0.53 (p<0.001)
  151. 151. Conclusions • Plantar tissue thickness measurement is a useful alternative method to study patients at risk of foot ulceration • Follow up of these patients will point to the importance of these measurements in clinical practice Abouaesha et al, Diabetes Care 2001;24:1270
  152. 152. The ‘Instant Total-Contact Cast’ • TCC ‘gold standard’ but labor-intensive, expensive and time-consuming • Why not use cast-walker or Scotchcast boot made ‘irremovable’ • Removable device wrapped with cohesive bandage (Coband) or plaster • The device can then be re-attached weekly after removal of bandage and wound inspection • Conclusions: an ‘instant’ or ‘poor man’s’ TCC Armstrong et al, JAPMA, 2001
  153. 153. Why are trials of removable devices so disappointing? • When given specialist footwear, only 20% of patients report wearing regularly • DH walker offloads as well as TCC • DH walker worn for only 28% of daily activity • Conclusions: Despite all good intentions, offloading devices are used for a minority of daily walking activity Knowles & Boulton 1996, Lavery et al, 1996 Armstrong et al,
  154. 154. INTERNATIONAL MEETINGS ON THE DIABETIC FOOT DECEMBER 1988, Howard Johnson 57 Hotel, Boston, Mass, USA Meeting on Diabetic Foot organized by Bob Frykberg. In Attendance: Karel Bakker, John Dooren, Jan Rauwerda, Andrew Boulton
  155. 155. ‘I don’t like peripheral neuritis – it interferes with work RD Lawrence, 1923
  156. 156. Neuropathy and Foot Ulceration: Prospective Study – 169 patients, 22 controls: Manchester, UK – Spectrum of neuropathic deficits. Six year follow up – 37% ulcers, 11% amputation, 18% died – MNCV best predictor of ulcers, arterial calcification & PPT, amputation; MNCV,Creatinine & TcPO2 predicted mortality CONCLUSION: MNCV is the best surrogate endpoint for end-stage neuropathy Carrington et al, Diabetes Care 2002;25:2010-2015

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