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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.  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
4.  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
5.  Wound Care Specialization: The Current Status and Future Plans to Move Wound Care into the Medical Community 
Advances in Wound Care  2012;1(5):184-188.
Background
There has been an explosion of basic science results in the field of wound care over the past 20 years. Initially, wound dressings were the only therapeutic option available to the wound practitioner. With advanced basic science knowledge, technical innovation, and the recent participation of pharmaceutical companies, the wound clinician now has an arsenal of dressings, biological tissue replacements, gene therapy, and cell-based treatment options. What has not, however, kept pace with these changes is the education and practical training for those treating nonhealing wounds. The pace of innovation in wound diagnostic tools has also lagged, creating even more pressure on the clinician to use experience, skill, and training to properly diagnose the root cause for the nonhealing wound. As wound healing is not considered a medical specialty, there is no formal training process for physicians, and subsequently, allied health practitioners are often the only ones available to provide care for these complex patients. Wound care training, however, is also not part of any formal curriculum for these healthcare providers as well, creating confusion for patients, payors, regulators, researchers, and product manufacturers.
The Problem
In all other fields of medicine there is a formal process in place for physicians to train, certify, and credential. Medicine is constantly evolving and there have been several new fields of specialty care created over the past two decades that can serve as examples for the wound care field to follow. Without academic-based, clinical residency/fellowship training in wound healing ultimately leading to formal certification, the field will be unable to achieve an appropriate status in the medical establishment. Achieving this goal will impact product innovation, payment, and the sustainability of the field.
Basic/Clinical Science Advances
The enhanced understanding of normal and dysregulated wound healing processes, which have been uncovered by basic scientists, has translated to the bedside through the creation of multiple advanced biological solutions for patients with nonhealing wounds.
Clinical Care Relevance
These advanced wound care therapeutics will require physician involvement in a way not previously seen in wound care. It will no longer be possible to practice wound care “part time” in the near future. The amount of new information and massive base of core knowledge required will mandate a full-time commitment. The increase in patients with this condition because of an aging population, increased numbers of diabetic patients, and the ever growing epidemic of obesity will mandate that all clinicians providing wound care will need to increase their skill sets through formal training. In addition, underserved patient populations are disproportionately affected and their outcomes are comparatively worse, further complicating the problem at a healthcare structural and policy level.
Conclusion
The American College of Wound Healing and Tissue Repair was founded in Illinois as a nonprofit organization whose express function is to organize university-based medical school programs around a common curriculum for physicians who want to specialize in wound healing. Currently, two wound care fellows have graduated from the University of Illinois at Chicago and other programs are under development. The ultimate process will be achieved when certification is accredited by an organization such as the American Board of Medical Specialties. This article outlines the current process in place to achieve this goal within 10 years.
doi:10.1089/wound.2011.0346
PMCID: PMC3839023  PMID: 24527303
6.  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
7.  Choice of wound care in diabetic foot ulcer: A practical approach 
World Journal of Diabetes  2014;5(4):546-556.
Diabetic foot ulcers are the consequence of multiple factors including peripheral neuropathy, decreased blood supply, high plantar pressures, etc., and pose a significant risk for morbidity, limb loss and mortality. The critical aspects of the wound healing mechanism and host physiological status in patients with diabetes necessitate the selection of an appropriate treatment strategy based on the complexity and type of wound. In addition to systemic antibiotics and surgical intervention, wound care is considered to be an important component of diabetic foot ulcer management. This article will focus on the use of different wound care materials in diabetic foot. From a clinical perspective, it is important to decide on the wound care material depending on the type and grade of the ulcer. This article will also provide clinicians with a simple approach to the choice of wound care materials in diabetic foot ulcer.
doi:10.4239/wjd.v5.i4.546
PMCID: PMC4127589  PMID: 25126400
Diabetes; Foot; Wound; Debridement; Topical
8.  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
9.  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
10.  Glycerin-Based Hydrogel for Infection Control 
Advances in Wound Care  2012;1(1):48-51.
Problem
Infection is a major problem in the health and wellbeing of patients in hospitals, nursing homes, and other medical facilities as well as the homecare patients and the general public. According to Scientia Advisors, wound care costs the healthcare system over $7 billion in 2009. After adding the cost associated with potential complications such as infections, extended physician care, and lengthy hospital stays, the annual wound care expenditures well exceeded over $20 billion.1 There are 20 million reported cases of diabetes per year and more every day. Because of the fact that leg ulcers are the number one health problem of men coupled with the rise in drug resistance of infections, the importance of providing the professional and the public with relatively simple and affordable wound care is of extreme importance. Often the wounds can become chronic wounds, which then result in long-term nursing expense in time and supplies or, worse yet, can result in expensive amputations ranging from $5000 to $40,000 per patient.
Solution
There are many dressing options now available for treating wounds with components such as glycerin, honey, salt, and many other natural products, with some dressings being more appropriate than others. In 1988, a patented glycerin-based dressing was introduced to the market, called Elasto-Gel™.2
New Technology
Elasto-Gel™ is a glycerin-based gel sheet (65%) combined with a hydrophilic polymer that causes the sheet to absorb the exudate from the wound and simultaneously release the glycerin from the gel, which adds many benefits to the wound for excellent healing outcomes. The gel sheet is 1/8th of an inch thick with a four-way stretch backing. It has the ability to absorb 3–4 times its own weight of fluids. The dressing will not dry out or allow the exudate to dry out, thus keeping the dressing from becoming bonded to the wound or the surrounding tissue. It does not have adhesive properties and, therefore, will not cause damage to the wound bed or periwound area upon dressing removal. Because of the thickness, the product provides excellent cushion and padding support. It has been also proven to be bacteriostatic/fungistatic. (Bacteriostatic is the ability to restrain the development or reproduction of bacteria.3)
Product Technology
Glycerin is a huamectant by definition and has been recognized by the U.S. Food and Drug Administration (FDA). Humectants attract, bind, and hold moisture to the site of application. The actual concentration of glycerin in a wound dressing is indicative of the ability to absorb excess moisture. Exudate management is an important function of topical treatment. The ability to absorb drainage and prevent pooling of exudate in the wound or on the surrounding skin are attributes specific to high glycerin content. Perhaps, the most significant advantage of the glycerin-based hydrogel sheet is its impact on wound bioburden and pathogenic organisms.4 Glycerin is a simple three-carbon tri-alcohol and is a natural humectant. It is used as a carrier in many medicines and as plasticizer in gelatin gel capsules. Glycerin is a component of cosmetics, conditioners, soaps, foods, and other common products. It is a component of mono-, di-, and triglycerides naturally occurring in the body. These glycerides and glycerin are constantly reacted with each other by the natural enzymes and reversed with the natural metabolic processes already present in the body. Any glycerin that may be absorbed into the body fluid is rapidly diluted in these fluids and is no longer toxic but is metabolized as another component of the food chain. It is well known that glycerin in high concentration will exhibit dehydrating effect on many systems including living cells by the commonly known process of osmosis. (Osmosis: the flow or diffusion that takes place through a semipermable membrane, as of living cell, typically separating a solvent such as water, thus bringing about equilibrium conditions.5) It has been shown that glycerin at high concentration will be cytotoxic to all cells that have been tested if they are exposed long enough. These properties of glycerin have been recognized by the European Skin Bank, where they use 85% glycerin solutions to store cadaver skin at ∼42F, and can be used for potential wound coverings. The cadaver skin that has been prepared by this method has been available since 1994.6 The concern for safety resulted in a three-day international synmposium7 with emphasis on glycerin-preserved cadaver skin providing healthy environment for the preserved skin to be successfully accepted without rejection, having no complications of infection and providing excellent healing outcomes and minimal scaring. Additional research by Dr. David P. Mackie of the Red Cross Hospital, The Netherlands, reported that using 85% glycerin solutions had slow bactericidal effects and also showed virocidal activity on several types of viruses.8 Dr. Hoekstra has observed that within 2 hours after application of Elasto-Gel™, the inflammatory reaction is reduced.9 Vandeputte, Belgium, showed that wounds covered with Elasto-Gel™ had fewer myofibroblasts than those covered with hydrocolloid.10 It has been proposed that myofibroblasts in high concentrations contribute to the formation of hypertrophic and keloid scars. As noted earlier, there is less scar formation when glycerin-based gel sheets are used. The data sited here have shown that glycerin and glycerin-based products are effective antimicrobial agents with less side effects. Many verbal reports along with personal communications have indicated that applying glycerin-based gel sheets to stalled wounds, some 15–20-year-old chronic wounds, resulted in healing in 1–20 weeks (data/case studies on file).
Indications for Use
Elasto-Gel™ has been approved for all types of wounds, that is, pressure ulcers, acute and chronic wounds, diabetic wounds, traumatic wounds, dermatology wounds, cancer tumors, and first- and second-degree burns, to name a few. Because of the product's features and benefits, it may be used on a variety of wounds. Because of its padding properties, it may be also used as a preventative product over bony prominence areas so that wounds do not occur. The glycerin properties act as a skin substitute and may also be used for scar reduction.
Caution
Elasto-Gel™ is not approved for third-degree burns as no dressing has been approved by the FDA for this type of wound.
doi:10.1089/wound.2011.0288
PMCID: PMC3839013  PMID: 24527279
11.  Topical Silver for Infected Wounds 
Journal of Athletic Training  2009;44(5):531-533.
Abstract
Reference/Citation:
Vermeulen H, van Hattem JM, Storm-Versloot MN, Ubbink DT. Topical silver for treating infected wounds. Cochrane Database Syst Rev. 2007(1);CD005486.
Clinical Question:
What is the clinical evidence base for silver dressings in the management of contaminated and infected acute and chronic wounds?
Data Sources:
Investigations were identified by Cochrane Wounds Group Specialized Register (2006), CENTRAL (2006), MEDLINE (2002–2006), EMBASE (2002–2006), CINAHL (2002–2006), and digital dissertations (2006) searches. Product manufacturers were contacted to identify additional eligible studies. The search terms included wound infection, surgical wound infection, ulcer, wound healing, and silver.
Study Selection:
Each study fulfilled the following criteria: (1) The study was a randomized controlled trial of human participants that compared dressings containing silver with any dressings without silver, dressings with other antiseptics, or dressings with different dosages of silver. (2) The participants were aged 18 years and older with contaminated and infected open wounds of any cause. (3) The study had to evaluate the effectiveness of the dressings using an objective measure of healing. No language or publication status restrictions were imposed, and participants could be recruited in any care setting. Studies were excluded if the wounds were ostomies (surgically formed passages).
Data Extraction:
Study quality assessment was conducted independently by 3 authors using the Dutch Institute for Health Care Improvement and Dutch Cochrane Centre protocols. Characteristics of the study, participants, interventions, and outcome measures were extracted by one author and verified by a second using a standard form. The principal outcome measure was healing (time to complete healing, rate of change in wound area and volume, number and proportion of wounds healed within trial period). Secondary measures were adverse events (eg, pain, maceration, erythema), dressing leakage, and wound odor. Based on the unique comparisons in the studies, a meta-analysis was not conducted. As a result, summary estimates of treatment effect were calculated for each outcome comparison. RevMan software (version 4.2; Cochrane Centre, Oxford, United Kingdom) was used for statistical analysis.
Main Results:
Specific search criteria identified 31 studies for review, of which 3 met the inclusion and exclusion criteria. Lack of randomization and absence of wound infections excluded the majority of studies from the review. In the 3 studies selected, silver-containing dressings were compared with nonsilver dressings and dressings with other antimicrobials. One group used a silver-containing foam dressing and a nonsilver foam dressing; another group used a silver-containing alginate and a nonsilver alginate; and a third group used a silver-containing foam and various dressings (nonsilver foams, alginates, hydrocolloids, and gauze and other antimicrobial dressings). Sample sizes ranged between 99 and 619 participants. Most of the wounds in the included studies were pressure, diabetic, and venous leg ulcers. Wound infection was subjectively defined by 1 group as the presence of 2 or more signs and symptoms (eg, continuous pain, erythema, heat, or moderate to high levels of exudate) and by the other 2 groups as signs of critical colonization (eg, delayed healing, increased pain and exudate levels, discoloration, and odor). The primary measure in the included studies was healing outcome. The 3 groups used various assessments of healing, including relative and absolute reduction in wound area and number of wounds healed during the trial period. The trial period in each study was 4 weeks. In the 3 trials, the authors randomized the participants to the treatment groups.
Examining healing, one group (129 participants) compared Contreet silver foam (Coloplast A/S, Humlebaek, Denmark) with Allevyn foam (Smith & Nephew, St-Laurent, Quebec, Canada). The authors reported no differences for rates of complete healing (risk difference [RD]  =  0.00, 95% confidence interval [CI]  =  −0.09, 0.09) and median wound area reduction (weighted mean difference [WMD]  =  −0.30 cm2, 95% CI  =  −2.92, 2.35). However, Contreet was favored over Allevyn (P  =  .034) for median relative reduction in wound area (WMD  =  −15.70 cm2, 95% CI  =  −29.5, −1.90). One group (99 participants) compared Silvercel silver alginate (Johnson & Johnson Wound Management, Somerville, NJ) with Algosteril alginate (Johnson & Johnson Wound Management). The authors found no differences in rates of complete healing (RD  =  0.00, 95% CI  =  −0.06, 0.05), mean absolute (WMD  =  4.50 cm2, 95% CI  =  −0.93, 9.93) and relative wound area reduction (WMD  =  −0.30 cm2, 95% CI  =  −17.08, 16.48), or healing rate per day (week 1 to 4) (WMD  =  0.16 cm2, 95% CI  =  −0.03, 0.35). One group (619 participants) compared Contreet with various dressings (nonsilver foams, alginates, hydrocolloids, and gauze and other antimicrobial dressings). For median relative wound area reduction, the authors noted a superiority of Contreet over the various dressings (P  =  .0019).
Examining secondary outcomes, 2 groups used subjective analysis to compare adverse reactions among the dressings. One group reported no difference between Contreet (in satellite ulcers, deterioration of periwound tissue) and Allevyn (in satellite ulcers, maceration, eczema) (RD  =  0.02, 95% CI  =  −0.07, 0.12), and one group found no difference between Silvercel (in pain during dressing change, eczema, periwound erythema, maceration) and Algosteril (in pain during dressing change, eczema, erythema) (RD  =  −0.01, 95% CI  =  −0.12, 0.11). Two groups subjectively assessed leakage among silver and nonsilver dressings. The data from one group demonstrated superiority of Contreet over Allevyn (P  =  .002; RD  =  −0.30, 95% CI  =  −0.47, −0.13), and one group found Contreet better than various dressings (eg, nonsilver foams, alginates, hydrocolloids, and gauze, and other antimicrobial dressings) (P  =  .0005; RD  =  −0.11, 95% CI  =  −0.18, −0.05). Using a subjective 4-point scale, one group compared silver and nonsilver dressings and reported a difference favoring Contreet over Allevyn in terms of wound odor (P  =  .030; RD  =  −0.19, 95% CI  =  −0.36, −0.03).
Conclusions:
Overall, this review provides no clear evidence to support the use of silver-containing foam and alginate dressings in the management of infected chronic wounds for up to 4 weeks. However, the use of silver foam dressings resulted in a greater reduction in wound size and more effective control of leakage and odor than did use of nonsilver dressings. Randomized controlled trials using standardized outcome measures and longer follow-up periods are needed to determine the most appropriate dressing for contaminated and infected acute and chronic wounds.
doi:10.4085/1062-6050-44.5.531
PMCID: PMC2742464  PMID: 19771293
antiseptics; moist dressings; critical colonization; contamination
12.  Smoking, Chronic Wound Healing, and Implications for Evidence-Based Practice 
Chronic wounds are rising in prevalence and creating significant socioeconomic burdens for patients and healthcare systems worldwide. Therefore, it is now more important than ever that clinicians follow evidence-based guidelines for wound care when developing personalized treatment plans for their patients with chronic wounds. Evidence-based guidelines for treating venous leg ulcers, diabetic foot ulcers, and pressure ulcers, the 3 main categories of chronic wounds, focus primarily on biologic therapies. However, there are also evidence-based guidelines for treating behavioral risks to poor healing, such as smoking, which should be incorporated into treatment plans when appropriate. The purpose of this article was to review the mechanisms through which smoking adversely impacts the wound healing process, and propose strategies for incorporating evidence-based guidelines for treating tobacco dependence into treatment plans for patients with chronic wounds who smoke.
doi:10.1097/WON.0000000000000057
PMCID: PMC4241583  PMID: 25188797
chronic wound healing; evidence-based practice; smoking; tobacco dependence treatment
13.  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
14.  Systematic review and mixed treatment comparison: dressings to heal diabetic foot ulcers 
Diabetologia  2012;55(7):1902-1910.
Aims/hypothesis
Foot ulcers in people with diabetes are a common and serious global health issue. Dressings form a key part of ulcer treatment. Existing systematic reviews are limited by the lack of head-to-head comparisons of alternative dressings in a field where there are several different dressing options. We aimed to determine the relative effects of alternative wound dressings on the healing of diabetic foot ulcers.
Methods
This study was a systematic review involving Bayesian mixed treatment comparison. We included randomised controlled trials evaluating the effects on diabetic foot ulcer healing of one or more wound dressings. There were no restrictions based on language or publication status.
Results
Fifteen eligible studies, evaluating nine dressing types, were included. Ten direct treatment comparisons were made. Whilst there was increased healing associated with hydrogel and foam dressings compared with basic wound contact materials, these findings were based on data from small studies at unclear or high risk of bias. The mixed treatment comparison suggested that hydrocolloid-matrix dressings were associated with higher odds of ulcer healing than all other dressing types; there was a high degree of uncertainty around these estimates, which were deemed to be of very low quality.
Conclusions/interpretation
These findings summarise all available trial evidence regarding the use of dressings to heal diabetic foot ulcers. More expensive dressings may offer no advantages in terms of healing than cheaper basic dressings. In addition, evidence pointing to a difference in favour of ‘advanced’ dressing types over basic wound contact materials is of low or very low quality.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-012-2558-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
doi:10.1007/s00125-012-2558-5
PMCID: PMC3369130  PMID: 22544222
Diabetic foot ulcers; Dressings; GRADE; Meta-analysis; Mixed treatment comparison; Systematic review
15.  Systematic review of economic evaluations of human cell-derived wound care products for the treatment of venous leg and diabetic foot ulcers 
Background
Tissue engineering is an emerging field. Novel bioengineered skin substitutes and genetically derived growth factors offer innovative approaches to reduce the burden of diabetic foot and venous leg ulcers for both patients and health care systems. However, they frequently are very costly. Based on a systematic review of the literature, this study assesses the cost-effectiveness of these growth factors and tissue-engineered artificial skin for treating chronic wounds.
Methods
On the basis of an extensive explorative search, an appropriate algorithm for a systematic database search was developed. The following databases were searched: BIOSIS Previews, CRD databases, Cochrane Library, EconLit, Embase, Medline, and Web of Science. Only completed and published trial- or model-based studies which contained a full economic evaluation of growth factors and bioengineered skin substitutes for the treatment of chronic wounds were included. Two reviewers independently undertook the assessment of study quality. The relevant studies were assessed by a modified version of the Consensus on Health Economic Criteria (CHEC) list and a published checklist for evaluating model-based economic evaluations.
Results
Eleven health economic evaluations were included. Three biotechnology products were identified for which topical growth factors or bioengineered skin substitutes for the treatment of chronic leg ulceration were economically assessed: (1) Apligraf®, a bilayered living human skin equivalent indicated for the treatment of diabetic foot and venous leg ulcers (five studies); (2) Dermagraft®, a human fibroblast-derived dermal substitute, which is indicated only for use in the treatment of full-thickness diabetic foot ulcers (one study); (3) REGRANEX® Gel, a human platelet-derived growth factor for the treatment of deep neuropathic diabetic foot ulcers (five studies). The studies considered in this review were of varying and partly low methodological quality. They calculated that due to shorter treatment periods, fewer complications and fewer inpatient episodes the initial cost of the novel biotechnology products may be offset, making the treatment cost-effective or even cost-saving. The results of most studies were sensitive to initial costs of the products and the evidence of effectiveness.
Conclusion
The study results suggest that some growth factors and tissue-engineered artificial skin products feature favourable cost-effectiveness ratios in selected patient groups with chronic wounds. Despite the limitations of the studies considered, it is evident that health care providers and coverage decision makers should take not only the high cost of the biotechnology product but the total cost of care into account when deciding about the appropriate allocation of their financial resources. However, not only the cost-effectiveness but first of all the effectiveness of these novel biotechnology products deserve further research.
doi:10.1186/1472-6963-9-115
PMCID: PMC2716319  PMID: 19591680
16.  Low Level Laser Therapy for the Treatment of Diabetic Foot Ulcers: A Critical Survey 
Diabetic foot ulcers as one of the most common complications of diabetes mellitus are defined as nonhealing or long-lasting chronic skin ulcers in diabetic patients. Multidisciplinary care for the diabetic foot is common, but treatment results are often unsatisfactory. Low level laser therapy (LLLT) on wound areas as well as on acupuncture points, as a noninvasive, pain-free method with minor side effects, has been considered as a possible treatment option for the diabetic foot syndrome. A systematic literature review identified 1764 articles on this topic. Finally, we adopted 22 eligible references; 8 of them were cell studies, 6 were animal studies, and 8 were clinical trials. Cell studies and animal studies gave evidence of cellular migration, viability, and proliferation of fibroblast cells, quicker reepithelization and reformed connective tissue, enhancement of microcirculation, and anti-inflammatory effects by inhibition of prostaglandine, interleukin, and cytokine as well as direct antibacterial effects by induction of reactive oxygen species (ROS). The transferral of these data into clinical medicine is under debate. The majority of clinical studies show a potential benefit of LLLT in wound healing of diabetic ulcers. But there are a lot of aspects in these studies limiting final evidence about the actual output of this kind of treatment method. In summary, all studies give enough evidence to continue research on laser therapy for diabetic ulcers, but clinical trials using human models do not provide sufficient evidence to establish the usefulness of LLLT as an effective tool in wound care regimes at present. Further well designed research trials are required to determine the true value of LLLT in routine wound care.
doi:10.1155/2014/626127
PMCID: PMC3976827  PMID: 24744814
17.  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
18.  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
19.  Applying 21st Century Imaging Technology to Wound Healing: An Avant-Gardist Approach 
A significant arising complication in the care of patients with diabetes is increased susceptibility to chronic wounds, including diabetic foot ulcers and pressure sores. This is driven by, e.g., neuropathy and peripheral arterial disease. It is well recognized that best practice in wound care requires wound assessment, including measurement, on presentation and regularly throughout the treatment program. Proper assessment is necessary to ensure that the most appropriate and cost-effective therapy is used at all times, with quantitative measurement necessary to track the efficacy of the chosen approach. A documented assessment can also assist patient–clinician dialog and discussion within the multidisciplinary team. Remote evaluation and assessment of the wound is also of increasing importance and practicality through the use of a telemedicine approach. There has been considerable progress in the space of imaging for wounds, including systems that include three-dimensional measurement and telemedicine features. This literature review examines the available options and reviews the clinical evidence for measurement accuracy, scope for remote assessment, and published user feedback on the systems.
PMCID: PMC3876362  PMID: 24124945
diabetic foot; imaging; technology; wound healing; wounds
20.  Recent advances on the association of apoptosis in chronic non healing diabetic wound 
World Journal of Diabetes  2014;5(6):756-762.
Generally, wounds are of two categories, such as chronic and acute. Chronic wounds takes time to heal when compared to the acute wounds. Chronic wounds include vasculitis, non healing ulcer, pyoderma gangrenosum, and diseases that cause ischemia. Chronic wounds are rapidly increasing among the elderly population with dysfunctional valves in their lower extremity deep veins, ulcer, neuropathic foot and pressure ulcers. The process of the healing of wounds has several steps with the involvement of immune cells and several other cell types. There are many evidences supporting the hypothesis that apoptosis of immune cells is involved in the wound healing process by ending inflammatory condition. It is also involved in the resolution of various phases of tissue repair. During final steps of wound healing most of the endothelial cells, macrophages and myofibroblasts undergo apoptosis or exit from the wound, leaving a mass that contains few cells and consists mostly of collagen and other extracellular matrix proteins to provide strength to the healing tissue. This review discusses the various phases of wound healing both in the chronic and acute wounds especially during diabetes mellitus and thus support the hypothesis that the oxidative stress, apoptosis, connexins and other molecules involved in the regulation of chronic wound healing in diabetes mellitus and gives proper understanding of the mechanisms controlling apoptosis and tissue repair during diabetes and may eventually develop therapeutic modalities to fasten the healing process in diabetic patients.
doi:10.4239/wjd.v5.i6.756
PMCID: PMC4265862  PMID: 25512778
Apoptosis; Diabetes mellitus; Diabetic foot; Chronic wound; Oxidative stress
21.  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
22.  Evaluation of the use of prognostic information for the care of individuals with venous leg ulcers or diabetic neuropathic foot ulcers 
This is a randomized factorial design clinical trial which investigates the efficacy and feasibility of providing prognostic information on wound healing. Prognostic information was provided based on baseline or four-week wound characteristics. Healing rates were then determined at 24 weeks for venous leg ulcers and 20 weeks for diabetic neuropathic foot ulcers. Centers that had access to baseline information for venous leg ulcer prognosis had an OR of healing of 1.42 (95%CI: 1.03, 1.95) while centers that had access to information at four weeks had an OR of healing of 1.43 (95%CI: 1.05, 1.95) compared to controls. Diabetic neuropathic foot ulcer patients treated in centers that had been randomized to receive only four-week prognostic information were more likely to heal than individuals seen in centers randomized to receive no intervention (OR 1.50, 95%CI: 1.05, 2.14). Our study found that it is feasible and efficacious to provide prognostic information on venous leg and diabetic neuropathic foot ulcers in a wound care setting using an existing administrative database. This intervention was easy to administer and likely had low associated costs. This method of dispersing prognostic information to healthcare providers should be expanded to include recently published treatment algorithms.
doi:10.1111/j.1524-475X.2009.00487.x
PMCID: PMC2724840  PMID: 19660039
venous leg ulcer; diabetic foot ulcer; randomized trial; prognostic information
23.  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
24.  Collagen-based wound dressings for the treatment of diabetes-related foot ulcers: a systematic review 
Background
Diabetic foot ulcers are a major source of morbidity, limb loss, and mortality. A prolonged inflammatory response, extracellular matrix degradation irregularities, and increased bacteria presence have all been hypothesized as major contributing factors in the delayed healing of diabetic wounds. Collagen components such as fibroblast and keratinocytes are fundamental to the process of wound healing and skin formation. Wound dressings that contain collagen products create a biological scaffold matrix that supports the regulation of extracellular components and promotes wound healing.
Methods
A systematic review of studies reporting collagen wound dressings used in the treatment of Diabetic foot ulcers was conducted. Comprehensive searches were run in Ovid MEDLINE, PubMed, EMBASE, and ISI Web of Science to capture citations pertaining to the use of collagen wound dressings in the treatment of diabetic foot ulcers. The searches were limited to human studies reported in English.
Results
Using our search strategy, 26 papers were discussed, and included 13 randomized designs, twelve prospective cohorts, and one retrospective cohort, representing 2386 patients with diabetic foot ulcers. Our design was not a formal meta-analysis. In those studies where complete epithelialization, 58% of collagen-treated wounds completely healed (weighted mean 67%). Only 23% of studies reported control group healing with 29% healing (weighted mean 11%) described for controls.
Conclusion
Collagen-based wound dressings can be an effective tool in the healing of diabetic foot wounds. The current studies show an overall increase in healing rates despite limitations in study designs. This study suggests that future works focus on biofilms and extracellular regulation, and include high risk patients.
doi:10.2147/DMSO.S36024
PMCID: PMC3555551  PMID: 23357897
bio films; matrix; wound healing; scaffold; dressings
25.  The use of propeller perforator flaps for diabetic limb salvage: a retrospective review of 25 cases 
Diabetic Foot & Ankle  2012;3:10.3402/dfa.v3i0.18978.
Background
Peripheral vascular disease and/or diabetic neuropathy represent one of the main etiologies for the development of lower leg and/or diabetic foot ulcerations, and especially after acute trauma or chronic mechanical stress. The reconstruction of such wounds is challenging due to the paucity of soft tissue resources in this region. Various procedures including orthobiologics, skin grafting (SG) with or without negative pressure wound therapy and local random flaps have been used with varying degrees of success to cover diabetic lower leg or foot ulcerations. Other methods include: local or regional muscle and fasciocutaneous flaps, free muscle and fasciocutaneous, or perforator flaps, which also have varying degrees of success.
Patients and methods
This article reviews 25 propeller perforator flaps (PPF) which were performed in 24 diabetic patients with acute and chronic wounds involving the foot and/or lower leg. These patients were admitted beween 2008 and 2011. Fifteen PPF were based on perforators from the peroneal artery, nine from the posterior tibial artery, and one from the anterior tibial artery.
Results
A primary healing rate (96%) was obtained in 18 (72%) cases. Revisional surgery and SG for skin necrosis was performed in six (24%) cases with one complete loss of the flap (4%) which led to a lower extremity amputation.
Conclusions
The purpose of this article is to review the use of PPF as an effective method for soft tissue coverage of the diabetic lower extremity and/or foot. In well-controlled diabetic patients that present with at least one permeable artery in the affected lower leg, the use of PPF may provide an alternative option for soft tissue reconstruction of acute and chronic diabetic wounds.
doi:10.3402/dfa.v3i0.18978
PMCID: PMC3464067  PMID: 23050066
diabetes mellitus; ulcers; lower leg; foot; propeller perforator flaps

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