**3.5 Management of infection**

All open wounds can potentially provide warm, moist environments attractive to microorganisms and thus run the risk of being colonized making infection difficult to diagnose microscopically. The diagnosis of infection is typically based on the presence of purulent drainage or at least 2 clinical signs of inflammation (warmth, erythema, induration, pain, and tenderness) but as these can be mimicked and obscured by the presence of neuropathy or ischemia; it has been proposed that friable tissue, wound undermining and foul odor be used to indicate infection (Pittet et al., 1999; Edmonds and Foster, 2004). Systemic signs of infection such as fever and leukocytosis are not typically seen with diabetic foot ulcers but when present, signal the infection is likely severe (Cavanagh et al., 2005).

As noted earlier, virtually all wounds are colonized so tissue specimens obtained via biopsy, curettage, or aspiration are preferable to wound swabs because results are more specific and sensitive (Lipsky et al., 2004). The most important pathogens implicated in DFU infections are aerobic gram-positive cocci especially *Staph. Aureus* but also *β* hemolytic streptococci and coagulase-negative staphylococci. Treatment of infection in bone underlying a diabetic foot ulcer presents a particular challenge. Osteomyelitis should be considered present if bone is visible in the wound or palpable with a probe. Bone scans and labeled white blood cell scans are more sensitive for detecting osteomyelitis than plain film x-rays but relatively non-specific and less accurate than MRI. A bone biopsy preferably obtained percutaneously or by surgical debridement is the gold standard test for osteomyelitis but carries the obvious risks associated with invasive testing.

#### **3.6 Wound care**

In one sense, care of a wound on a diabetic foot is no different from the care of any other wound in that the basic tenets of wound care apply. A healthy wound environment must be created by removing necrotic tissue, managing bacterial load and maintaining an appropriate moisture balance. Effective use of wound dressings provides a wound environment that encourages angiogenesis, prevents tissue dehydration, promotes cell migration and interaction of growth factors with target cells (Field, 1994). Wound care products are available in a dazzling array to address all aspects of wound bed management but there are unfortunately few RCTs available to support clinical effectiveness. However, it is important to note that local wound care is insufficient for healing of diabetic foot ulcers in most cases unless the underlying diabetic etiologic factors are addressed.

#### **3.7 Preventive surgery**

10 Rehabilitation Medicine

Debridement is necessary for removal of devitalized tissue in order to create a healthier wound bed. Removal of nonviable tissue permits better visualization of the wound base, removes a growth medium for bacteria and stimulates release of growth factors. Sharp debridement is the gold standard for diabetic foot ulcers and is the most efficient method for removing large amounts of tissue quickly. Other types of debridement include autolytic,

All open wounds can potentially provide warm, moist environments attractive to microorganisms and thus run the risk of being colonized making infection difficult to diagnose microscopically. The diagnosis of infection is typically based on the presence of purulent drainage or at least 2 clinical signs of inflammation (warmth, erythema, induration, pain, and tenderness) but as these can be mimicked and obscured by the presence of neuropathy or ischemia; it has been proposed that friable tissue, wound undermining and foul odor be used to indicate infection (Pittet et al., 1999; Edmonds and Foster, 2004). Systemic signs of infection such as fever and leukocytosis are not typically seen with diabetic foot ulcers but when present, signal the infection is likely severe (Cavanagh et al.,

As noted earlier, virtually all wounds are colonized so tissue specimens obtained via biopsy, curettage, or aspiration are preferable to wound swabs because results are more specific and sensitive (Lipsky et al., 2004). The most important pathogens implicated in DFU infections are aerobic gram-positive cocci especially *Staph. Aureus* but also *β* hemolytic streptococci and coagulase-negative staphylococci. Treatment of infection in bone underlying a diabetic foot ulcer presents a particular challenge. Osteomyelitis should be considered present if bone is visible in the wound or palpable with a probe. Bone scans and labeled white blood cell scans are more sensitive for detecting osteomyelitis than plain film x-rays but relatively non-specific and less accurate than MRI. A bone biopsy preferably obtained percutaneously or by surgical debridement is the gold standard test for osteomyelitis but carries the obvious

In one sense, care of a wound on a diabetic foot is no different from the care of any other wound in that the basic tenets of wound care apply. A healthy wound environment must be created by removing necrotic tissue, managing bacterial load and maintaining an appropriate moisture balance. Effective use of wound dressings provides a wound environment that encourages angiogenesis, prevents tissue dehydration, promotes cell migration and interaction of growth factors with target cells (Field, 1994). Wound care products are available in a dazzling array to address all aspects of wound bed management but there are unfortunately few RCTs available to support clinical effectiveness. However, it is important to note that local wound care is insufficient for healing of diabetic foot ulcers in most cases unless the underlying diabetic etiologic

**3.4 Debridement**

enzymatic, and biologic.

2005).

**3.5 Management of infection** 

risks associated with invasive testing.

**3.6 Wound care** 

factors are addressed.

Surgery may be necessary to correct biomechanical faults and/or distribute pressure in order to promote healing of a diabetic foot ulcer or prevent re-ulceration. Prophylactic surgery to correct deformities prior to ulceration has been advocated as a preventive strategy (Mueller et al., 2003). Ulcer healing can be accelerated and recurrence prevented in feet with toe deformities by utilization of extensor tenotomy (Margolis et al., 2005). Achilles tendon lengthening reduces pressure under the metatarsal heads and promotes ulcer healing but the concomitant gait alteration increases the risk of heel ulcers prompting these authors to recommend avoiding this procedure in individuals with complete sensory loss of the heel pad (Holstein et al., 2004). Metatarsal osteotomy and metatarsal head resection have been advocated by some but these procedures pose the risk of secondary ulceration or Charcot foot formation (Petrov et al., 1996; Fleischli et al., 1999). RCTs comparing surgical and non-surgical management of DFUs are scarce. Finally, any surgery is producing a wound that carries a risk of non-healing and infection.

#### **3.8 Negative pressure wound therapy**

Negative pressure wound therapy utilizes a vacuum pump to create a subatmospheric wound environment. A wound dressing, typically an open cell foam or saline moistened gauze is placed in the wound cavity to distribute the pressure. A tube connects the cavity to the vacuum pump and the area is sealed with an adhesive film. The portable vacuum pump exerts and maintains a negative pressure in the range of about 50 to 125 mmHg. The mechanical force exerted by the vacuum on the wound surface creates microstrain induced microdeformations of the wound tissue which in turn promotes cellular stretch and proliferation. Micromechanical forces resulting from the negative pressure encourage cell proliferation and migration, extracellular matrix deposition and gene expression. The subatmospheric pressure also prompts angiogenesis and reduction in local edema, excess interstitial fluid, increased lymphatic flow, and removal of waste by-products (Krasner Diane L; Rodeheaver, 2007). Authors of an RCT examining the effectiveness of NPWT in DFUs reported the incidence of secondary amputation was significantly lower when using NPWT (4.1%) compared to moist wound care (10.2%) (Blume et al., 2008). Increased granulation tissue formation and decreased healing times were seen in a RCT of 162 diabetic subjects with partial foot amputations (Armstrong et al., 2005).

#### **3.9 Hyperbaric oxygen therapy**

Recognizing that a fundamental problem in non-healing wounds was hypoxia; researchers sought ways to raise tissue oxygen levels. Hyperbaric oxygen therapy entails breathing 100% oxygen pressurized typically between 2.0 and 2.5 absolute atmospheres or ATAs (1 ATA = atmospheric pressure at sea level) with the goal of raising the oxygen partial pressure to about 1500 mmHg. Oxygen delivery to the wound is subsequently improved by the HBO-provided increase in blood oxygen concentration. In addition, HBO has been shown stimulate angiogenesis, enhance neutrophil killing ability, and stimulate fibroblast activity and collagen synthesis (Hunt and Pai, 1972; Knighton et al., 1986). A number of RCTs supporting the efficacy of HBO in the treatment of DFUs have been published but there are still questions about its therapeutic benefits (Tecilazich et al., 2011) and its nonselective use among persons with diabetic foot ulcers (Londahl et al., 2011).

Diabetic Foot Ulceration and Amputation 13

This study was supported by the Oklahoma Center for the Advancement of Science and

Abbott, C. A., A. L. Carrington, H. Ashe, S. Bath, L. C. Every, et al. (2002). "The North-West

Abouaesha, F., C. H. van Schie, G. D. Griffths, R. J. Young and A. J. Boulton (2001). "Plantar

Adler, A., S. Erqou, T. Lima and A. Robinson (2010). "Association between glycated

Adler, A. I., E. J. Boyko, J. H. Ahroni and D. G. Smith (1999). "Lower-extremity amputation

Andreassen, C. S., J. Jakobsen and H. Andersen (2006). "Muscle Weakness: A Progressive

Apelqvist, J., T. Elgzyri, J. Larsson, M. Londahl, P. Nyberg, et al. (2011). "Factors related to

Apelqvist, J., J. Larsson and C. D. Agardh (1993). "Long-term prognosis for diabetic patients

Armstrong, D. G. and L. A. Lavery (1998). "Elevated peak plantar pressures in patients who

Armstrong, D. G., L. A. Lavery and C. Diabetic Foot Study (2005). "Negative pressure

Armstrong, D. G., L. A. Lavery and L. B. Harkless (1998). "Validation of a diabetic wound

Arora, S., F. Pomposelli, F. W. LoGerfo and A. Veves (2002). "Cutaneous microcirculation in

Aso, Y., T. Inukai and Y. Takemura (1997). "Evaluation of skin vasomotor reflexes in

Benbow, S. J., D. W. Pryce, K. Noblett, I. A. MacFarlane, P. S. Friedmann, et al. (1995). "Flow motion in peripheral diabetic neuropathy." Clinical Science 88(2): 191-196.

mellitus—review and meta-analysis." Diabetologia 53(5): 840-849.

neuropathy, and foot ulcers." Diabetes Care 22(7): 1029-1035.

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tissue thickness is related to peak plantar pressure in the high-risk diabetic foot."

haemoglobin and the risk of lower extremity amputation in patients with diabetes

in diabetes. The independent effects of peripheral vascular disease, sensory

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outcome of neuroischemic/ischemic foot ulcer in diabetic patients." Journal of

have Charcot arthropathy." Journal of Bone & Joint Surgery - American Volume

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the neuropathic diabetic foot improves significantly but not completely after successful lower extremity revascularization." Journal of Vascular Surgery 35(3):

response to deep inspiration in diabetic patients by laser Doppler flowmetry. A new approach to the diagnosis of diabetic peripheral autonomic neuropathy."

**5. Acknowledgment** 

**6. References** 

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501-505.

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Diabetes Care 20(8): 1324-1328.

#### **3.10 Advanced wound care products**

Wound healing is regulated at least in part by the action of growth factors at various points in the healing cascade. Growth factors are polypeptides transiently produced by cells that exert hormone-like effects on other cells by binding to surface receptors and activating cellular proliferation and differentiation. Some of the more important growth factors for healing include platelet-derived growth factor, transforming growth factor alpha and beta, fibroblast growth factor and epithelial growth factor. Many growth factors are decreased in chronic diabetic foot ulcers. An example of a topically applied growth factor is the genetically engineered, recombinant DNA platelet-derived growth factor, becaplermin. Becaplermin addresses the lack of platelet-derived growth factor-BB and stimulates chemotaxis and mitogenesis of neutrophils, fibroblasts and monocytes. On a cautionary note, the FDA issued a black box warning for this product citing increased risk of death from cancer in patients who used 3 or more tubes of the product.

Living skin equivalents (LSE) comprise another class of advanced local wound care products that is rapidly expanding. These tissue-engineered skins offer notable advantages over skin grafting: because their use is non-invasive, anesthesia is not required, they can be applied in out-patient settings and potential donor site complications such as infection and scarring are avoided. Bioengineered tissue acts not only as a biological dressing but also facilitates healing by filling the wound with extracellular matrix and inducing the expression of growth factors and cytokines which in turn facilitate the healing cascade. LSEs are available for epidermal, dermal and composite (dermal and epidermal) wounds. Autologous grafts or autografts are comprised of cells harvested from the patient then cultured. Grafts from these master cell cultures can then be subcultured into sheets and obtained from an unrelated donor. Allergenic grafts are tissue engineered from neonatal fibroblasts and keratinocytes.
