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1.  Hyperbaric Oxygen Therapy for Non-Healing Ulcers in Diabetes Mellitus 
Executive Summary
Objective
To examine the effectiveness and cost-effectiveness of hyperbaric oxygen therapy (HBOT) to treat people with diabetes mellitus (DM) and non-healing ulcers. This policy appraisal systematically reviews the published literature in the above patient population, and applies the results and conclusions of the review to current health care practices in Ontario, Canada.
Although HBOT is an insured service in Ontario, the costs for the technical provision of this technology are not covered publicly outside the hospital setting. Moreover, access to this treatment is limited, because many hospitals do not offer it, or are not expanding capacity to meet the demand.
Clinical Need
Diabetes mellitus is a chronic disease characterized by an increase in blood sugar that can lead to many severe conditions such as vision, cardiac, and vascular disorders. The prevalence of DM is difficult to estimate, because some people who have the condition are undiagnosed or may not be captured through data that reflect access to the health care system. The Canadian Diabetic Association estimates there are about 2 million people in Canada with diabetes (almost 7% of the population). According to recent data, the prevalence of DM increased from 4.72% of the population aged 20 years and over in 1995, to 6.19% of the population aged 20 years and over in 1999, or about 680,900 people in 1999. Prevalence estimates expanded to 700,000 in 2003.
About 10% to 15% of people with DM develop a foot wound in their lifetimes because of underlying peripheral neuropathy and peripheral vascular disease. This equals between 70,000 and 105,000 people in Ontario, based on the DM prevalence estimate of 700,000 people. Without early treatment, a foot ulcer may fester until it becomes infected and chronic. Chronic wounds are difficult to heal, despite medical and nursing care, and may lead to impaired quality of life and functioning, amputation, or even death.
The Technology
Hyperbaric oxygen therapy has been in use for about 40 years. It is thought to aid wound healing by supplying oxygen to the wound. According to the Hyperbaric Oxygen Therapy Association, HBOT acts as a bactericidal, stops toxin production, and promotes tissue growth to heal difficult wounds.
During the procedure, a patient is placed in a compression chamber with increased pressure between 2.0 and 2.5 atmospheres absolute for 60 to 120 minutes, once or twice daily. In the chamber, the patient inhales 100% oxygen. Treatment usually runs for 15 to 20 sessions.
Noted complications are rare but may include claustrophobia; ear, sinus, or lung damage due to pressure; temporary worsening of short sightedness; and oxygen poisoning. Careful monitoring during the treatment sessions and follow-up by a trained health care provider is recommended.
Review Strategy
The aims of this health technology policy appraisal were to assess the effectiveness, safety, and cost-effectiveness of HBOT, either alone, or as an adjunct, compared with the standard treatments for non-healing foot or leg ulcers in patients with DM. The following questions were asked:
Alone or as an adjunct therapy, is HBOT more effective than other therapies for non-healing foot or leg ulcers in patients with DM?
If HBOT is effective, what is the incremental benefit over and above currently used strategies?
When is the best time in a wound treatment strategy to use HBOT?
What is the best treatment algorithm with HBOT?
The Medical Advisory Secretariat searched for health technology assessments in the published and grey literature. The search yielded 4 reports, which were published from 2000 to 2005. The most recent from the Cochrane Collaboration had a literature review and analysis of randomized control trials to 2003.
As an update to this review, as per the standard Medical Advisory Secretariat systematic review strategy, the abstracts of peer-reviewed publications were identified using Ovid MEDLINE, EMBASE, MEDLINE in-process and not-yet-indexed citations, Cochrane Database of Systematic Reviews, Cochrane CENTRAL, and INAHTA using key words and searching from January 1, 2003 to 2004.
The criteria for inclusion were as follows:
Patients with diabetes
Live human study
English-language study
HBOT as adjunctive therapy or alone
Randomized control trial
The number of excluded studies included the following:
2 animal studies
13 focus on condition other than DM
8 review/protocol for HBOT use
3 HBOT not focus of report
2 health technology assessments (2)
1 non-RCT
Outcomes of interest were wound healing and prevention of amputation.
The search yielded 29 articles published between 2003 and 2004. All 29 of these were excluded, as shown beside the exclusion criteria above. Therefore, this health technology policy assessment focused exclusively on the most recently published health technology assessments and systematic reviews.
Summary of Findings
Four health technology assessments and reviews were found. Cochrane Collaboration researchers published the most recent review in 2005. They included only randomized controlled trials and conducted a meta-analysis to examine wound healing and amputation outcomes. They found that, based on findings from 118 patients in 3 studies, HBOT may help to prevent major amputation (relative risk, 0.31; 95% confidence interval [CI], 0.13–0.71) with a number needed to treat (NNT) of 4 (95% CI, 3–11). They noted, however, that the point estimates derived from trials were not well reported, and had varying populations with respect to wound severity, HBOT regimens, and outcome measures. These noted limitations rendered the comparison of results from the trials difficult. Further, they suggested that the evidence was not strong enough to suggest a benefit for wound healing in general or for prevention of minor amputations.
The Medical Advisory Secretariat also evaluated the studies that the Cochrane Collaboration used in their analysis, and agreed with their evaluation that the quality of the evidence was low for major and minor amputations, but low to moderate for wound healing, suggesting that the results from new and well-conducted studies would likely change the estimates calculated by Cochrane and others.
Conclusions
In 2003, the Ontario Health Technology Advisory Committee recommended a more coordinated strategy for wound care in Ontario to the Ministry of Health and Long-term Care. This strategy has begun at the community care and long-term care institution levels, but is pending in other areas of the health care system.
There are about 700,000 people in Ontario with diabetes; of these, 10% to 15% may have a foot ulcer sometime in their lifetimes. Foot ulcers are treatable, however, when they are identified, diagnosed and treated early according to best practice guidelines. Routine follow-up for people with diabetes who may be at risk for neuropathy and/or peripheral vascular disease may prevent subsequent foot ulcers. There are 4 chambers that provide HBOT in Ontario. Fewer than 20 people with DM received HBOT in 2003.
The quality of the evidence assessing the effectiveness of HBOT as an adjunct to standard therapy for people with non-healing diabetic foot ulcers is low, and the results are inconsistent. The results of a recent meta-analysis that found benefit of HBOT to prevent amputation are therefore uncertain. Future well-conducted studies may change the currently published estimates of effectiveness for wound healing and prevention of amputation using HBOT in the treatment of non-healing diabetic foot ulcers.
Although HBOT is an insured service in Ontario, a well conducted, randomized controlled trial that has wound healing and amputation as the primary end-points is needed before this technology is used widely among patients with foot wounds due to diabetes.
PMCID: PMC3382405  PMID: 23074462
2.  Community-Based Care for Chronic Wound Management 
Executive Summary
In August 2008, the Medical Advisory Secretariat (MAS) presented a vignette to the Ontario Health Technology Advisory Committee (OHTAC) on a proposed targeted health care delivery model for chronic care. The proposed model was defined as multidisciplinary, ambulatory, community-based care that bridged the gap between primary and tertiary care, and was intended for individuals with a chronic disease who were at risk of a hospital admission or emergency department visit. The goals of this care model were thought to include: the prevention of emergency department visits, a reduction in hospital admissions and re-admissions, facilitation of earlier hospital discharge, a reduction or delay in long-term care admissions, and an improvement in mortality and other disease-specific patient outcomes.
OHTAC approved the development of an evidence-based assessment to determine the effectiveness of specialized community based care for the management of heart failure, Type 2 diabetes and chronic wounds.
Please visit the Medical Advisory Secretariat Web site at: www.health.gov.on.ca/ohtas to review the following reports associated with the Specialized Multidisciplinary Community-Based care series.
Specialized multidisciplinary community-based care series: a summary of evidence-based analyses
Community-based care for the specialized management of heart failure: an evidence-based analysis
Community-based care for chronic wound management: an evidence-based analysis
Please note that the evidence-based analysis of specialized community-based care for the management of diabetes titled: “Community-based care for the management of type 2 diabetes: an evidence-based analysis” has been published as part of the Diabetes Strategy Evidence Platform at this URL: http://www.health.gov.on.ca/english/providers/program/mas/tech/ohtas/tech_diabetes_20091020.html
Please visit the Toronto Health Economics and Technology Assessment Collaborative Web site at: http://theta.utoronto.ca/papers/MAS_CHF_Clinics_Report.pdf to review the following economic project associated with this series:
Community-based Care for the specialized management of heart failure: a cost-effectiveness and budget impact analysis.
Objective
The objective of this evidence-based review is to determine the effectiveness of a multidisciplinary wound care team for the management of chronic wounds.
Clinical Need: Condition and Target Population
Chronic wounds develop from various aetiologies including pressure, diabetes, venous pathology, and surgery. A pressure ulcer is defined as a localized injury to the skin/and or underlying tissue occurring most often over a bony prominence and caused, alone or in combination, by pressure, shear, or friction. Up to three fifths of venous leg ulcers are due to venous aetiology.
Approximately 1.5 million Ontarians will sustain a pressure ulcer, 111,000 will develop a diabetic foot ulcer, and between 80,000 and 130,000 will develop a venous leg ulcer. Up to 65% of those afflicted by chronic leg ulcers report experiencing decreased quality of life, restricted mobility, anxiety, depression, and/or severe or continuous pain.
Multidisciplinary Wound Care Teams
The term ‘multidisciplinary’ refers to multiple disciplines on a team and ‘interdisciplinary’ to such a team functioning in a coordinated and collaborative manner. There is general consensus that a group of multidisciplinary professionals is necessary for optimum specialist management of chronic wounds stemming from all aetiologies. However, there is little evidence to guide the decision of which professionals might be needed form an optimal wound care team.
Evidence-Based Analysis Methods
Literature Search
A literature search was performed on July 7, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, Wiley Cochrane, Centre for Reviews and Dissemination/International Agency for Health Technology Assessment, and on July 13, 2009 using the Cumulative Index to Nursing & Allied Health Literature (CINAHL), and the International Agency for Health Technology Assessment (INAHTA) for studies pertaining to leg and foot ulcers. A similar literature search was conducted on July 29’ 2009 for studies pertaining to pressure ulcers. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established.
Inclusion Criteria
Randomized controlled trials and Controlled clinical Trials (CCT)
Systematic review with meta analysis
Population includes persons with pressure ulcers (anywhere) and/or leg and foot ulcers
The intervention includes a multidisciplinary (two or more disciplines) wound care team.
The control group does not receive care by a wound care team
Studies published in the English language between 2004 and 2009
Exclusion Criteria
Single centre retrospective observational studies
Outcomes of Interest
Proportion of persons and/or wounds completely healed
Time to complete healing
Quality of Life
Pain assessment
Summary of Findings
Two studies met the inclusion and exclusion criteria, one a randomized controlled trial (RCT), the other a CCT using a before and after study design. There was variation in the setting, composition of the wound care team, outcome measures, and follow up periods between the studies. In both studies, however, the wound care team members received training in wound care management and followed a wound care management protocol.
In the RCT, Vu et al. reported a non-significant difference between the proportion of wounds healed in 6 months using a univariate analysis (61.7% for treatment vs. 52.5% for control; p=0.074, RR=1.19) There was also a non-significant difference in the mean time to healing in days (82 for treatment vs. 101 for control; p=0.095). More persons in the intervention group had a Brief Pain Inventory (BPI) score equal to zero (better pain control) at 6 months when compared with the control group (38.6% for intervention vs. 24.4% for control; p=0.017, RR=1.58). By multivariate analysis a statistically significant hazard ratio was reported in the intervention group (1.73, 95% CI 1.20-1.50; p=0.003).
In the CCT, Harrison et al. reported a statistically significant difference in healing rates between the pre (control) and post (intervention) phases of the study. Of patients in the pre phase, 23% had healed ulcers 3 months after study enrolment, whereas 56% were healed in the post phase (P<0.001, OR=4.17) (Figure 3). Furthermore, 27% of patients were treated daily or more often in the pre phase whereas only 6% were treated at this frequency in the post phase (P<0.001), equal to a 34% relative risk reduction in frequency of daily treatments. The authors did not report the results of pain relief assessment.
The body of evidence was assessed using the GRADE methodology for 4 outcomes: proportion of wounds healed, proportion of persons with healed wounds, wound associated pain relief, and proportion of persons needing daily wound treatments. In general, the evidence was found to be low to very low quality.
Conclusion
The evidence supports that managing chronic wounds with a multidisciplinary wound care team significantly increases wound healing and reduces the severity of wound-associated pain and the required daily wound treatments compared to persons not managed by a wound care team. The quality of evidence supporting these outcomes is low to very low meaning that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
PMCID: PMC3377537  PMID: 23074522
3.  Foot ulcers in the diabetic patient, prevention and treatment 
Lower extremity complications in persons with diabetes have become an increasingly significant public health concern in both the developed and developing world. These complications, beginning with neuropathy and subsequent diabetic foot wounds frequently lead to infection and lower extremity amputation even in the absence of critical limb ischemia. In order to diminish the detrimental consequences associated with diabetic foot ulcers, a com-mon-sense-based treatment approach must be implemented. Many of the etiological factors contributing to the formation of diabetic foot ulceration may be identified using simple, inexpensive equipment in a clinical setting. Prevention of diabetic foot ulcers can be accomplished in a primary care setting with a brief history and screening for loss of protective sensation via the Semmes-Weinstein monofilament. Specialist clinics may quantify neuropathy, plantar foot pressure, and assess vascular status with Doppler ultrasound and ankle-brachial blood pressure indices. These measurements, in conjunction with other findings from the history and physical examination, may enable clinicians to stratify patients based on risk and help determine the type of intervention. Other effective clinical interventions may include patient education, optimizing glycemic control, smoking cessation, and diligent foot care. Recent technological advanced combined with better understanding of the wound healing process have resulted in a myriad of advanced wound healing modalities in the treatment of diabetic foot ulcers. However, it is imperative to remember the fundamental basics in the healing of diabetic foot ulcers: adequate perfusion, debridement, infection control, and pressure mitigation. Early recognition of the etiological factors along with prompt management of diabetic foot ulcers is essential for successful outcome.
PMCID: PMC1994045  PMID: 17583176
diabetes; ulcer; prevention; infection; amputation
4.  Inpatient Management of Diabetic Foot Disorders: A Clinical Guide 
Diabetes Care  2013;36(9):2862-2871.
The implementation of an inpatient diabetic foot service should be the goal of all institutions that care for patients with diabetes. The objectives of this team are to prevent problems in patients while hospitalized, provide curative measures for patients admitted with diabetic foot disorders, and optimize the transition from inpatient to outpatient care. Essential skills that are required for an inpatient team include the ability to stage a foot wound, assess for peripheral vascular disease, neuropathy, wound infection, and the need for debridement; appropriately culture a wound and select antibiotic therapy; provide, directly or indirectly, for optimal metabolic control; and implement effective discharge planning to prevent a recurrence. Diabetic foot ulcers may be present in patients who are admitted for nonfoot problems, and these ulcers should be evaluated by the diabetic foot team during the hospitalization. Pathways should be in place for urgent or emergent treatment of diabetic foot infections and neuropathic fractures/dislocations. Surgeons involved with these patients should have knowledge and interest in limb preservation techniques. Prevention of iatrogenic foot complications, such as pressure sores of the heel, should be a priority in patients with diabetes who are admitted for any reason: all hospitalized diabetic patients require a clinical foot exam on admission to identify risk factors such as loss of sensation or ischemia. Appropriate posthospitalization monitoring to reduce the risk of reulceration and infection should be available, which should include optimal glycemic control and correction of any fluid and electrolyte disturbances.
doi:10.2337/dc12-2712
PMCID: PMC3747877  PMID: 23970716
5.  Negative Pressure Wound Therapy 
Executive Summary
Objective
This review was conducted to assess the effectiveness of negative pressure wound therapy.
Clinical Need: Target Population and Condition
Many wounds are difficult to heal, despite medical and nursing care. They may result from complications of an underlying disease, like diabetes; or from surgery, constant pressure, trauma, or burns. Chronic wounds are more often found in elderly people and in those with immunologic or chronic diseases. Chronic wounds may lead to impaired quality of life and functioning, to amputation, or even to death.
The prevalence of chronic ulcers is difficult to ascertain. It varies by condition and complications due to the condition that caused the ulcer. There are, however, some data on condition-specific prevalence rates; for example, of patients with diabetes, 15% are thought to have foot ulcers at some time during their lives. The approximate community care cost of treating leg ulcers in Canada, without reference to cause, has been estimated at upward of $100 million per year.
Surgically created wounds can also become chronic, especially if they become infected. For example, the reported incidence of sternal wound infections after median sternotomy is 1% to 5%. Abdominal surgery also creates large open wounds. Because it is sometimes necessary to leave these wounds open and allow them to heal on their own (secondary intention), some may become infected and be difficult to heal.
Yet, little is known about the wound healing process, and this makes treating wounds challenging. Many types of interventions are used to treat wounds.
Current best practice for the treatment of ulcers and other chronic wounds includes debridement (the removal of dead or contaminated tissue), which can be surgical, mechanical, or chemical; bacterial balance; and moisture balance. Treating the cause, ensuring good nutrition, and preventing primary infection also help wounds to heal. Saline or wet-to-moist dressings are reported as traditional or conventional therapy in the literature, although they typically are not the first line of treatment in Ontario. Modern moist interactive dressings are foams, calcium alginates, hydrogels, hydrocolloids, and films. Topical antibacterial agents—antiseptics, topical antibiotics, and newer antimicrobial dressings—are used to treat infection.
The Technology Being Reviewed
Negative pressure wound therapy is not a new concept in wound therapy. It is also called subatmospheric pressure therapy, vacuum sealing, vacuum pack therapy, and sealing aspirative therapy.
The aim of the procedure is to use negative pressure to create suction, which drains the wound of exudate (i.e., fluid, cells, and cellular waste that has escaped from blood vessels and seeped into tissue) and influences the shape and growth of the surface tissues in a way that helps healing. During the procedure, a piece of foam is placed over the wound, and a drain tube is placed over the foam. A large piece of transparent tape is placed over the whole area, including the healthy tissue, to secure the foam and drain the wound. The tube is connected to a vacuum source, and fluid is drawn from the wound through the foam into a disposable canister. Thus, the entire wound area is subjected to negative pressure. The device can be programmed to provide varying degrees of pressure either continuously or intermittently. It has an alarm to alert the provider or patient if the pressure seal breaks or the canister is full.
Negative pressure wound therapy may be used for patients with chronic and acute wounds; subacute wounds (dehisced incisions); chronic, diabetic wounds or pressure ulcers; meshed grafts (before and after); or flaps. It should not be used for patients with fistulae to organs/body cavities, necrotic tissue that has not been debrided, untreated osteomyelitis, wound malignancy, wounds that require hemostasis, or for patients who are taking anticoagulants.
Review Strategy
The inclusion criteria were as follows:
Randomized controlled trial (RCT) with a sample size of 20 or more
Human study
Published in English
Summary of Findings
Seven international health technology assessments on NPWT were identified. Included in this list of health technology assessments is the original health technology review on NPWT by the Medical Advisory Secretariat from 2004. The Medical Advisory Secretariat found that the health technology assessments consistently reported that NPWT may be useful for healing various types of wounds, but that its effectiveness could not be empirically quantified because the studies were poorly done, the patient populations and outcome measures could not be compared, and the sample sizes were small.
Six RCTs were identified that compared NPWT to standard care. Five of the 6 studies were of low or very low quality according to Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. The low and very low quality RCTs were flawed owing to small sample sizes, inconsistent reporting of results, and patients lost to follow-up. The highest quality study, which forms the basis of this health technology policy assessment, found that:
There was not a statistically significant difference (≥ 20%) between NPWT and standard care in the rate of complete wound closure in patients who had complete wound closure but did not undergo surgical wound closure (P = .15).
The authors of this study did not report the length of time to complete wound closure between NPWT and standard care in patients who had complete wound closure but who did not undergo surgical wound closure
There was no statistically significant difference (≥ 20%) in the rate of secondary amputations between the patients that received NPWT and those that had standard care (P = .06)
There may be an increased risk of wound infection in patients that receive NPWT compared with those that receive standard care.
Conclusion
Based on the evidence to date, the clinical effectiveness of NPWT to heal wounds is unclear. Furthermore, saline dressings are not standard practice in Ontario, thereby rendering the literature base irrelevant in an Ontario context. Nonetheless, despite the lack of methodologically sound studies, NPWT has diffused across Ontario.
Discussions with Ontario clinical experts have highlighted some deficiencies in the current approach to wound management, especially in the community. Because NPWT is readily available, easy to administer, and may save costs, compared with multiple daily conventional dressing changes, it may be used inappropriately. The discussion group highlighted the need to put in place a coordinated, multidisciplinary strategy for wound care in Ontario to ensure the best, continuous care of patients.
PMCID: PMC3379164  PMID: 23074484
6.  Diabetes: foot ulcers and amputations 
Clinical Evidence  2009;2009:0602.
Introduction
Diabetic foot ulceration is full-thickness penetration of the dermis of the foot in a person with diabetes. Severity is classified using the Wagner system, which grades it from 1 to 5. The annual incidence of ulcers among people with diabetes is 2.5-10.7% in resource-rich countries, and the annual incidence of amputation for any reason is 0.25-1.8%.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent foot ulcers and amputations in people with diabetes? What are the effects of treatments in people with diabetes with foot ulceration? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 41 systematic reviews and RCTs that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: debridement, human cultured dermis, human skin equivalent, patient education, pressure off-loading with felted foam or pressure-relief half-shoe, pressure off-loading with total-contact or non-removable casts, screening and referral to foot care clinics, systemic hyperbaric oxygen for non-infected ulcers, systemic hyperbaric oxygen in infected ulcers, therapeutic footwear, topical growth factors, and wound dressings.
Key Points
Diabetic foot ulceration is full-thickness penetration of the dermis of the foot in a person with diabetes. Severity is classified using the Wagner system, which grades it from 1 to 5. The annual incidence of ulcers among people with diabetes is 2.5-10.7% in resource-rich countries, and the annual incidence of amputation for any reason is 0.25-1.8%.For people with healed diabetic foot ulcers, the 5-year cumulative rate of ulcer recurrence is 66% and of amputation is 12%.
The most effective preventive measure for major amputation seems to be screening and referral to a foot care clinic if high-risk features are present. Other interventions for reducing the risk of foot ulcers include wearing therapeutic footware, and increasing patient education for prevention, but we found no sufficient evidence to ascertain the effectiveness of these treatments.
Pressure off-loading with total-contact casting or non-removable fibreglass casts successfully improves healing of ulcers. Removable-cast walkers rendered irremovable seem equally effective, but have the added benefit of requiring less technical expertise for fitting. We don't know whether pressure off-loading with felted foam or pressure-relief half-shoe is effective in treating diabetic foot ulcers.
Human skin equivalent (applied weekly for a maximum of 5 weeks) seems better at promoting ulcer healing than saline moistened gauze. Human cultured dermis does not seem effective at promoting healing.
Topical growth factors seem to increase healing rates, but there has been little long-term follow-up of people treated with these factors.
Systemic hyperbaric oxygen seems to be effective in treating people with severely infected ulcers, although it is unclear whether it is useful in people with non-infected, non-ischaemic ulcers.
We don't know whether debridement or wound dressings are effective in healing ulcers. However, debridement with hydrogel and dimethyl sulfoxide wound dressings does seem to help ulcer healing.Debridement and wound dressings have been included together because the exact mechanism of the treatment can be unclear (e.g. hydrogel).
PMCID: PMC2907821  PMID: 19445774
7.  Diabetes: foot ulcers and amputations 
Clinical Evidence  2011;2011:0602.
Introduction
Diabetic foot ulceration is full-thickness penetration of the dermis of the foot in a person with diabetes. Severity is classified using the Wagner system, which grades it from 1 to 5. The annual incidence of ulcers among people with diabetes is 2.5% to 10.7% in resource-rich countries, and the annual incidence of amputation for any reason is 0.25% to 1.8%.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent foot ulcers and amputations in people with diabetes? What are the effects of treatments in people with diabetes with foot ulceration? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 50 systematic reviews and RCTs that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: debridement, human cultured dermis, human skin equivalent, patient education, pressure off-loading with felted foam or pressure-relief half-shoe, pressure off-loading with total-contact or non-removable casts, screening and referral to foot-care clinics, systemic hyperbaric oxygen for non-infected ulcers, systemic hyperbaric oxygen in infected ulcers, therapeutic footwear, topical growth factors, and wound dressings.
Key Points
Diabetic foot ulceration is full-thickness penetration of the dermis of the foot in a person with diabetes. Severity is classified using the Wagner system, which grades it from 1 to 5. The annual incidence of ulcers among people with diabetes is 2.5% to 10.7% in resource-rich countries, and the annual incidence of amputation for any reason is 0.25% to 1.8%.For people with healed diabetic foot ulcers, the 5-year cumulative rate of ulcer recurrence is 66% and of amputation is 12%.
The most effective preventive measure for major amputation seems to be screening and referral to a foot-care clinic if high-risk features are present. Other interventions for reducing the risk of foot ulcers include wearing therapeutic footware and increasing patient education for prevention, but we found no sufficient evidence to ascertain the effectiveness of these treatments.
Pressure off-loading with total-contact casting or non-removable fibreglass casts successfully improves healing of ulcers. Removable-cast walkers rendered irremovable seem equally effective, but have the added benefit of requiring less technical expertise for fitting. We don't know whether pressure off-loading with felted foam or pressure-relief half-shoe is effective in treating diabetic foot ulcers.
Human skin equivalent (applied weekly for a maximum of 5 weeks) seems better at promoting ulcer healing than saline-moistened gauze. Human cultured dermis does not seem effective at promoting healing.
Topical growth factors seem to increase healing rates, but there has been little long-term follow-up of people treated with these factors.
Systemic hyperbaric oxygen seems to be effective in treating people with severely infected ulcers, although it is unclear whether it is useful in people with non-infected, non-ischaemic ulcers.
We don't know whether debridement or wound dressings are effective in healing ulcers. However, debridement with hydrogel and dimethyl sulfoxide wound dressings does seem to help ulcer healing.Debridement and wound dressings have been included together because the exact mechanism of the treatment can be unclear (e.g., hydrogel).
PMCID: PMC3275104  PMID: 21871137
8.  Management of Chronic Pressure Ulcers 
Executive Summary
In April 2008, the Medical Advisory Secretariat began an evidence-based review of the literature concerning pressure ulcers.
Please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/tech/tech_mn.html to review these titles that are currently available within the Pressure Ulcers series.
Pressure ulcer prevention: an evidence based analysis
The cost-effectiveness of prevention strategies for pressure ulcers in long-term care homes in Ontario: projections of the Ontario Pressure Ulcer Model (field evaluation)
Management of chronic pressure ulcers: an evidence-based analysis
Objective
The Medical Advisory Secretariat (MAS) conducted a systematic review on interventions used to treat pressure ulcers in order to answer the following questions:
Do currently available interventions for the treatment of pressure ulcers increase the healing rate of pressure ulcers compared with standard care, a placebo, or other similar interventions?
Within each category of intervention, which one is most effective in promoting the healing of existing pressure ulcers?
Background
A pressure ulcer is a localized injury to the skin and/or underlying tissue usually over a bony prominence, as a result of pressure, or pressure in conjunction with shear and/or friction. Many areas of the body, especially the sacrum and the heel, are prone to the development of pressure ulcers. People with impaired mobility (e.g., stroke or spinal cord injury patients) are most vulnerable to pressure ulcers. Other factors that predispose people to pressure ulcer formation are poor nutrition, poor sensation, urinary and fecal incontinence, and poor overall physical and mental health.
The prevalence of pressure ulcers in Ontario has been estimated to range from a median of 22.1% in community settings to a median of 29.9% in nonacute care facilities. Pressure ulcers have been shown to increase the risk of mortality among geriatric patients by as much as 400%, to increase the frequency and duration of hospitalization, and to decrease the quality of life of affected patients. The cost of treating pressure ulcers has been estimated at approximately $9,000 (Cdn) per patient per month in the community setting. Considering the high prevalence of pressure ulcers in the Ontario health care system, the total cost of treating pressure ulcers is substantial.
Technology
Wounds normally heal in 3 phases (inflammatory phase, a proliferative phase of new tissue and matrix formation, and a remodelling phase). However, pressure ulcers often fail to progress past the inflammatory stage. Current practice for treating pressure ulcers includes treating the underlying causes, debridement to remove necrotic tissues and contaminated tissues, dressings to provide a moist wound environment and to manage exudates, devices and frequent turning of patients to provide pressure relief, topical applications of biologic agents, and nutritional support to correct nutritional deficiencies. A variety of adjunctive physical therapies are also in use.
Method
Health technology assessment databases and medical databases were searched from 1996 (Medline), 1980 (EMBASE), and 1982 (CINAHL) systematically up to March 2008 to identify randomized controlled trials (RCTs) on the following treatments of pressure ulcers: cleansing, debridement, dressings, biological therapies, pressure-relieving devices, physical therapies, nutritional therapies, and multidisciplinary wound care teams. Full literature search strategies are reported in appendix 1. English-language studies in previous systematic reviews and studies published since the last systematic review were included if they had more than 10 subjects, were randomized, and provided objective outcome measures on the healing of pressure ulcers. In the absence of RCTs, studies of the highest level of evidence available were included. Studies on wounds other than pressure ulcers and on surgical treatment of pressure ulcers were excluded. A total of 18 systematic reviews, 104 RCTs, and 4 observational studies were included in this review.
Data were extracted from studies using standardized forms. The quality of individual studies was assessed based on adequacy of randomization, concealment of treatment allocation, comparability of groups, blinded assessment, and intention-to-treat analysis. Meta-analysis to estimate the relative risk (RR) or weighted mean difference (WMD) for measures of healing was performed when appropriate. A descriptive synthesis was provided where pooled analysis was not appropriate or not feasible. The quality of the overall evidence on each intervention was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) criteria.
Findings
Findings from the analysis of the included studies are summarized below:
Cleansing
There is no good trial evidence to support the use of any particular wound cleansing solution or technique for pressure ulcers.
Debridement
There was no evidence that debridement using collagenase, dextranomer, cadexomer iodine, or maggots significantly improved complete healing compared with placebo.
There were no statistically significant differences between enzymatic or mechanical debridement agents with the following exceptions:
Papain urea resulted in better debridement than collagenase.
Calcium alginate resulted in a greater reduction in ulcer size compared to dextranomer.
Adding streptokinase/streptodornase to hydrogel resulted in faster debridement.
Maggot debridement resulted in more complete debridement than conventional treatment.
There is limited evidence on the healing effects of debridement devices.
Dressings
Hydrocolloid dressing was associated with almost three-times more complete healing compared with saline gauze.
There is evidence that hydrogel and hydropolymer may be associated with 50% to 70% more complete healing of pressure ulcers than hydrocolloid dressing.
No statistically significant differences in complete healing were detected among other modern dressings.
There is evidence that polyurethane foam dressings and hydrocellular dressings are more absorbent and easier to remove than hydrocolloid dressings in ulcers with moderate to high exudates.
In deeper ulcers (stage III and IV), the use of alginate with hydrocolloid resulted in significantly greater reduction in the size of the ulcers compared to hydrocolloid alone.
Studies on sustained silver-releasing dressing demonstrated a tendency for reducing the risk of infection and promoting faster healing, but the sample sizes were too small for statistical analysis or for drawing conclusions.
Biological Therapies
The efficacy of platelet-derived growth factors (PDGFs), fibroblast growth factor, and granulocyte-macrophage colony stimulating factor in improving complete healing of chronic pressure ulcers has not been established.
Presently only Regranex, a recombinant PDGF, has been approved by Health Canada and only for treatment of diabetic ulcers in the lower extremities.
A March 2008 US Food and Drug Administration (FDA) communication reported increased deaths from cancers in people given three or more prescriptions for Regranex.
Limited low-quality evidence on skin matrix and engineered skin equivalent suggests a potential role for these products in healing refractory advanced chronic pressure ulcers, but the evidence is insufficient to draw a conclusion.
Adjunctive Physical Therapy
There is evidence that electrical stimulation may result in a significantly greater reduction in the surface area and more complete healing of stage II to IV ulcers compared with sham therapy. No conclusion on the efficacy of electrotherapy can be drawn because of significant statistical heterogeneity, small sample sizes, and methodological flaws.
The efficacy of other adjunctive physical therapies [electromagnetic therapy, low-level laser (LLL) therapy, ultrasound therapy, ultraviolet light therapy, and negative pressure therapy] in improving complete closure of pressure ulcers has not been established.
Nutrition Therapy
Supplementation with 15 grams of hydrolyzed protein 3 times daily did not affect complete healing but resulted in a 2-fold improvement in Pressure Ulcer Scale for Healing (PUSH) score compared with placebo.
Supplementation with 200 mg of zinc three times per day did not have any significant impact on the healing of pressure ulcers compared with a placebo.
Supplementation of 500 mg ascorbic acid twice daily was associated with a significantly greater decrease in the size of the ulcer compared with a placebo but did not have any significant impact on healing when compared with supplementation of 10 mg ascorbic acid three times daily.
A very high protein tube feeding (25% of energy as protein) resulted in a greater reduction in ulcer area in institutionalized tube-fed patients compared with a high protein tube feeding (16% of energy as protein).
Multinutrient supplements that contain zinc, arginine, and vitamin C were associated with a greater reduction in the area of the ulcers compared with standard hospital diet or to a standard supplement without zinc, arginine, or vitamin C.
Firm conclusions cannot be drawn because of methodological flaws and small sample sizes.
Multidisciplinary Wound Care Teams
The only RCT suggests that multidisciplinary wound care teams may significantly improve healing in the acute care setting in 8 weeks and may significantly shorten the length of hospitalization. However, since only an abstract is available, study biases cannot be assessed and no conclusions can be drawn on the quality of this evidence.
PMCID: PMC3377577  PMID: 23074533
9.  The importance of growth factors for the treatment of chronic wounds in the case of diabetic foot ulcers 
Introduction
Ulcers as a result of diabetes mellitus are a serious problem with an enormous impact on the overall global disease burden due to the increasing prevalence of diabetes. Because of long hospital stays, rehabilitation, often required home care and the use of social services diabetic foot complications are costly. Therapy with growth factors could be an effective and innovative add-on to standard wound care.
Research questions
What is the benefit of therapies with growth factors alone or in combination with other technologies in the treatment of diabetic foot ulcer assessed regarding medical, economical, social, ethical and juridical aspects?
Methods
We systematically searched relevant databases limited to English and German language and publications since 1990. Cost values were adjusted to the price level of 2008 and converted into Euro. A review and an assessment of the quality of publications were conducted following approved methodical standards conforming to evidence-based medicine and health economics.
Results
We identified 25 studies (14 randomized controlled trials (RCT), nine cost-effectiveness analyses, two meta-analyses).
The RCT compared an add-on therapy to standard wound care with standard wound care/placebo alone or extracellular wound matrix: in six studies becaplermin, in two rhEGF, in one bFGF, and in five studies the metabolically active skin grafts Dermagraft and Apligraf.
The study duration ranged from twelve to 20 weeks and the study population included between 17 to 382 patients, average 130 patients.
The treatment with becaplermin, rhEGF and skin implants Dermagraft and Apligraf showed in eight out of 13 studies an advantage concerning complete wound closure and the time to complete wound healing. Evidence for a benefit of treatment with bFGF could not be found. In four out of 14 studies the proportion of adverse events was 30% per study group with no difference between the treatment groups. The methodological quality of the studies was affected by significant deficiencies.
The results showed becaplermin being cost-effective whereas no obvious statement can be made regarding Dermagraft and Apligraf because of diverging cost bases and incremental cost-effectiveness ratios.
Discussion
Differences in standard wound care are complicating the comparison of study results. Taking into consideration the small to very small sample sizes and other methodological flaws with high potential of bias, the validity of the results with regard to effectiveness and cost-effectiveness has to be considered limited. The duration of treatment and follow-up examinations is not long enough to assess the sustainability of the intervention and the surveillance of ulcer recurrences or treatment related adverse events like the development of malignancy.
Conclusions
There are indications of an advantage for the add-on therapy with growth factors in diabetic foot ulcers concerning complete wound closure and the time to complete wound healing. Further more studies of high methodological quality with adequate sample sizes and sufficient follow-up periods are necessary also investigating patient-relevant parameters like the health-related quality of life, the acceptance and tolerance of the intervention in addition to clinical outcomes.
doi:10.3205/hta000090
PMCID: PMC3010891  PMID: 21289885
diabetic foot; diabetes mellitus; diabetes mellitus type 01; diabetes mellitus type 02; diabetes mellitus, type 1; diabetes mellitus, type 2; diabetes mellitus, type I; diabetes mellitus, type II; diabetes related complications; wound healing; platelet activating factor; platelet-derived growth factor; recombinant proteins; controlled clinical trials, randomized; random allocation; review literature as topic; growth factor; therapy with growth factors; diabetes; foot ulcer; infection control; wound care; wound management; diabetic ulcer; diabetic foot ulcer; podology; hard healing wound; care; interdisciplinary team; efficiency; efficacy; cost-effectiveness; systematic review; HTA; Health Technology Assessment; health economics
10.  The Influence of Beliefs About Health and Illness on Foot Care in Ugandan Persons with Diabetic Foot Ulcers 
The Open Nursing Journal  2013;7:123-132.
Diabetes mellitus is becoming pandemic, particularly affecting Sub-Saharan Africa, and the prevalence of complications is increasing. Diabetic foot disorders are a major source of morbidity and disability. Delay in the health care process due to patients’ beliefs may have deleterious consequences for limb and life in persons with diabetic foot ulcers. No previous studies of beliefs about health and illness in persons with diabetic foot ulcers living in Africa have been found. The aim of the study was to explore beliefs about health and illness among Ugandans with diabetic foot ulcers that might affect self-care and care seeking behaviour. In an explorative study with consecutive sample semi-structured interviews were held with 14 Ugandan men and women, aged 40-79, with diabetic foot ulcer. Knowledge was limited about causes, management and prevention of diabetic foot ulcers. Foot ulcers were often detected as painful sores, perceived to heal or improve, and led to stress and social isolation due to smell and reduced mobility. Most lacked awareness of the importance of complete daily foot care and seldom practised self-care. Health was described as absence of disease and pain. Many feared future health and related it to contact with nurses in the professional sector from whom they sought information, blood tests and wound dressings and desired better organised diabetes clinics offering health education and more opening hours. Many have an underutilised potential for self-care and need education urgently, delivered in well-organised diabetes clinics working to raise awareness of the threat and prevent foot ulcers.
doi:10.2174/1874434601307010123
PMCID: PMC3771228  PMID: 24039644
Africans; attitudes to health/illness; beliefs about health/illness; care-seeking behaviour; diabetes mellitus complications; foot ulcer; self-care.
11.  The management of neuropathic ulcers of the foot in diabetes by shock wave therapy 
Background
Diabetes is becoming one of the most common chronic diseases, and ulcers are its most serious complication. Beginning with neuropathy, the subsequent foot wounds frequently lead to lower extremity amputation, even in the absence of critical limb ischemia. In recent years, some researchers have studied external shock wave therapy (ESWT) as a new approach to soft tissue wound healing. The rationale of this study was to evaluate if ESWT is effective in the management of neuropathic diabetic foot ulcers.
Methods
We designed a randomized, prospective, controlled study in which we recruited 30 patients affected by neuropathic diabetic foot ulcers and then divided them into two groups based on different management strategies. One group was treated with standard care and shock wave therapy. The other group was treated with only standard care. The healing of the ulcers was evaluated over 20 weeks by the rate of re-epithelization.
Results
After 20 weeks of treatment, 53.33% of the ESWT-treated patients had complete wound closure compared with 33.33% of the control patients, and the healing times were 60.8 and 82.2 days, respectively (p < 0.001). Significant differences in the index of the re-epithelization were observed between the two groups, with values of 2.97 mm2/die in the ESWT-group and 1.30 mm2/die in the control group (p < 0.001).
Conclusion
Therefore, ESWT may be a useful adjunct in the management of diabetic foot ulceration.
Trial registration
Current Controlled Trials ISRCTN21800909
doi:10.1186/1471-2474-10-54
PMCID: PMC2693140  PMID: 19473538
12.  Prognostic Significance of Circulating and Endothelial Progenitor Cell Markers in Type 2 Diabetic Foot 
Objective. We studied circulating precursor cells (CPC) in type 2 diabetes mellitus (T2DM) with neuropathic foot lesions with or without critical limb ischemia and relationships between endothelial precursor cells (EPC) and peripheral neuropathy. Methods and Subjects. We measured peripheral blood CD34, CD133, and CD45 markers for CPC and KDR, CD31 markers for EPC by citofluorimetry and systemic neural nociceptor CGRP (calcitonin gene related protein) by ELISA in 8 healthy controls (C) and 62 T2DM patients: 14 with neuropathy (N), 20 with neuropathic foot lesions (N1), and 28 with neuroischemic recent revascularized (N2) foot lesions. Timing of lesions was: acute (until 6 weeks), healed, and not healed. Results. CD34+ and CD133+ were reduced in N, N1, and N2 versus C, and CD34+ were lower in N2 versus N1 (P = 0.03). In N2 CD34+KDR+ remain elevated in healed versus chronic lesions and, in N1 CD133+31+ were elevated in acute lesions. CGRP was reduced in N2 and N1 versus C (P < 0.04 versus C 26 ± 2 pg/mL). CD34+KDR+ correlated in N2 with oximetry and negatively in N1 with CGRP. Conclusions. CD34+ CPC are reduced in diabetes with advanced complications and diabetic foot. CD34+KDR+ and CD31+133+ EPC differentiation could have a prognostic and therapeutic significance in the healing process of neuropathic and neuroischemic lesions.
doi:10.1155/2014/589412
PMCID: PMC3929532  PMID: 24624298
13.  Commentary on the Conversion to an Advanced Standard of Care for the Treatment of Diabetic Foot Ulcers and Other Chronic Wounds 
There have been notable contributions in the literature regarding the consensus for a new standard for the treatment of diabetic foot ulcers. The more recent advances in wound care therapies, modalities, and evidence-based research have demonstrated that an advanced standard of care for wound healing should exist. Failure of treatment protocols, which center on a 50% area of wound reduction within 4 weeks as a response to standard conventional care, should indicate the use of adjuvant therapies. Negative pressure wound therapy (NPWT), hyperbaric oxygen therapy (HBOT), growth factors, human-derived bioengineered tissue, and extracellular matrix products are readily available. This commentary will explore a brief selection of the current wound care literature as it relates to the acceptance of a new advanced standard of care. Furthermore, the intention is to stimulate further discussion and thought on the relevance of this approach in the treatment of diabetic foot ulcers and chronic wounds and how it may correlate with the ultimate outcome of healing in general.
doi:10.1016/j.jcws.2010.09.003
PMCID: PMC3601923  PMID: 24527143
Adjuvant therapy; Advanced standard of care; Bioengineered tissue; Chronic wounds; Diabetic ulcers; Extracellular matrix; HBOT; NPWT; Standard of care; Timely wound care; Wound healing; Wound management
14.  Diabetic foot ulcers. Pathophysiology, assessment, and therapy. 
Canadian Family Physician  2001;47:1007-1016.
OBJECTIVE: To review underlying causes of diabetic foot ulceration, provide a practical assessment of patients at risk, and outline an evidence-based approach to therapy for diabetic patients with foot ulcers. QUALITY OF EVIDENCE: A MEDLINE search was conducted for the period from 1979 to 1999 for articles relating to diabetic foot ulcers. Most studies found were case series or small controlled trials. MAIN MESSAGE: Foot ulcers in diabetic patients are common and frequently lead to lower limb amputation unless a prompt, rational, multidisciplinary approach to therapy is taken. Factors that affect development and healing of diabetic patients' foot ulcers include the degree of metabolic control, the presence of ischemia or infection, and continuing trauma to feet from excessive plantar pressure or poorly fitting shoes. Appropriate wound care for diabetic patients addresses these issues and provides optimal local ulcer therapy with débridement of necrotic tissue and provision of a moist wound-healing environment. Therapies that have no known therapeutic value, such as foot soaking and topical antiseptics, can actually be harmful and should be avoided. CONCLUSION: Family physicians are often primary medical contacts for patients with diabetes. Patients should be screened regularly for diabetic foot complications, and preventive measures should be initiated for those at risk of ulceration.
PMCID: PMC2018500  PMID: 11398715
15.  Patients' perspectives on foot complications in type 2 diabetes: a qualitative study 
Background
Foot ulceration is a major health problem for people with diabetes. To minimise the risk of ulceration, patients are advised to perform preventive foot self-care.
Aim
To explore beliefs about diabetic foot complications and everyday foot self-care practices among people with type 2 diabetes.
Design of study
Qualitative study using one-to-one interviews.
Setting
A suburban primary care health centre.
Method
Semi-structured interviews with a purposive sample of adults with type 2 diabetes but with no experience of foot ulceration.
Results
Most participants were unsure of what a foot ulcer is and unaware of the difficulties associated with ulcer healing. Prevention of accidental damage to the skin was not considered a priority, as few participants knew that this is a common cause of foot ulceration. Although it was recognised that lower-limb amputation is more common in people with diabetes, this was perceived to be predominantly caused by poor blood supply to the feet and unrelated to foot ulceration. Therefore, preventive foot care focused on stimulating blood circulation, for example by walking barefoot. Consequently, some of the behaviours participants considered beneficial for foot health could potentially increase the risk of ulceration. In some cases the uptake of advice regarding preventive foot care was hampered because participants found it difficult to communicate with health professionals.
Conclusion
Patients with type 2 diabetes may have beliefs about foot complications that differ from medical evidence. Such illness beliefs may play a role in foot-related behaviours that have previously been unrecognised. Health professionals need to explore and address the beliefs underlying patients' foot self-care practices.
doi:10.3399/bjgp08X319657
PMCID: PMC2566520  PMID: 18682014
diabetes mellitus; foot complications; foot self-care; illness beliefs; ulcer prevention
16.  Neuropathic diabetic foot ulcers – evidence-to-practice 
Foot ulcers and their attendant complications are disquietingly high in people with diabetes, a majority of whom have underlying neuropathy. This review examines the evidence base underpinning the prevention and management of neuropathic diabetic foot ulcers in order to inform best clinical practice. Since it may be impractical to ask patients not to weight-bear at all, relief of pressure through the use of offloading casting devices remains the mainstay for management of neuropathic ulcers, whilst provision of appropriate footwear is essential in ulcer prevention. Simple non-surgical debridement and application of hydrogels are both effective in preparing the wound bed for healthy granulation and therefore enhancing healing. Initial empirical antibiotic therapy for infected ulcers should cover the most common bacterial flora. There is limited evidence supporting the use of adjunctive therapies such as hyperbaric oxygen and cytokines or growth factors. In selected cases, recombinant human platelet-derived growth factor has been shown to enhance healing; however, its widespread use cannot be advised due to the availability of more cost-effective approaches. While patient education may be beneficial, the evidence base remains thin and conflicting. In conclusion, best management of foot ulcers is achieved by what is taken out of the foot (pressure, callus, infection, and slough) rather than what is put on the foot (adjuvant treatment).
Video abstract
Video
doi:10.2147/IJGM.S10328
PMCID: PMC3282596  PMID: 22371655
diabetic foot ulcers; neuropathic foot ulcers; foot ulcers
17.  Contemporary Evaluation and Management of the Diabetic Foot 
Scientifica  2012;2012:435487.
Foot problems in patients with diabetes remain a major public health issue and are the commonest reason for hospitalization of patients with diabetes with prevalence as high as 25%. Ulcers are breaks in the dermal barrier with subsequent erosion of underlying subcutaneous tissue that may extend to muscle and bone, and superimposed infection is a frequent and costly complication. The pathophysiology of diabetic foot disease is multifactorial and includes neuropathy, infection, ischemia, and abnormal foot structure and biomechanics. Early recognition of the etiology of these foot lesions is essential for good functional outcome. Managing the diabetic foot is a complex clinical problem requiring a multidisciplinary collaboration of health care workers to achieve limb salvage. Adequate off-loading, frequent debridement, moist wound care, treatment of infection, and revascularization of ischemic limbs are the mainstays of therapy. Even when properly managed, some of the foot ulcers do not heal and are arrested in a state of chronic inflammation. These wounds can frequently benefit from various adjuvants, such as aggressive debridement, growth factors, bioactive skin equivalents, and negative pressure wound therapy. While these, increasingly expensive, therapies have shown promising results in clinical trials, the results have yet to be translated into widespread clinical practice leaving a huge scope for further research in this field.
doi:10.6064/2012/435487
PMCID: PMC3820495  PMID: 24278695
18.  Effect of telemedicine follow-up care of leg and foot ulcers: a systematic review 
Background
Leg ulcers and diabetes-related foot ulcers are frequent and costly complications of their underlying diseases and thus represent a critical issue for public health. Since the population is aging, the prevalence of these conditions will probably increase considerably and require more resources. Treatment of leg and foot ulcers often demands frequent contact with the health care system, may pose great burden on the patient, and involves follow-up in both primary and specialist care. Telemedicine provides potential for more effective care management of leg and foot ulcers. The objective of this systematic review of the literature was to assess the effect of telemedicine follow-up care on clinical, behavioral or organizational outcomes among patients with leg and foot ulcers.
Methods
We searched Ovid MEDLINE (1980–), Ovid EMBASE (1980–), Clinical Trials in the Cochrane Library (via Wiley), Ebsco CINAHL with Fulltext (1981–) and SveMed + (1977–) up to May 2014 for relevant articles. We considered randomized controlled trials, non-randomized trials, controlled before-after studies and prospective cohort studies for inclusion and selected studies according to predefined criteria. Three reviewers independently assessed the included studies using the Cochrane Collaboration risk-of-bias tool. We performed a narrative synthesis of results and assessed the strength of evidence for each outcome using GRADE (grading of recommendations, assessment, development and evaluation).
Results
Only one non-randomized study was included. The study (n = 140) measured the effect of real-time interactive video consultation compared with face-to-face follow-up on healing time, adjusted healing ratio and the number of ulcers at 12 weeks among patients with neuropathic forefoot ulcerations. There were no statistically significant differences in results of the different outcomes between patients receiving telemedicine and traditional follow-up. We assessed the study to have a high risk of bias.
Conclusions
There is insufficient evidence available to unambiguously determine whether telemedicine consultation of leg and foot ulcers is as effective as traditional follow-up.
doi:10.1186/s12913-014-0565-6
PMCID: PMC4230629  PMID: 25373875
Systematic review; Foot ulcers; Leg ulcers; Telemedicine
19.  A Three Species Model to Simulate Application of Hyperbaric Oxygen Therapy to Chronic Wounds 
PLoS Computational Biology  2009;5(7):e1000451.
Chronic wounds are a significant socioeconomic problem for governments worldwide. Approximately 15% of people who suffer from diabetes will experience a lower-limb ulcer at some stage of their lives, and 24% of these wounds will ultimately result in amputation of the lower limb. Hyperbaric Oxygen Therapy (HBOT) has been shown to aid the healing of chronic wounds; however, the causal reasons for the improved healing remain unclear and hence current HBOT protocols remain empirical. Here we develop a three-species mathematical model of wound healing that is used to simulate the application of hyperbaric oxygen therapy in the treatment of wounds. Based on our modelling, we predict that intermittent HBOT will assist chronic wound healing while normobaric oxygen is ineffective in treating such wounds. Furthermore, treatment should continue until healing is complete, and HBOT will not stimulate healing under all circumstances, leading us to conclude that finding the right protocol for an individual patient is crucial if HBOT is to be effective. We provide constraints that depend on the model parameters for the range of HBOT protocols that will stimulate healing. More specifically, we predict that patients with a poor arterial supply of oxygen, high consumption of oxygen by the wound tissue, chronically hypoxic wounds, and/or a dysfunctional endothelial cell response to oxygen are at risk of nonresponsiveness to HBOT. The work of this paper can, in some way, highlight which patients are most likely to respond well to HBOT (for example, those with a good arterial supply), and thus has the potential to assist in improving both the success rate and hence the cost-effectiveness of this therapy.
Author Summary
In the time it takes you to read this paragraph, one person will have undergone a lower limb amputation due to diabetic foot disease. With the global diabetes population on the rise and set to reach 330 million by 2025, the need for research into therapies and technologies that have the potential to prevent amputation is dire. There is much debate about the best way to treat these wounds, and one treatment that is shrouded with controversy is Hyperbaric Oxygen Therapy (HBOT). There are currently no conclusive data showing that HBOT can assist chronic wound healing, but there has been some clinical success. In light of how expensive properly designed clinical trials can be, we must turn to alternative methods of assessment, such as the theoretical model presented here. The mathematical model reproduces a number of clinical observations. A key result is that while HBOT can assist chronic diabetic wounds, it holds little benefit for wounds that would heal of their own accord. This model represents a useful tool to analyse the optimal protocol, and the results and insights gained from the model may be used to improve both the success rate and thus the cost-effectiveness of this therapy.
doi:10.1371/journal.pcbi.1000451
PMCID: PMC2710516  PMID: 19649306
20.  Effects of topical Kiwifruit on healing of neuropathic diabetic foot ulcer 
Background:
Kiwifruit (Actindia Deliciosa) is demonstrated to have antibacterial and pro-angiogenic effects. It also contains proteolytic enzymes (actinidin) and ascorbic acid. In this study, the effects of Kiwifruit on neuropathic diabetic foot ulcer healing in clinical settings were evaluated.
Materials and Methods:
In this randomized clinical trial of 37 patients (17 in experimental and 20 in control groups) with neuropathic diabetic foot ulcer were studied in Isfahan-Iran. Patients of the control group received just the standard treatments. In the experimental group, in addition to the standard treatments, ulcers were dressed with pure extract of kiwifruit twice daily for 21 days. The ulcers were examined and evaluated based on macroscopic, microscopic and microbiological status. Pre- and post-interventions, biopsies were taken from the ulcers to perform microbiological and histological studies.
Results:
Mean reduction in surface area of foot ulcer in the experimental group was significantly higher than the control group (168.11 ± 22.31 vs. 88.80 ± 12.04 mm2 respectively, P < 0.0001). The amount of collagen and granulation tissues was significantly higher in the experimental groups than the control group (P value < 0.0001). Significantly higher levels of angiogenesis and vascularization were found in the kiwifruit treated patients (P value < 0.0001). No significant antibacterial effect was observed for kiwifruit.
Conclusion:
Natural compounds in the kiwifruit including protein-dissolving enzymes (Actinidin) improved different aspects of the wound healing process. Based on these benefits and safety aspects, we conclude that using kiwifruit is a simple, applicable and effective way for treatment of neuropathic diabetic foot ulcer.
PMCID: PMC4155706  PMID: 25197293
Diabetic foot; diabetic foot ulcer; fruit; kiwifruit; wound healing
21.  Improved Survival of Diabetic Foot Ulcer Patients 1995–2008 
Diabetes Care  2008;31(11):2143-2147.
OBJECTIVE—The purpose of this study was to determine whether a strategy of aggressive cardiovascular risk management reduced the mortality associated with diabetic foot ulceration.
RESEARCH DESIGN AND METHODS—After an initial audit of outcomes demonstrating a high mortality rate in 404 diabetic foot ulcer patients with the first ulceration developing between 1995 and 1999, a new aggressive cardiovascular risk policy was introduced as standard practice at the Diabetic Foot Clinic, Royal Infirmary of Edinburgh, in 2001. In the first 3 years of this policy, 251 patients were screened and identified. The audit cycle was then closed by reauditing the 5-year mortality for this second group of foot ulcer patients in 2008.
RESULTS—Overall 5-year mortality was reduced from 48.0% in cohort 1 to 26.8% in cohort 2 (P < 0.001). Improvement in survival was seen for both neuroischemic patients (5-year mortality of 58% reduced to 36%; relative reduction 38%) and neuropathic patients (36% reduction to 19%; relative reduction 47%) (both P < 0.001). Patients were more likely to die if they were older at the time of ulceration or had type 2 diabetes, renal impairment, or preexisting cardiovascular disease or were already taking aspirin. Prior statin use, current smoker or ex-smoker status, blood pressure, A1C, and total cholesterol were not significantly different between survivors and those who died in the follow-up periods.
CONCLUSIONS—Diabetic foot ulcer patients have a high risk of death. Survival has improved over the past 13 years. The adoption of an aggressive cardiovascular risk management policy in diabetic foot ulcer clinics is recommended for these patients.
doi:10.2337/dc08-1242
PMCID: PMC2571064  PMID: 18697900
22.  Dialysis Treatment Is an Independent Risk Factor for Foot Ulceration in Patients With Diabetes and Stage 4 or 5 Chronic Kidney Disease 
Diabetes Care  2010;33(8):1811-1816.
OBJECTIVE
To determine whether dialysis treatment is an independent risk factor for foot ulceration in patients with diabetes and renal impairment.
RESEARCH DESIGN AND METHODS
We performed a cross-sectional study of consecutive patients with diabetes and stage 4 or 5 chronic kidney disease (CKD) attending clinics in Manchester (U.K.). Patients were classified as either receiving dialysis therapy (dialysis) or not (no dialysis). Foot assessment included diabetic peripheral neuropathy (DPN), peripheral arterial disease (PAD), prior foot ulceration and amputation, and foot self-care. Risk factors for prevalent foot ulceration were assessed by logistic regression.
RESULTS
We studied 326 patients with diabetes and CKD (mean age 64 years; 61% male; 78% type 2 diabetes; 11% prevalent foot ulceration). Compared with no dialysis patients, dialysis patients had a higher prevalence of DPN (79 vs. 65%), PAD (64 vs. 43%), prior amputations (15 vs. 6.4%), prior foot ulceration (32 vs. 20%), and prevalent foot ulceration (21 vs. 5%, all P < 0.05). In univariate analyses, foot ulceration was related to wearing bespoke footwear (odds ratio 5.6 [95% CI 2.5–13]) dialysis treatment (5.1 [2.3–11]), prior foot ulceration (4.8 [2.3–9.8], PAD (2.8 [1.3–6.0], and years of diabetes (1.0 [1.0–1.1], all P < 0.01). In multivariate logistic regression, only dialysis treatment (4.2 [1.7–10], P = 0.002) and prior foot ulceration (3.1 [1.3–7.1], P = 0.008) were associated with prevalent foot ulceration.
CONCLUSIONS
Dialysis treatment was independently associated with foot ulceration. Guidelines should highlight dialysis as an important risk factor for foot ulceration requiring intensive foot care.
doi:10.2337/dc10-0255
PMCID: PMC2909067  PMID: 20484126
23.  Cascade® Autologous System Platelet-Rich Fibrin Matrix in the Treatment of Chronic Leg Ulcers 
Advances in Wound Care  2012;1(1):52-55.
Problem
Lower extremity ulcers (venous, diabetic) are often unresponsive to standard treatment. Various systemic and local cellular, vascular, and anatomical factors can result in nonhealing wounds that are refractory to normal healing processes and standard care.
Solution
Several published wound care guidelines strongly suggest that if an ulcer does not respond to standard good wound care within 4 weeks, then advanced wound therapies should be considered. These advanced therapies include wound bed preparation agents (negative wound pressure therapy, hyperbaric oxygen), recombinant growth factors, or bioengineered cell therapies.
New Technology
The Cascade® system produces platelet-rich fibrin matrix (PRFM), a novel autologous sterile biologic, produced at the bedside from a small volume (18 mL) of the patient's own blood by using Vacutainer® separation technology optimized for fibrin and platelet isolation. Prepared as an easy to apply, suturable membrane, without the use of exogenous thrombin, PRFM consists of a dense cross-linked fibrin lattice containing intact, viable platelets with their full complement of platelet-derived growth factors.
Indications for Use
From the FDA 510(k) clearance: The Cascade system “is designed to be used for the safe and rapid preparation of autologous platelet-rich plasma from a small sample of blood at the patient point of care.” PRFM has been used to successfully treat severe venous leg ulcer (VLU), neuropathic diabetic foot ulcer (DFU), mixed arterial and Charcot-deformity associated foot ulcers.
Cautions
When treating venous or DFUs, the Cascade system should be used together with standard wound care practice (therapeutic compression for VLU and weight off-loading, debridement, and infection control for DFU) in patients with an adequate blood supply to the lower limb.
doi:10.1089/wound.2011.0290
PMCID: PMC3839008  PMID: 24527280
24.  Infrared Thermal Imaging for Automated Detection of Diabetic Foot Complications 
Background
Although thermal imaging can be a valuable technology in the prevention and management of diabetic foot disease, it is not yet widely used in clinical practice. Technological advancement in infrared imaging increases its application range. The aim was to explore the first steps in the applicability of high-resolution infrared thermal imaging for noninvasive automated detection of signs of diabetic foot disease.
Methods
The plantar foot surfaces of 15 diabetes patients were imaged with an infrared camera (resolution, 1.2 mm/pixel): 5 patients had no visible signs of foot complications, 5 patients had local complications (e.g., abundant callus or neuropathic ulcer), and 5 patients had diffuse complications (e.g., Charcot foot, infected ulcer, or critical ischemia). Foot temperature was calculated as mean temperature across pixels for the whole foot and for specified regions of interest (ROIs).
Results
No differences in mean temperature >1.5 °C between the ipsilateral and the contralateral foot were found in patients without complications. In patients with local complications, mean temperatures of the ipsilateral and the contralateral foot were similar, but temperature at the ROI was >2 °C higher compared with the corresponding region in the contralateral foot and to the mean of the whole ipsilateral foot. In patients with diffuse complications, mean temperature differences of >3 °C between ipsilateral and contralateral foot were found.
Conclusions
With an algorithm based on parameters that can be captured and analyzed with a high-resolution infrared camera and a computer, it is possible to detect signs of diabetic foot disease and to discriminate between no, local, or diffuse diabetic foot complications. As such, an intelligent telemedicine monitoring system for noninvasive automated detection of signs of diabetic foot disease is one step closer. Future studies are essential to confirm and extend these promising early findings.
PMCID: PMC3876354  PMID: 24124937
automatic detection; diabetic foot; infrared imaging; prevention; telemedicine; thermography
25.  A review of becaplermin gel in the treatment of diabetic neuropathic foot ulcers 
Diabetic neuropathic foot ulcers represent a serious health care burden to patients and to society. While the management of chronic diabetic foot ulcers has improved in recent years, it remains a frustrating problem for a variety of clinicians. This review examines the scientific underpinnings supporting the use of becaplermin (Regranex®; Ortho-McNeil Pharmaceutical, Raritan, NJ), or recombinant human platelet-derived growth factor (rhPDGF-BB), in diabetic forefoot wounds. An emphasis is placed upon proper medical and surgical care of diabetic foot wounds, as multiple studies have demonstrated that the success of this growth factor in accelerating healing is ultimately dependent on proper ulcer care. A focus on the cost-effectiveness of this form of therapy in the treatment of diabetic foot ulcers is also outlined.
PMCID: PMC2727777  PMID: 19707423
becaplermin; diabetes; foot ulcer; growth factor

Results 1-25 (1084507)