Skin & Aging’s sister journal Wounds is the nation’s leading wound care research journal, and it’s the major source of current research, treatment methodology, and current protocol in the field of wound care. In addition, this journal is the standard reference tool of those healthcare professionals who are leaders in establishing wound care programs and treatment centers both nationally and internationally. This month, we bring you the top 10 selections from the whole body of research published in Wounds in 2008. Dermatologist and wound care expert, Dr. Robert Kirsner, who is Section Editor for Wounds and an Editorial Advisory Board Member for Skin & Aging, selected the following research findings as the most relevant to dermatology. Read on for Dr. Kirsner’s commentary on the relevance of this research as well as synopses of these wound care findings.
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Oxygen is a Drug Dr. Kirsner’s Comments: A conceptual hurdle to understanding the role of oxygen is appreciating how hyperbaric oxygen helps to heal wounds when the wounds are without the treatment for 22 out of every 24 hours, even on the days patients receive the treatment. If these wounds are in need of oxygen, one would think that they would need oxygen all the time, not just a couple of hours daily. This, at first blush, is anti-intuitive until one begins to think of oxygen not as a nutrient but rather as a drug. The drug oxygen can be dosed similarly to more typical drugs like antibiotics. The drug oxygen is needed for a variety of critical functions ranging from antimicrobial activities such as nicotinamide adenine dinucleotide phosphate (NADPH) in leukocytes and bactericidal effect of superoxides as well as cross linking of collagen. Like any drug, delivery to tissue is critical, and while the majority of oxygen is carried on hemoglobin, more critical is partial pressure of oxygen in the blood, which leads to oxygen diffusion to wounded tissue. Thus, the high partial pressure of oxygen caused by hyperbaric treatment appears to be among the most effective ways to deliver the drug oxygen to tissue. Studying oxygen is often most easily accomplished in animal models. Myers and Gould highlight the most important and applicable animal models to study the effect of oxygen, hypoxia, and hyperbaric treatment. Using a variety of relevant models helps one gain a better understanding of how oxygen helps heal wounds, the effect of diminished oxygen, and the role of oxygen therapy to treat a variety of wounds. Synopsis of the Research: Effective and dependable influx and efflux of blood, fluid, and nutrient supply is essential for wound healing. The delicate balance between adequate oxygenation and hypoxia is an important aspect of this process. Due to the wide variety of wounds that occur in humans, along with multiple comorbidities, it is difficult to define, understand, and optimize treatments for chronic wounds. Although valuable for examining mechanisms at a molecular level, in vitro cell culture models cannot replicate the complex environment of a wound. A stable, reliable, and reproducible animal wound model that mimics the chronic wound state has yet to be found. Myers and Gould reviewed the current understanding of the effect of ischemia on wound healing and examined the features of currently available animal models that simulate ischemic wounds. Although it is not a chronic wound model, the authors believe that the ischemic bipedicle flap model has the potential to be a valuable tool for understanding the contribution of ischemia to impaired wound healing. This flap does not develop necrosis, yet, it remains ischemic for up to 2 weeks with markedly impaired wound healing. Although it is very flexible, by suturing to both the skin flap and to the dorsal muscle fascia, the silicone sheet also acts as a splint and can prevent wound contraction to some extent. This model was standardized so trained personnel with minimal surgical experience could perform the model with good reproducibility and flap survival. Rats tolerate the flap well and can be treated with systemic or topical agents. The wounds can be measured and excised, providing sufficient tissue for multiple biochemical analyses. The researchers noted that the Sprague-Dawley ischemic flap showed that hyperbaric oxygen (HBO) improves the rate of wound closure in ischemic wounds but has no effect on the wound closure rate in nonischemic wounds. According to the researchers, biochemical and histologic analyses demonstrated that apoptosis is attenuated by HBO treatment of ischemic wounds and that this effect is blocked by systemic administration of the free radical scavenger, N-acetylcysteine. Reduced inducible nitric oxide synthase, reduced 3-nitrotyrosine, and induction of copper/zinc superoxide dismutase, catalase, and glutathione peroxidase in the hyperbaric-treated ischemic wounds indicate modulation of the balance between reactive oxygen species and endogenous antioxidants. SOURCE: Wesley T. Myers, MD, and Lisa J. Gould, MD, PhD. Animal Models of Tissue Ischemia to Evaluate the Importance of Oxygen in the Wound Healing Environment. Wounds. January 2008;20:9-17.
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Ulceration is a Complication of Neuropathy, Not Diabetes Dr. Kirsner’s Comments: We are in the midst of an epidemic in diabetes. Within the United States and abroad, the prevalence of diabetes, by conservative estimates, is expected to increase 50% to 100% in the next 2 decades. As a consequence, complications of diabetes will increase as well. Of the 20 million Americans with diabetes, 15% will get a foot ulcer. The presence of a foot ulcer represents the most common risk factor for osteomyelitis, amputation, and increased mortality. Foot ulcers occur most commonly from neuropathy, and validated scales for both signs and symptoms for neuropathy exist. Testing for the signs and symptoms of neuropathy are simple, and no patient with diabetes should go untested for neuropathy. Bacarin and colleagues teach us a number of important lessons in their study of diabetics with and without foot ulcers. First is that signs of neuropathy were more commonly seen in those with diabetic foot ulcers compared with symptoms of neuropathy. Thus, examination of signs (physical examination) may be a better test for risk than merely asking about symptoms. Signs of neuropathy were more severe in those patients with ulcers than those without ulcers, suggesting the severity of neuropathy to be the critical component for those developing ulcers. Additionally, the duration of diabetes was not related to severity of neuropathy, suggesting that all patients with diabetes undergo neurologic assessment as opposed to only those with longstanding disease. Synopsis of the Research: Previous research has shown that patients with a plantar ulcer due to diabetes tend to have had diabetes for a longer duration and are older than those patients who have diabetes but no ulcers. It’s known that diabetic peripheral neuropathy (DPN), a common condition in patients with diabetes, causes loss of protective sensation, a major risk factor for ulceration in diabetic feet. Researchers from Brazil conducted a study to determine if patients with a history of plantar ulcers due to DPN have more symptoms, a longer duration of disease, and poorer foot sensitivity — parameters that previously had not been studied together in patients with ulcers who had diabetes. This study conducted by Bacarin et al compared the duration of disease, the prevalence of neuropathy symptoms, and plantar insensitivity among three groups — patients with diabetic neuropathy with a history of plantar ulcers (UDG), patients with diabetic neuropathy without a history of plantar ulcers (DG), and a nondiabetic group of patients (the control group [CG]). (See Table 1.) Investigators used the Michigan Neuropathy Screening Instrument (MNSI) to study the neuropathy symptoms. The evaluation of plantar sensitivity was composed of three sensory tests — sensitive chronaxie, and thermal and tactile sensitivities. Plantar sensitivity was investigated in five areas of the plantar surface of both feet, including the heel, mid-foot, lateral forefoot, medial forefoot, and hallux. Results showed the neuropathic groups did not differ in duration of diabetes, and, according to MNSI scores, presented a similar number of symptoms. Abnormal sensitivity was highest in the UDG. A delay in sensing the electrical stimulus was higher in the UDG. The number of areas with sensitive chronaxie values higher than 0.30 ms did not show any difference among groups (P = 0.593). However, the UDG had more areas with values higher than the threshold (2 areas for CG, 3 areas for DG; 5 areas for UDG). In terms of tactile sensitivity, the median number of areas with deficit of tactile sensitivity were no areas for CF, 2 areas for DG, and 6 areas for UDG — with five patients (55.5%) from UDG unable to feel the 10-g monofilament pressure in more than 5 areas of the feet. The medians for the number of areas with inability to discriminate hot and cold temperatures were: 0 areas for CG, 2 areas for DG, and 3 areas for UDG. The MNSI total score achieved a weak and insignificant correlation with sensitive chronaxie (r = -0.17; P > 0.05) and with thermal sensitivity (r = -0.11;P > 0.05) for all areas. The results of this study led the researchers to conclude that patients with diabetic neuropathic ulceration had decreased sensitivity in their feet, confirmed by the high number of insensitive plantar areas as well as by the high values of sensitive chronaxie. The authors wrote, “These findings were not related to the duration of diabetes onset, nor to the symptoms reported by the patients. However, the symptoms may be an indicator of decreased foot sensitivity, but the symptoms alone are not able to differentiate between groups with variation in progression of diabetic neuropathy.” Source: Tatiana de A. Bacarin, MSc, Dip PT; Paula M. H. Akashi, MSc, Dip PT; Prof. Isabel de C. N. Sacco, PhD. Duration of Disease, Neuropathic Symptoms, and Plantar Sensitivity in Patients With Diabetes With and Without Previous Plantar Ulceration. Wounds. February 2008;20:37-45.
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Charcot Foot Deformity: When Amputation May be Avoided Dr. Kirsner’s Comments: Neuropathy and vascular disease take many clinical forms. Neuropathy, for example, has effects not solely on the sensory nerves, leading to insensate feet; but also to the motor nerves, leading to atrophy of major muscle groups, as well as autonomic neuropathy, leading to the dry, scaling, and calloused skin seen in patients with diabetes. In an analogous fashion, both small and large vessel disease may occur in diabetics, leading to a variety of clinical presentations. One manifestation of diabetes — and less often of other conditions — is Charcot foot. While several theories have been proposed for why only a small subset of patients with diabetes develops this, the crux of the problem appears to be a bony collapse of the foot, leading to foot deformity. Once developed, repetitive trauma can worsen disease and lead to progression, so early recognition and prompt intervention may prevent complications. Thomas and Huffman teach us that the Charcot foot progresses through 3 stages, with the earliest stage of edema and inflammation often mimicking an active infection. Indium-labeled leukocyte scans may be the best technique to differentiate Charcot from infection and off loading is critical in hopes of preventing progression to stages 2 and 3. However, late presentation and development of ulcer formation may require more aggressive treatment, including a variety of surgical options leading to correction of the foot deformity and ulcer healing. Synopsis of the Research: Because patients with diabetes are living longer, studies have shown that there has been an increase in the number of Charcot arthropathy, a non-infective progressive process characterized by painless joint destruction, fracture, and eventual dislocation. Charcot arthropathy can have a significant impact on patients in terms of limb salvage and overall health. Its treatment has long been a topic of debate, with amputation being the most common surgical treatment for many years. However, with a better understanding of the disease and the development of new fixation and surgical techniques, it’s possible to avoid amputation. Thomas and Huffman note, “Proper preoperative evaluation, often by a multidisciplinary team of specialists, is critical as well as the assurance of the necessary vascular perfusion to achieve healing.” Surgical options include exostectomy and reconstruction, with or without various plastic surgical procedures, and amputation, which should only be considered for the nonsalvegable extremity. Using three case studies to demonstrate successful surgical treatment of Charcot foot, the authors found that surgical reconstruction is a viable option in selected patients, even when other specialists had recommended amputation. They found plastic surgical techniques and new fixation methods, such as external ring fixation (see Figure 1), seem to provide better outcomes and more flexibility. The keys to achieving and maintaining postoperative results include surgical planning, preoperative work-up with a multidisciplinary team, and proper orthotic management after surgery to avoid recurrence of ulcers. Source: James L. Thomas, DPM, FACFAS, and Lanie Huffman, DPM. Charcot Foot Deformity: Surgical Treatment Options. Wounds. March 2008; 20:67-73.
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Measuring Blood Flow Dr. Kirsner’s Comments: The performance of a vascular assessment is part of most algorithms of care of lower extremity wounds. This assessment is routine, as it is generally accepted that adequate blood flow is required for healing. While physical examination findings of good pulses and capillary perfusion are often used, there is a subset of patients with vascular disease who have normal physical examinations. A variety of methods have been developed and used to measure blood flow in the lower extremity. Most common perhaps is the ankle-brachial index, or ABI, which is a ratio of the systolic blood pressure in the leg compared with the arm. Normally, lower ABIs have correlated with worse vascular disease. Importantly, an ABI of less than 0.9 is an independent risk factor for cardiovascular disease. Limitations to the ABI exist, as the ABI is a measure of large vessel disease, and hardening of the vessels through glycosalation in patients with diabetes and calcification in the elderly can give false negative results. Tissue oxygen measures, by way of measuring transcutaneous oxygen (TcPO2), have also been used. Somewhat tedious to perform and requiring rigorous standardization of body temperature, measuring oxygen at the site of the wound is a more direct approach than measuring large vessel disease. TcPO2 is limited by things such as limb edema. More recently skin perfusion pressure (SPP) using laser Doppler directly measures skin perfusion at the site of the wound by slowing releasing pressure from blood pressure cuffs and measuring perfusion to the site. The fact that it is simple and fast to use makes SPP attractive. But the question remains about how well it works. Tsuji and colleagues teach us that SPP is, in fact, very good. In their study of consecutive lower limb wounds, the SPP was able to dichotomize healing from nonhealing wounds (60 mmHg vs. 31 mmHg), was shown to increase in patients who underwent revascularization and healed, and predicted the need for amputation in a patient who underwent revascularization but whose SPP did not change and whose wound did not heal. As this technology becomes more prevalent, it is likely SPP will become standard of care in wounds centers throughout the United States. Synopsis of the Research: In previous studies, SPP has been shown to be a reliable predictor of wound healing. The authors of this study wanted to determine if SPP measurements can be used to accurately predict wound healing in critical limb ischemia (CLI) and to select peripheral arterial reconstructive procedures. The authors measured SPP at the proximal margin of foot ulcers (not in the wound bed) in patients referred to the Wound Treatment Center at Shin-Suma General Hospital (Kobe, Japan) for the treatment of intractable foot ulcers, and compared it with the outcomes of treatment (healed or failed to heal). Foot ulcers that did not heal within 12 weeks after debridement or minor amputation or that required peripheral arterial reconstruction or more proximal amputation were evaluated as “failed to heal.” Those that demonstrated complete wound closure without additional surgery were evaluated as “healed.” Skin perfusion pressure was compared before and after peripheral arterial reconstruction. The effect of SPP elevation on wound healing was also evaluated. The study found the average SPP of patients with healed wounds was 60 mmHg, while the average SPP for patient with unhealed wounds was 31 mmHg. The data, analyzed to determine the optimal cutoff level for SPP, showed that SPP levels below the threshold gave a positive result and were predictive of healing failure, while SPP levels above the threshold gave a negative result and were predictive of healing success. The sensitivity, specificity, and the positive and negative predictive values of SPP measurement were calculated, and then the data was analyzed by the receiver operation characteristic (ROC) curve. According to the ROC curve, the optimal SPP lies at 35 mmHg. In contrast, at a threshold of 60 mmHg, the negative predictive value dropped to 62.8%, suggesting that peripheral arterial reconstruction may not always be necessary to facilitate an efficient wound healing process, or that a proximal amputation level is necessary. Based on these findings, the authors propose “that when the SPP value is not ≥ 35 mmHg, any surgical debridement should be secondary to the restoration of adequate skin blood flow to minimize invasive debridement. When the SPP is ≥ 35 mmHg, surgical debridement of necrotic tissue is feasible without any peripheral arterial reconstruction.” The study showed that SPP measurement is useful in accurately planning minimally invasive amputation and for predicting successful wound healing in CLI. Source: Yoriko Tsuji, MD; Terashi Hiroto, MD, PhD; Ikuro Kitano, MD, PhD; Shinya Tahara, MD, PhD; Daisuke Sugiyama, MD, MPH. Importance of Skin Perfusion Pressure in Treatment of Critical Limb Ischemia. Wounds. April 2008; 20:95-100.
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Improving the Quality of Healing Dr. Kirsner’s Comments: While, at times, just getting a chronic wound to heal is a major accomplishment, for many, excessive healing leads to excessive fibrosis, scarring, and even keloid formation. Additionally, fibrosis is a major medical problem, with protean manifestations ranging from keloids and scleroderma in the skin to arthritis affecting joints, cirrhosis affecting the liver, and other life-threatening fibrosis affecting the lungs and heart, as a result of pulmonary hypertension and myocardial infarction, respectively. Clearly, novel ways to reduce scarring are needed, and any general or gastrointestinal surgeon would also welcome ways to reduce adhesions and their accompanying complications. Recently, angiotensin II (ANG II) has become an attractive target to study in an effort to reduce fibrosis. This is partly because ANG II has been shown to stimulate collagen deposition and fibroblast proliferation, and inhibition of ANG II ameliorates this effect. Additionally, ANG II is produced locally in the skin, and pharmaceutical companies have already created drugs targeting the angiotensin-renin pathway to treat hypertension. Stemming from this rationale, Ardekani and colleagues studied the New Zealand White Rabbit to study the benefit of topical captopril to prevent scar formation. Creating two equal sized wounds on each ear, these investigators were able to demonstrate significant improvement in the scar index with a greater than 30% clinical benefit after 7 days. From a mechanistic standpoint, captopril reduced collagen organization typical of scar formation, but it did not have an effect on inflammation at a histologic level. This study opens the idea of addressing fibrosis through the use of ANG II inhibitors and for follow-up studies in humans, researchers might consider evaluating keloid formation among systemic captopril and non-captopril uses as well as performing trials comparing topical and systemic captopril with the aim of improved quality of healing. Synopsis of the Research: The extracellular matrix in tissues such as bone, cartilage, and skin, is primarily made up of collagen, which is known to play a major role in wound healing processes. Overproduction and/or decreased degradation of collagen fibers can lead to abnormal wound healing, which could result in hypertrophic scarring or keloid formation. According to the study authors, “Hypertrophic scar (HS) and keloid are two disfiguring and debilitating forms of wound healing that can cause serious psychological and functional complications.” Most of the available treatments for these conditions are inadequate or associated with adverse events and high recurrence. Recently, ANG II has been shown to be present in several cutaneous cells and to stimulate fibroblast proliferation and collagen synthesis, and to suppress matrix metalloproteinase activity. Ardekani et al conducted a study to examine the effect of topical captopril, an ANG II production inhibitor, against hypertrophic scar formation in six 3-month-old female New Zealand white rabbits. Under sterile conditions, two circular, 7-mm, full-thickness, dermal ulcers were created on the ventral surface of the ears of each rabbit, and the perichondrium was also removed. In each animal, one ulcer was made at the middle part of the left ear and another made at the same level on the right ear. The wounds on the left ears were treated with topical 5% captopril, and the wounds on the right ears were treated with the vehicle (70% ethanol/30% propylene glycol) alone. Daily topical applications were started at the time of wounding and were continued for 7 consecutive days. Applications were always performed by the same technician, who was blinded to the treatment identifications. The wounds were uncovered and exposed to air at day 28. At that time, researchers evaluated the scar elevation index (SEI) and the collagen organization. The SEI was reduced from 3.06 in the vehicle-treated wounds to 1.94 in the captopril-treated wounds (P < 0.05). An increase in collagen organization was achieved by captopril, and an 8.5% decrease in collagen organization scale was derived by captopril compared to vehicle. This study shows captopril is efficacious in preventing hypertrophic scars in an animal model. The authors note that more studies are needed to assess the minimal effective concentration and the optimal frequency of captopril application, and to verify if captopril exerts any significant therapeutic efficacy against HS and keloid formation in humans. Source: Gholamreza Safaee Ardekani, MD; Saeed Ebrahimi, MD; Mitra Amini, MD, MPH; Fatemeh Sari Aslani, MD; Farhad Handjani, MD; Gholamhossein Ranjbar Omrani, MD; Leila Safaee Ardekani, BS; Seyed Hamidreza Hosseini Alhashemi, MD; Behrooz Kasraee, MD. Topical Captopril as a Novel Agent Against Hypertrophic Scar Formation in New Zealand White Rabbit Skin. Wounds. April 2008; 20:101-106.
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Good News For Women Dr. Kirsner’s Comments: Disparities in health care and health services are a hot topic. At-risk populations based on race/ethnicity, socioeconomic status and gender all affect patient outcomes. For example, in a disease common in dermatology, blacks, Hispanics, lower socioeconomic groups, and women all have reduced quality of care as measured by late-stage melanoma diagnoses and worse survival compared to whites, higher socioeconomic status groups, and men, respectively. These differences in outcomes appear more likely related to health services than to biology, but active study to determine if biologic heterogeneity contributes to differential outcomes is underway. Related to wound care, do differences exists based on some of these same parameters? It is known, for example, that Hispanics have a very high prevalence of diabetes and resultant diabetic complications such as diabetic foot ulcers. Dinh and Veves contribute to our knowledge base by studying the prevalence of diabetic foot ulcers and parameters of neuropathy in both men and women. In a study of 248 patients, foot ulcers developed more frequently in men (40% vs. 19%), and men had greater neuropathy disability scores, higher plantar pressures, and reduced mobility. The reason for these differences in neuropathy and ulceration is not entirely clear, but it’s been hypothesized that there are more (longer) at-risk nerves in taller men, or that perhaps estrogen may play a protective role for women. In sum, as seen in the change in the workforce in recent months, it’s good to be a woman. Synopsis of the Research: There are numerous risk factors known for the development of foot ulceration, including peripheral neuropathy, high plantar foot pressures, limited joint mobility, and peripheral vascular disease. Studies also have found that socio-demographic factors, such as race, education level, and gender, appear to influence the likelihood of foot ulceration. In a previous large, prospective trial that the authors’ unit coordinated, 29% of all patients with diabetes, including men and women, were shown to ulcerate over a 30-month period. To try to determine if gender poses a significant risk factor, the authors of this study analyzed these same data separately for men and women. A total of 248 patients with diabetes were enrolled in a 30-month, multicenter, prospective study. There were 124 men and 124 women. Patient demographics were similar between men and women in terms of age, duration of diabetes mellitus, and body mass index. Neuropathy disability score (NDS), vibration perception threshold (VPT), Semmes Weinstein monofilament (SWM), plantar peak foot pressures, subtalar joint (STJ), and first metatarsal joint (MTJP) mobility risk factors were measured in both groups. Men had higher NDS (13 ± 8 versus 8 ± 7, P < 0.0001), VPT (36 ± 17 V versus 23 ± 16, P < 0.0001), SWM (5.9 ± 1.4 versus 5.9 ± 1.3, P < 0.0001), and plantar peak foot pressures (6.4 ± 3.4 kg/cm2 versus 5.0 ± 2.3, P < 0.0001), while women had higher MTPJ mobility (69 ± 24 degrees versus 77 ± 23, P < 0.0001) and STJ mobility (22 ± 10 degrees versus 26 ± 8, P < 0.0001). Plantar foot ulceration developed in 49 (40%) men compared to 24 (19%) women (P < 0.0001) during the study. When men and women were analyzed separately, univariate logistical regression analysis yielded similar odds ratios in both groups for high NDS (≥ 5, M 6.1, W 8.3), high VPT (≥ 25 V, M 6.0, W 8.9), SWM (M 6.6, W 3.7), high foot pressures (≥ 6 kg/cm2, M 2.7, W 3.0), and MTPJ mobility (M 0.97, W 0.98). This study showed that women have a lower risk than men for foot ulceration, but the lower risk appears to be the result of less severe neuropathy, increased joint mobility, and lower foot pressures. Once neuropathy or other risk factors are present, women were found to have the same risk of developing foot ulcerations as men, according the results. Source: Thanh Dinh, DPM, and Aristidis Veves, MD, DSc. The Influence of Gender as a Risk Factor in Diabetic Foot Ulceration. Wounds. May 2008;20:127-131.
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Optimal Treatment for Burns Dr. Kirsner’s Comments: Burn wound injury is a catastrophic event, at times life threatening or life altering. While advances in critical care have led to increased survival, there have been fewer advances in care of the actual burn wounds. One significant advance has been the appreciation that early debridement leads to faster healing of burn wounds due to the reversal of the healing lag typical of non-debrided burn wounds. Since major burns limit the reservoir of available autologous skin to graft, another major advance has been the use of skin substitutes. In addition to speeding the healing of the wounds, skin substitutes serve as mechanisms to prevent excessive fluid and electrolyte loss and as barriers to infection. The perfect skin substitute for burns would possess a number of important characteristics. It would be readily available and made of non-antigenic tissue that would serve as a permanent replacement applied in a single procedure. The result would be a rapidly healed wound that would result in little or no scarring. Unfortunately, the perfect skin substitute has not yet been developed for burn wounds. Paul reviews the currently available skin substitutes used for burn wounds and highlights the various characteristics, advantages, and limitations. This serves as an excellent resource until the perfect substitute is developed. Synopsis of Research: To gain a better understanding of the history on the use of graft material aside from skin for both partial- and full-thickness burns, Paul performed Medline and Google searches using the key words: skin graft, skin substitute, allograft, homograft, xenograft, heterograft, autograft, burn grafting, and burn coverage. Articles retrieved were visually scanned for applicability, and those thought to apply were reviewed. Appropriate references within the articles were also reviewed. Based on this review, the author concluded that although there have been numerous advances in the science of biological tissue engineering in the past few decades, an ideal skin replacement has not been found yet. There is no available product that fulfills all the criteria of an ideal skin replacement. The patient’s skin remains the best alternative to replace burned tissues, though the addition of dermal replacement alternatives has improved the long-term success of split-thickness skin grafts. The author noted, “Further progress will undoubtedly be made in the years to come. Unfortunately, ideal skin replacement remains an ephemeral goal that must be diligently pursued. Hopefully this replacement will be found sooner rather than later.” Source: Chester N. Paul, MD, FACS. Skin Substitutes in Burn Care. Wounds. July 2008; 20:203-205.
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Do Not Fear Fungi Dr. Kirsner’s Comments: Much scientific investigation has focused on why chronic wounds are refractory. Among the reasons why well-vascularized wounds in otherwise healthy nourished patients fail to heal include the presence of excessive or resistant bacteria, an inflammatory or proteolytic wound environment with reduced or unavailable growth factors, and senescent or unresponsive cells. These factors appear to be more common in nonhealing chronic wounds compared to those chronic wounds that are healing and represent potential therapeutic targets for clinicians. However, do other targets for intervention exist, whereby nonhealing wounds can be converted to healing wounds? Veraldi and co-workers sought to study the role of fungi in chronic non-healing wounds. Studying 149 patients with long-standing chronic wounds greater than 2 months duration and performing fungal culture twice in each patient, they were able to set our minds at ease regarding a major role of fungi in nonhealing wounds. Only 11 patients had any fungi detected in their wounds — all candida species, with C. albicans found in 7 patients, C. parapsilosis in 2 patients, and C. krusei and C. lipolytica (1 patient each). No other fungi (dermatophytes or molds) were isolated. Seven of the patients were treated with combination oral antifungal without clinical improvement of the ulcers. Synopsis of the Research: To date, the role of fungi in superinfection of chronic leg ulcers has been poorly studied. What has been published is typically based on either a small number of patients or single cases, and the study conclusions are conflicting. Veraldi et al conducted a study to evaluate the percentage of mycotic superinfections and their clinical importance in chronic leg ulcers. For this study, mycologic examinations were performed on 149 patients without diabetes who had chronic leg ulcers for at least 2 months. (See Table 2.) Two specimens were obtained from each ulcer. Mycologic examinations were positive in 11 patients (7.4%). Five of the 11 patients had venous ulcers, 2 had atherosclerotic ulcers, and 1 each had a post-traumatic, pressure, vasculitic, and neuropathic ulcer. The following fungal species were isolated: Candida albicans (7 patients), C. parapsilosis (2 patients), C. krusei (1 patient), C. parapsilosis and C. lipolytica (1 patient each). No other fungi (dermatophytes or molds) were isolated. Seven patients were treated with oral fluconazole (100 mg/day for 2 weeks) and 4 with oral itraconazole (200 mg/day for 2 weeks). No clinical improvement of the ulcers was observed with this therapy. This data shows that mycotic superinfections of chronic ulcers of the legs are rare; mycotic superinfections were exclusively caused by yeasts; clinical appearance of skin ulcers superinfected by fungi is not characterized by particular features; and oral antimycotic treatment did not provide clinical improvement for the ulcers with mycotic superinfection. Based on the results of this study, the authors concluded that mycologic examinations may be considered unnecessary in patients without diabetes who suffer with chronic leg ulcers. Source: Stefano Veraldi, MD; Anna Maria Tortorano, MD; Luisa Lunardon, MD; Maria Chiara Persico, MD; Claudia Francia, MD. Mycologic Evaluations in Chronic Leg Ulcers. Wounds. September 2008; 20:250-253.
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High Bacterial Counts Are Common But Are They Meaningful? Dr. Kirsner’s Comments: In non-healing wounds, bacteria have long been thought of as a potential target for intervention. For example, pressure ulcer guidelines recommend topical anti-microbial therapy for nonhealing wounds. In spite of this, most chronic wounds that heal do so with 3 or more bacteria present, and in acute partial-thickness wounds, faster healing with occlusive dressings is accompanied by increased bacterial numbers. So should we fear bacterial numbers? Ratliff and others from Virginia attempted to answer that question when they studied 30 clean wounds for the bacteria number and type. What they found was extremely interesting. First, they reported a majority (19 of 30, more than 60%) of these clean wounds had bacterial levels that were ≥ 105 ccfu/cm2 — the vast majority being aerobic bacteria. They also found that the number of bacteria did not correlate with wound reduction and worsening wounds in some cases had low numbers of bacteria. Several lessons can be drawn from this study. The first is that clinical signs and symptoms of infection should be the determinant of whether bacteria are causing delayed healing as opposed to sheer number. Additionally, we are learning that it is possible that a complex relationship between bacteria numbers, the virulence of the bacteria present as well as local and systemic host resistance may be more important than numbers alone. Finally, some data suggest the lifestyle in which bacteria exist in wounds, such as those living in a biofilm, may be more important in determining wound chronicity than the number of planktonic or free-floating bacteria present. Synopsis of the Research: Among wound care professionals, it is accepted that open, chronic wounds are colonized with bacteria, and most physicians have believed that it can be assumed that if a wound shows no signs of infection, the bacteria are not interfering with the healing process. However, new information is causing physicians to believe that high levels of bacteria may inhibit healing, even when there are no traditional signs of infection. The level of bacteria that inhibits wound healing but does not display the standard clinical signs of infection has been termed “critical colonization,” a situation that requires additional criteria to diagnose covert infection. Two previous studies assessed the validity of these additional criteria, including serous exudate, foul odor, discolored or friable granulation tissue, and delayed healing or wound deterioration using quantitative biopsies and a quantitative swab technique, respectively. Results of these studies caused the wound care plan to be altered to focus on reducing the level of bacteria in these wounds, which resulted in healing. Reseachers from the Department of Plastic Surgery Research, University of Virginia Health System, Charlottesville, VA, however, noted, “The use of quantitative bacteriology to direct a wound care program is limited by the technical difficulties and expertise required to process the samples.” They write that a simple diagnostic test to document if a clean, nonhealing wound contained ➢ 105 bacteria/g of tissue would be beneficial to wound care professionals. To develop such a test, it must be determined if anaerobic organisms play a significant role in the number of bacteria present in clean, nonhealing wounds, so these authors conducted a pilot study to quantitate the number of aerobic and obligate anaerobic organisms in a small number of clean, nonhealing wounds. Quantitative swabs were obtained from 30 clean, chronic wounds on 30 different patients. The number of organisms and the predominant organism were determined. All samples were processed under both aerobic and anaerobic conditions. Nineteen (63%) of the 30 clean wounds had bacterial levels that were ≥ 105 cfu/cm2. There was no correlation between ≥ 105 cfu/cm2 and delayed wound healing. The most frequently isolated predominant organism was Staphylococcus aureus. In these clean, chronic wounds, an obligate anaerobic organism was identified as predominant or co-predominant in only 2 (6.7%) of 30 wounds. The results indicated that the presence of obligate anaerobic organisms as the predominant organism in clean wounds is not frequent, which are in agreement with the results of those of much larger studies. Source: Catherine R. Ratliff, PhD, APRN-BC, CWOCN; Sandra I. Getchell-White, MT (ASCP), SM; George T. Rodeheaver, PhD. Quantitation of Bacteria in Clean, Nonhealing, Chronic Wounds. Wounds. October 2008. 20:279-283.
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Food for Thought Dr. Kirsner’s Comments: Impairment of healing occurs from a variety of sources ranging from age to comorbidities. One well-known cause of healing impairment is from the use of corticosteroids, a ubiquitous treatment for a variety of inflammatory conditions. Corticosteroids negatively affect all phases of wound healing, reducing inflammatory cell infiltration, granulation tissue formation and epithelial migration and collagen strength. For decades, attempts have been made to better understand reasons why steroids impair healing and to find potential treatments to reverse the healing impairment caused by steroids. Simplistically, steroids result in reduced growth factors and cytokines in the healing wound, which stagnate the healing cascade initiated by these key messengers. Among the treatments best studied and most utilized to reverse the healing impairment of steroids is the use of systemic and topical vitamin A and its derivative, retinoids. Cerci et al studied another compound to reverse the healing effects of corticosteroids — topical and systemic use of beta glucan. Four groups (control, steroid treated, and steroid treated plus either topical or systemic beta glucan) of 20 adult Wistar-albino rats each were studied after incisional and excisional wounding. As expected, steroids impaired healing, and as hypothesized, both topical and systemic beta glucan normalized healing and wound strength. Systemic beta glucan appeared superior to topical application. Easily tolerated, beta glucan may be beneficial for steroid-treated wounds. Whether systemic administration would also obviate the therapeutic effects is not known, but it does occur with systemic vitamin A administration. Additionally, whether the benefits of beta glucan extend beyond steroid-impaired wounds to a variety of other wounds that have difficulty healing — ranging from physiologic changes such as aging to diabetic or vascular wounds — would be interesting to better understand. Synopsis of the Research: Corticosteroid hormones are widely used to treat a variety of diseases, but corticosteriods have been shown to impair wound healing, which has become a serious clinical problem. Researchers from the Suleyman Demirel University in Isparta, Turkey, designed a study to evaluate the efficacy of topical and systemic beta glucan administration on wound healing impaired by corticosteroids. Beta glucan is a complex carbohydrate that is found in the cell walls of yeast, fungi, and cereal plants, and is known as a potent macrophage stimulator. Macrophage cells play an important role in wound healing. Wistar albino rats were used for the incision and excision wound models. Percentage of wound contraction, epithelialization period, hydroxyproline level, histopathological examination, and tensile strength were evaluated. Although both systemic and local administration of beta glucan enhanced percentage wound contraction, improved epithelialization time, improved tensile strength, and elevated hydroxyproline level, systemic administration was found to be more effective. (See Figure 3.) Researchers concluded that these results indicate that systemic and topical beta glucan improve wound healing that has been impaired by corticosteroids, and that systemic administration is more effective than topical application. Source: Celal Cerci, MD; Mehmet Yildirim, MD; Murat Ceyhan, MD; Serkan Bozkurt, MD; Duygu Doguc, MD; Alpaslan Gokicimen, MD. The Effects of Topical and Systemic Beta Glucan Administration on Wound Healing Impaired by Corticosteroids. Wounds. December 2008. 20:341-346. Dr. Kirsner is Vice Chairman & Stiefel Laboratories Professor, Department of Dermatology & Cutaneous Surgery at the University of Miami Miller School of Medicine.
Skin & Aging’s sister journal Wounds is the nation’s leading wound care research journal, and it’s the major source of current research, treatment methodology, and current protocol in the field of wound care. In addition, this journal is the standard reference tool of those healthcare professionals who are leaders in establishing wound care programs and treatment centers both nationally and internationally. This month, we bring you the top 10 selections from the whole body of research published in Wounds in 2008. Dermatologist and wound care expert, Dr. Robert Kirsner, who is Section Editor for Wounds and an Editorial Advisory Board Member for Skin & Aging, selected the following research findings as the most relevant to dermatology. Read on for Dr. Kirsner’s commentary on the relevance of this research as well as synopses of these wound care findings.
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Oxygen is a Drug Dr. Kirsner’s Comments: A conceptual hurdle to understanding the role of oxygen is appreciating how hyperbaric oxygen helps to heal wounds when the wounds are without the treatment for 22 out of every 24 hours, even on the days patients receive the treatment. If these wounds are in need of oxygen, one would think that they would need oxygen all the time, not just a couple of hours daily. This, at first blush, is anti-intuitive until one begins to think of oxygen not as a nutrient but rather as a drug. The drug oxygen can be dosed similarly to more typical drugs like antibiotics. The drug oxygen is needed for a variety of critical functions ranging from antimicrobial activities such as nicotinamide adenine dinucleotide phosphate (NADPH) in leukocytes and bactericidal effect of superoxides as well as cross linking of collagen. Like any drug, delivery to tissue is critical, and while the majority of oxygen is carried on hemoglobin, more critical is partial pressure of oxygen in the blood, which leads to oxygen diffusion to wounded tissue. Thus, the high partial pressure of oxygen caused by hyperbaric treatment appears to be among the most effective ways to deliver the drug oxygen to tissue. Studying oxygen is often most easily accomplished in animal models. Myers and Gould highlight the most important and applicable animal models to study the effect of oxygen, hypoxia, and hyperbaric treatment. Using a variety of relevant models helps one gain a better understanding of how oxygen helps heal wounds, the effect of diminished oxygen, and the role of oxygen therapy to treat a variety of wounds. Synopsis of the Research: Effective and dependable influx and efflux of blood, fluid, and nutrient supply is essential for wound healing. The delicate balance between adequate oxygenation and hypoxia is an important aspect of this process. Due to the wide variety of wounds that occur in humans, along with multiple comorbidities, it is difficult to define, understand, and optimize treatments for chronic wounds. Although valuable for examining mechanisms at a molecular level, in vitro cell culture models cannot replicate the complex environment of a wound. A stable, reliable, and reproducible animal wound model that mimics the chronic wound state has yet to be found. Myers and Gould reviewed the current understanding of the effect of ischemia on wound healing and examined the features of currently available animal models that simulate ischemic wounds. Although it is not a chronic wound model, the authors believe that the ischemic bipedicle flap model has the potential to be a valuable tool for understanding the contribution of ischemia to impaired wound healing. This flap does not develop necrosis, yet, it remains ischemic for up to 2 weeks with markedly impaired wound healing. Although it is very flexible, by suturing to both the skin flap and to the dorsal muscle fascia, the silicone sheet also acts as a splint and can prevent wound contraction to some extent. This model was standardized so trained personnel with minimal surgical experience could perform the model with good reproducibility and flap survival. Rats tolerate the flap well and can be treated with systemic or topical agents. The wounds can be measured and excised, providing sufficient tissue for multiple biochemical analyses. The researchers noted that the Sprague-Dawley ischemic flap showed that hyperbaric oxygen (HBO) improves the rate of wound closure in ischemic wounds but has no effect on the wound closure rate in nonischemic wounds. According to the researchers, biochemical and histologic analyses demonstrated that apoptosis is attenuated by HBO treatment of ischemic wounds and that this effect is blocked by systemic administration of the free radical scavenger, N-acetylcysteine. Reduced inducible nitric oxide synthase, reduced 3-nitrotyrosine, and induction of copper/zinc superoxide dismutase, catalase, and glutathione peroxidase in the hyperbaric-treated ischemic wounds indicate modulation of the balance between reactive oxygen species and endogenous antioxidants. SOURCE: Wesley T. Myers, MD, and Lisa J. Gould, MD, PhD. Animal Models of Tissue Ischemia to Evaluate the Importance of Oxygen in the Wound Healing Environment. Wounds. January 2008;20:9-17.
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Ulceration is a Complication of Neuropathy, Not Diabetes Dr. Kirsner’s Comments: We are in the midst of an epidemic in diabetes. Within the United States and abroad, the prevalence of diabetes, by conservative estimates, is expected to increase 50% to 100% in the next 2 decades. As a consequence, complications of diabetes will increase as well. Of the 20 million Americans with diabetes, 15% will get a foot ulcer. The presence of a foot ulcer represents the most common risk factor for osteomyelitis, amputation, and increased mortality. Foot ulcers occur most commonly from neuropathy, and validated scales for both signs and symptoms for neuropathy exist. Testing for the signs and symptoms of neuropathy are simple, and no patient with diabetes should go untested for neuropathy. Bacarin and colleagues teach us a number of important lessons in their study of diabetics with and without foot ulcers. First is that signs of neuropathy were more commonly seen in those with diabetic foot ulcers compared with symptoms of neuropathy. Thus, examination of signs (physical examination) may be a better test for risk than merely asking about symptoms. Signs of neuropathy were more severe in those patients with ulcers than those without ulcers, suggesting the severity of neuropathy to be the critical component for those developing ulcers. Additionally, the duration of diabetes was not related to severity of neuropathy, suggesting that all patients with diabetes undergo neurologic assessment as opposed to only those with longstanding disease. Synopsis of the Research: Previous research has shown that patients with a plantar ulcer due to diabetes tend to have had diabetes for a longer duration and are older than those patients who have diabetes but no ulcers. It’s known that diabetic peripheral neuropathy (DPN), a common condition in patients with diabetes, causes loss of protective sensation, a major risk factor for ulceration in diabetic feet. Researchers from Brazil conducted a study to determine if patients with a history of plantar ulcers due to DPN have more symptoms, a longer duration of disease, and poorer foot sensitivity — parameters that previously had not been studied together in patients with ulcers who had diabetes. This study conducted by Bacarin et al compared the duration of disease, the prevalence of neuropathy symptoms, and plantar insensitivity among three groups — patients with diabetic neuropathy with a history of plantar ulcers (UDG), patients with diabetic neuropathy without a history of plantar ulcers (DG), and a nondiabetic group of patients (the control group [CG]). (See Table 1.) Investigators used the Michigan Neuropathy Screening Instrument (MNSI) to study the neuropathy symptoms. The evaluation of plantar sensitivity was composed of three sensory tests — sensitive chronaxie, and thermal and tactile sensitivities. Plantar sensitivity was investigated in five areas of the plantar surface of both feet, including the heel, mid-foot, lateral forefoot, medial forefoot, and hallux. Results showed the neuropathic groups did not differ in duration of diabetes, and, according to MNSI scores, presented a similar number of symptoms. Abnormal sensitivity was highest in the UDG. A delay in sensing the electrical stimulus was higher in the UDG. The number of areas with sensitive chronaxie values higher than 0.30 ms did not show any difference among groups (P = 0.593). However, the UDG had more areas with values higher than the threshold (2 areas for CG, 3 areas for DG; 5 areas for UDG). In terms of tactile sensitivity, the median number of areas with deficit of tactile sensitivity were no areas for CF, 2 areas for DG, and 6 areas for UDG — with five patients (55.5%) from UDG unable to feel the 10-g monofilament pressure in more than 5 areas of the feet. The medians for the number of areas with inability to discriminate hot and cold temperatures were: 0 areas for CG, 2 areas for DG, and 3 areas for UDG. The MNSI total score achieved a weak and insignificant correlation with sensitive chronaxie (r = -0.17; P > 0.05) and with thermal sensitivity (r = -0.11;P > 0.05) for all areas. The results of this study led the researchers to conclude that patients with diabetic neuropathic ulceration had decreased sensitivity in their feet, confirmed by the high number of insensitive plantar areas as well as by the high values of sensitive chronaxie. The authors wrote, “These findings were not related to the duration of diabetes onset, nor to the symptoms reported by the patients. However, the symptoms may be an indicator of decreased foot sensitivity, but the symptoms alone are not able to differentiate between groups with variation in progression of diabetic neuropathy.” Source: Tatiana de A. Bacarin, MSc, Dip PT; Paula M. H. Akashi, MSc, Dip PT; Prof. Isabel de C. N. Sacco, PhD. Duration of Disease, Neuropathic Symptoms, and Plantar Sensitivity in Patients With Diabetes With and Without Previous Plantar Ulceration. Wounds. February 2008;20:37-45.
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Charcot Foot Deformity: When Amputation May be Avoided Dr. Kirsner’s Comments: Neuropathy and vascular disease take many clinical forms. Neuropathy, for example, has effects not solely on the sensory nerves, leading to insensate feet; but also to the motor nerves, leading to atrophy of major muscle groups, as well as autonomic neuropathy, leading to the dry, scaling, and calloused skin seen in patients with diabetes. In an analogous fashion, both small and large vessel disease may occur in diabetics, leading to a variety of clinical presentations. One manifestation of diabetes — and less often of other conditions — is Charcot foot. While several theories have been proposed for why only a small subset of patients with diabetes develops this, the crux of the problem appears to be a bony collapse of the foot, leading to foot deformity. Once developed, repetitive trauma can worsen disease and lead to progression, so early recognition and prompt intervention may prevent complications. Thomas and Huffman teach us that the Charcot foot progresses through 3 stages, with the earliest stage of edema and inflammation often mimicking an active infection. Indium-labeled leukocyte scans may be the best technique to differentiate Charcot from infection and off loading is critical in hopes of preventing progression to stages 2 and 3. However, late presentation and development of ulcer formation may require more aggressive treatment, including a variety of surgical options leading to correction of the foot deformity and ulcer healing. Synopsis of the Research: Because patients with diabetes are living longer, studies have shown that there has been an increase in the number of Charcot arthropathy, a non-infective progressive process characterized by painless joint destruction, fracture, and eventual dislocation. Charcot arthropathy can have a significant impact on patients in terms of limb salvage and overall health. Its treatment has long been a topic of debate, with amputation being the most common surgical treatment for many years. However, with a better understanding of the disease and the development of new fixation and surgical techniques, it’s possible to avoid amputation. Thomas and Huffman note, “Proper preoperative evaluation, often by a multidisciplinary team of specialists, is critical as well as the assurance of the necessary vascular perfusion to achieve healing.” Surgical options include exostectomy and reconstruction, with or without various plastic surgical procedures, and amputation, which should only be considered for the nonsalvegable extremity. Using three case studies to demonstrate successful surgical treatment of Charcot foot, the authors found that surgical reconstruction is a viable option in selected patients, even when other specialists had recommended amputation. They found plastic surgical techniques and new fixation methods, such as external ring fixation (see Figure 1), seem to provide better outcomes and more flexibility. The keys to achieving and maintaining postoperative results include surgical planning, preoperative work-up with a multidisciplinary team, and proper orthotic management after surgery to avoid recurrence of ulcers. Source: James L. Thomas, DPM, FACFAS, and Lanie Huffman, DPM. Charcot Foot Deformity: Surgical Treatment Options. Wounds. March 2008; 20:67-73.
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Measuring Blood Flow Dr. Kirsner’s Comments: The performance of a vascular assessment is part of most algorithms of care of lower extremity wounds. This assessment is routine, as it is generally accepted that adequate blood flow is required for healing. While physical examination findings of good pulses and capillary perfusion are often used, there is a subset of patients with vascular disease who have normal physical examinations. A variety of methods have been developed and used to measure blood flow in the lower extremity. Most common perhaps is the ankle-brachial index, or ABI, which is a ratio of the systolic blood pressure in the leg compared with the arm. Normally, lower ABIs have correlated with worse vascular disease. Importantly, an ABI of less than 0.9 is an independent risk factor for cardiovascular disease. Limitations to the ABI exist, as the ABI is a measure of large vessel disease, and hardening of the vessels through glycosalation in patients with diabetes and calcification in the elderly can give false negative results. Tissue oxygen measures, by way of measuring transcutaneous oxygen (TcPO2), have also been used. Somewhat tedious to perform and requiring rigorous standardization of body temperature, measuring oxygen at the site of the wound is a more direct approach than measuring large vessel disease. TcPO2 is limited by things such as limb edema. More recently skin perfusion pressure (SPP) using laser Doppler directly measures skin perfusion at the site of the wound by slowing releasing pressure from blood pressure cuffs and measuring perfusion to the site. The fact that it is simple and fast to use makes SPP attractive. But the question remains about how well it works. Tsuji and colleagues teach us that SPP is, in fact, very good. In their study of consecutive lower limb wounds, the SPP was able to dichotomize healing from nonhealing wounds (60 mmHg vs. 31 mmHg), was shown to increase in patients who underwent revascularization and healed, and predicted the need for amputation in a patient who underwent revascularization but whose SPP did not change and whose wound did not heal. As this technology becomes more prevalent, it is likely SPP will become standard of care in wounds centers throughout the United States. Synopsis of the Research: In previous studies, SPP has been shown to be a reliable predictor of wound healing. The authors of this study wanted to determine if SPP measurements can be used to accurately predict wound healing in critical limb ischemia (CLI) and to select peripheral arterial reconstructive procedures. The authors measured SPP at the proximal margin of foot ulcers (not in the wound bed) in patients referred to the Wound Treatment Center at Shin-Suma General Hospital (Kobe, Japan) for the treatment of intractable foot ulcers, and compared it with the outcomes of treatment (healed or failed to heal). Foot ulcers that did not heal within 12 weeks after debridement or minor amputation or that required peripheral arterial reconstruction or more proximal amputation were evaluated as “failed to heal.” Those that demonstrated complete wound closure without additional surgery were evaluated as “healed.” Skin perfusion pressure was compared before and after peripheral arterial reconstruction. The effect of SPP elevation on wound healing was also evaluated. The study found the average SPP of patients with healed wounds was 60 mmHg, while the average SPP for patient with unhealed wounds was 31 mmHg. The data, analyzed to determine the optimal cutoff level for SPP, showed that SPP levels below the threshold gave a positive result and were predictive of healing failure, while SPP levels above the threshold gave a negative result and were predictive of healing success. The sensitivity, specificity, and the positive and negative predictive values of SPP measurement were calculated, and then the data was analyzed by the receiver operation characteristic (ROC) curve. According to the ROC curve, the optimal SPP lies at 35 mmHg. In contrast, at a threshold of 60 mmHg, the negative predictive value dropped to 62.8%, suggesting that peripheral arterial reconstruction may not always be necessary to facilitate an efficient wound healing process, or that a proximal amputation level is necessary. Based on these findings, the authors propose “that when the SPP value is not ≥ 35 mmHg, any surgical debridement should be secondary to the restoration of adequate skin blood flow to minimize invasive debridement. When the SPP is ≥ 35 mmHg, surgical debridement of necrotic tissue is feasible without any peripheral arterial reconstruction.” The study showed that SPP measurement is useful in accurately planning minimally invasive amputation and for predicting successful wound healing in CLI. Source: Yoriko Tsuji, MD; Terashi Hiroto, MD, PhD; Ikuro Kitano, MD, PhD; Shinya Tahara, MD, PhD; Daisuke Sugiyama, MD, MPH. Importance of Skin Perfusion Pressure in Treatment of Critical Limb Ischemia. Wounds. April 2008; 20:95-100.
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Improving the Quality of Healing Dr. Kirsner’s Comments: While, at times, just getting a chronic wound to heal is a major accomplishment, for many, excessive healing leads to excessive fibrosis, scarring, and even keloid formation. Additionally, fibrosis is a major medical problem, with protean manifestations ranging from keloids and scleroderma in the skin to arthritis affecting joints, cirrhosis affecting the liver, and other life-threatening fibrosis affecting the lungs and heart, as a result of pulmonary hypertension and myocardial infarction, respectively. Clearly, novel ways to reduce scarring are needed, and any general or gastrointestinal surgeon would also welcome ways to reduce adhesions and their accompanying complications. Recently, angiotensin II (ANG II) has become an attractive target to study in an effort to reduce fibrosis. This is partly because ANG II has been shown to stimulate collagen deposition and fibroblast proliferation, and inhibition of ANG II ameliorates this effect. Additionally, ANG II is produced locally in the skin, and pharmaceutical companies have already created drugs targeting the angiotensin-renin pathway to treat hypertension. Stemming from this rationale, Ardekani and colleagues studied the New Zealand White Rabbit to study the benefit of topical captopril to prevent scar formation. Creating two equal sized wounds on each ear, these investigators were able to demonstrate significant improvement in the scar index with a greater than 30% clinical benefit after 7 days. From a mechanistic standpoint, captopril reduced collagen organization typical of scar formation, but it did not have an effect on inflammation at a histologic level. This study opens the idea of addressing fibrosis through the use of ANG II inhibitors and for follow-up studies in humans, researchers might consider evaluating keloid formation among systemic captopril and non-captopril uses as well as performing trials comparing topical and systemic captopril with the aim of improved quality of healing. Synopsis of the Research: The extracellular matrix in tissues such as bone, cartilage, and skin, is primarily made up of collagen, which is known to play a major role in wound healing processes. Overproduction and/or decreased degradation of collagen fibers can lead to abnormal wound healing, which could result in hypertrophic scarring or keloid formation. According to the study authors, “Hypertrophic scar (HS) and keloid are two disfiguring and debilitating forms of wound healing that can cause serious psychological and functional complications.” Most of the available treatments for these conditions are inadequate or associated with adverse events and high recurrence. Recently, ANG II has been shown to be present in several cutaneous cells and to stimulate fibroblast proliferation and collagen synthesis, and to suppress matrix metalloproteinase activity. Ardekani et al conducted a study to examine the effect of topical captopril, an ANG II production inhibitor, against hypertrophic scar formation in six 3-month-old female New Zealand white rabbits. Under sterile conditions, two circular, 7-mm, full-thickness, dermal ulcers were created on the ventral surface of the ears of each rabbit, and the perichondrium was also removed. In each animal, one ulcer was made at the middle part of the left ear and another made at the same level on the right ear. The wounds on the left ears were treated with topical 5% captopril, and the wounds on the right ears were treated with the vehicle (70% ethanol/30% propylene glycol) alone. Daily topical applications were started at the time of wounding and were continued for 7 consecutive days. Applications were always performed by the same technician, who was blinded to the treatment identifications. The wounds were uncovered and exposed to air at day 28. At that time, researchers evaluated the scar elevation index (SEI) and the collagen organization. The SEI was reduced from 3.06 in the vehicle-treated wounds to 1.94 in the captopril-treated wounds (P < 0.05). An increase in collagen organization was achieved by captopril, and an 8.5% decrease in collagen organization scale was derived by captopril compared to vehicle. This study shows captopril is efficacious in preventing hypertrophic scars in an animal model. The authors note that more studies are needed to assess the minimal effective concentration and the optimal frequency of captopril application, and to verify if captopril exerts any significant therapeutic efficacy against HS and keloid formation in humans. Source: Gholamreza Safaee Ardekani, MD; Saeed Ebrahimi, MD; Mitra Amini, MD, MPH; Fatemeh Sari Aslani, MD; Farhad Handjani, MD; Gholamhossein Ranjbar Omrani, MD; Leila Safaee Ardekani, BS; Seyed Hamidreza Hosseini Alhashemi, MD; Behrooz Kasraee, MD. Topical Captopril as a Novel Agent Against Hypertrophic Scar Formation in New Zealand White Rabbit Skin. Wounds. April 2008; 20:101-106.
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Good News For Women Dr. Kirsner’s Comments: Disparities in health care and health services are a hot topic. At-risk populations based on race/ethnicity, socioeconomic status and gender all affect patient outcomes. For example, in a disease common in dermatology, blacks, Hispanics, lower socioeconomic groups, and women all have reduced quality of care as measured by late-stage melanoma diagnoses and worse survival compared to whites, higher socioeconomic status groups, and men, respectively. These differences in outcomes appear more likely related to health services than to biology, but active study to determine if biologic heterogeneity contributes to differential outcomes is underway. Related to wound care, do differences exists based on some of these same parameters? It is known, for example, that Hispanics have a very high prevalence of diabetes and resultant diabetic complications such as diabetic foot ulcers. Dinh and Veves contribute to our knowledge base by studying the prevalence of diabetic foot ulcers and parameters of neuropathy in both men and women. In a study of 248 patients, foot ulcers developed more frequently in men (40% vs. 19%), and men had greater neuropathy disability scores, higher plantar pressures, and reduced mobility. The reason for these differences in neuropathy and ulceration is not entirely clear, but it’s been hypothesized that there are more (longer) at-risk nerves in taller men, or that perhaps estrogen may play a protective role for women. In sum, as seen in the change in the workforce in recent months, it’s good to be a woman. Synopsis of the Research: There are numerous risk factors known for the development of foot ulceration, including peripheral neuropathy, high plantar foot pressures, limited joint mobility, and peripheral vascular disease. Studies also have found that socio-demographic factors, such as race, education level, and gender, appear to influence the likelihood of foot ulceration. In a previous large, prospective trial that the authors’ unit coordinated, 29% of all patients with diabetes, including men and women, were shown to ulcerate over a 30-month period. To try to determine if gender poses a significant risk factor, the authors of this study analyzed these same data separately for men and women. A total of 248 patients with diabetes were enrolled in a 30-month, multicenter, prospective study. There were 124 men and 124 women. Patient demographics were similar between men and women in terms of age, duration of diabetes mellitus, and body mass index. Neuropathy disability score (NDS), vibration perception threshold (VPT), Semmes Weinstein monofilament (SWM), plantar peak foot pressures, subtalar joint (STJ), and first metatarsal joint (MTJP) mobility risk factors were measured in both groups. Men had higher NDS (13 ± 8 versus 8 ± 7, P < 0.0001), VPT (36 ± 17 V versus 23 ± 16, P < 0.0001), SWM (5.9 ± 1.4 versus 5.9 ± 1.3, P < 0.0001), and plantar peak foot pressures (6.4 ± 3.4 kg/cm2 versus 5.0 ± 2.3, P < 0.0001), while women had higher MTPJ mobility (69 ± 24 degrees versus 77 ± 23, P < 0.0001) and STJ mobility (22 ± 10 degrees versus 26 ± 8, P < 0.0001). Plantar foot ulceration developed in 49 (40%) men compared to 24 (19%) women (P < 0.0001) during the study. When men and women were analyzed separately, univariate logistical regression analysis yielded similar odds ratios in both groups for high NDS (≥ 5, M 6.1, W 8.3), high VPT (≥ 25 V, M 6.0, W 8.9), SWM (M 6.6, W 3.7), high foot pressures (≥ 6 kg/cm2, M 2.7, W 3.0), and MTPJ mobility (M 0.97, W 0.98). This study showed that women have a lower risk than men for foot ulceration, but the lower risk appears to be the result of less severe neuropathy, increased joint mobility, and lower foot pressures. Once neuropathy or other risk factors are present, women were found to have the same risk of developing foot ulcerations as men, according the results. Source: Thanh Dinh, DPM, and Aristidis Veves, MD, DSc. The Influence of Gender as a Risk Factor in Diabetic Foot Ulceration. Wounds. May 2008;20:127-131.
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Optimal Treatment for Burns Dr. Kirsner’s Comments: Burn wound injury is a catastrophic event, at times life threatening or life altering. While advances in critical care have led to increased survival, there have been fewer advances in care of the actual burn wounds. One significant advance has been the appreciation that early debridement leads to faster healing of burn wounds due to the reversal of the healing lag typical of non-debrided burn wounds. Since major burns limit the reservoir of available autologous skin to graft, another major advance has been the use of skin substitutes. In addition to speeding the healing of the wounds, skin substitutes serve as mechanisms to prevent excessive fluid and electrolyte loss and as barriers to infection. The perfect skin substitute for burns would possess a number of important characteristics. It would be readily available and made of non-antigenic tissue that would serve as a permanent replacement applied in a single procedure. The result would be a rapidly healed wound that would result in little or no scarring. Unfortunately, the perfect skin substitute has not yet been developed for burn wounds. Paul reviews the currently available skin substitutes used for burn wounds and highlights the various characteristics, advantages, and limitations. This serves as an excellent resource until the perfect substitute is developed. Synopsis of Research: To gain a better understanding of the history on the use of graft material aside from skin for both partial- and full-thickness burns, Paul performed Medline and Google searches using the key words: skin graft, skin substitute, allograft, homograft, xenograft, heterograft, autograft, burn grafting, and burn coverage. Articles retrieved were visually scanned for applicability, and those thought to apply were reviewed. Appropriate references within the articles were also reviewed. Based on this review, the author concluded that although there have been numerous advances in the science of biological tissue engineering in the past few decades, an ideal skin replacement has not been found yet. There is no available product that fulfills all the criteria of an ideal skin replacement. The patient’s skin remains the best alternative to replace burned tissues, though the addition of dermal replacement alternatives has improved the long-term success of split-thickness skin grafts. The author noted, “Further progress will undoubtedly be made in the years to come. Unfortunately, ideal skin replacement remains an ephemeral goal that must be diligently pursued. Hopefully this replacement will be found sooner rather than later.” Source: Chester N. Paul, MD, FACS. Skin Substitutes in Burn Care. Wounds. July 2008; 20:203-205.
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Do Not Fear Fungi Dr. Kirsner’s Comments: Much scientific investigation has focused on why chronic wounds are refractory. Among the reasons why well-vascularized wounds in otherwise healthy nourished patients fail to heal include the presence of excessive or resistant bacteria, an inflammatory or proteolytic wound environment with reduced or unavailable growth factors, and senescent or unresponsive cells. These factors appear to be more common in nonhealing chronic wounds compared to those chronic wounds that are healing and represent potential therapeutic targets for clinicians. However, do other targets for intervention exist, whereby nonhealing wounds can be converted to healing wounds? Veraldi and co-workers sought to study the role of fungi in chronic non-healing wounds. Studying 149 patients with long-standing chronic wounds greater than 2 months duration and performing fungal culture twice in each patient, they were able to set our minds at ease regarding a major role of fungi in nonhealing wounds. Only 11 patients had any fungi detected in their wounds — all candida species, with C. albicans found in 7 patients, C. parapsilosis in 2 patients, and C. krusei and C. lipolytica (1 patient each). No other fungi (dermatophytes or molds) were isolated. Seven of the patients were treated with combination oral antifungal without clinical improvement of the ulcers. Synopsis of the Research: To date, the role of fungi in superinfection of chronic leg ulcers has been poorly studied. What has been published is typically based on either a small number of patients or single cases, and the study conclusions are conflicting. Veraldi et al conducted a study to evaluate the percentage of mycotic superinfections and their clinical importance in chronic leg ulcers. For this study, mycologic examinations were performed on 149 patients without diabetes who had chronic leg ulcers for at least 2 months. (See Table 2.) Two specimens were obtained from each ulcer. Mycologic examinations were positive in 11 patients (7.4%). Five of the 11 patients had venous ulcers, 2 had atherosclerotic ulcers, and 1 each had a post-traumatic, pressure, vasculitic, and neuropathic ulcer. The following fungal species were isolated: Candida albicans (7 patients), C. parapsilosis (2 patients), C. krusei (1 patient), C. parapsilosis and C. lipolytica (1 patient each). No other fungi (dermatophytes or molds) were isolated. Seven patients were treated with oral fluconazole (100 mg/day for 2 weeks) and 4 with oral itraconazole (200 mg/day for 2 weeks). No clinical improvement of the ulcers was observed with this therapy. This data shows that mycotic superinfections of chronic ulcers of the legs are rare; mycotic superinfections were exclusively caused by yeasts; clinical appearance of skin ulcers superinfected by fungi is not characterized by particular features; and oral antimycotic treatment did not provide clinical improvement for the ulcers with mycotic superinfection. Based on the results of this study, the authors concluded that mycologic examinations may be considered unnecessary in patients without diabetes who suffer with chronic leg ulcers. Source: Stefano Veraldi, MD; Anna Maria Tortorano, MD; Luisa Lunardon, MD; Maria Chiara Persico, MD; Claudia Francia, MD. Mycologic Evaluations in Chronic Leg Ulcers. Wounds. September 2008; 20:250-253.
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High Bacterial Counts Are Common But Are They Meaningful? Dr. Kirsner’s Comments: In non-healing wounds, bacteria have long been thought of as a potential target for intervention. For example, pressure ulcer guidelines recommend topical anti-microbial therapy for nonhealing wounds. In spite of this, most chronic wounds that heal do so with 3 or more bacteria present, and in acute partial-thickness wounds, faster healing with occlusive dressings is accompanied by increased bacterial numbers. So should we fear bacterial numbers? Ratliff and others from Virginia attempted to answer that question when they studied 30 clean wounds for the bacteria number and type. What they found was extremely interesting. First, they reported a majority (19 of 30, more than 60%) of these clean wounds had bacterial levels that were ≥ 105 ccfu/cm2 — the vast majority being aerobic bacteria. They also found that the number of bacteria did not correlate with wound reduction and worsening wounds in some cases had low numbers of bacteria. Several lessons can be drawn from this study. The first is that clinical signs and symptoms of infection should be the determinant of whether bacteria are causing delayed healing as opposed to sheer number. Additionally, we are learning that it is possible that a complex relationship between bacteria numbers, the virulence of the bacteria present as well as local and systemic host resistance may be more important than numbers alone. Finally, some data suggest the lifestyle in which bacteria exist in wounds, such as those living in a biofilm, may be more important in determining wound chronicity than the number of planktonic or free-floating bacteria present. Synopsis of the Research: Among wound care professionals, it is accepted that open, chronic wounds are colonized with bacteria, and most physicians have believed that it can be assumed that if a wound shows no signs of infection, the bacteria are not interfering with the healing process. However, new information is causing physicians to believe that high levels of bacteria may inhibit healing, even when there are no traditional signs of infection. The level of bacteria that inhibits wound healing but does not display the standard clinical signs of infection has been termed “critical colonization,” a situation that requires additional criteria to diagnose covert infection. Two previous studies assessed the validity of these additional criteria, including serous exudate, foul odor, discolored or friable granulation tissue, and delayed healing or wound deterioration using quantitative biopsies and a quantitative swab technique, respectively. Results of these studies caused the wound care plan to be altered to focus on reducing the level of bacteria in these wounds, which resulted in healing. Reseachers from the Department of Plastic Surgery Research, University of Virginia Health System, Charlottesville, VA, however, noted, “The use of quantitative bacteriology to direct a wound care program is limited by the technical difficulties and expertise required to process the samples.” They write that a simple diagnostic test to document if a clean, nonhealing wound contained ➢ 105 bacteria/g of tissue would be beneficial to wound care professionals. To develop such a test, it must be determined if anaerobic organisms play a significant role in the number of bacteria present in clean, nonhealing wounds, so these authors conducted a pilot study to quantitate the number of aerobic and obligate anaerobic organisms in a small number of clean, nonhealing wounds. Quantitative swabs were obtained from 30 clean, chronic wounds on 30 different patients. The number of organisms and the predominant organism were determined. All samples were processed under both aerobic and anaerobic conditions. Nineteen (63%) of the 30 clean wounds had bacterial levels that were ≥ 105 cfu/cm2. There was no correlation between ≥ 105 cfu/cm2 and delayed wound healing. The most frequently isolated predominant organism was Staphylococcus aureus. In these clean, chronic wounds, an obligate anaerobic organism was identified as predominant or co-predominant in only 2 (6.7%) of 30 wounds. The results indicated that the presence of obligate anaerobic organisms as the predominant organism in clean wounds is not frequent, which are in agreement with the results of those of much larger studies. Source: Catherine R. Ratliff, PhD, APRN-BC, CWOCN; Sandra I. Getchell-White, MT (ASCP), SM; George T. Rodeheaver, PhD. Quantitation of Bacteria in Clean, Nonhealing, Chronic Wounds. Wounds. October 2008. 20:279-283.
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Food for Thought Dr. Kirsner’s Comments: Impairment of healing occurs from a variety of sources ranging from age to comorbidities. One well-known cause of healing impairment is from the use of corticosteroids, a ubiquitous treatment for a variety of inflammatory conditions. Corticosteroids negatively affect all phases of wound healing, reducing inflammatory cell infiltration, granulation tissue formation and epithelial migration and collagen strength. For decades, attempts have been made to better understand reasons why steroids impair healing and to find potential treatments to reverse the healing impairment caused by steroids. Simplistically, steroids result in reduced growth factors and cytokines in the healing wound, which stagnate the healing cascade initiated by these key messengers. Among the treatments best studied and most utilized to reverse the healing impairment of steroids is the use of systemic and topical vitamin A and its derivative, retinoids. Cerci et al studied another compound to reverse the healing effects of corticosteroids — topical and systemic use of beta glucan. Four groups (control, steroid treated, and steroid treated plus either topical or systemic beta glucan) of 20 adult Wistar-albino rats each were studied after incisional and excisional wounding. As expected, steroids impaired healing, and as hypothesized, both topical and systemic beta glucan normalized healing and wound strength. Systemic beta glucan appeared superior to topical application. Easily tolerated, beta glucan may be beneficial for steroid-treated wounds. Whether systemic administration would also obviate the therapeutic effects is not known, but it does occur with systemic vitamin A administration. Additionally, whether the benefits of beta glucan extend beyond steroid-impaired wounds to a variety of other wounds that have difficulty healing — ranging from physiologic changes such as aging to diabetic or vascular wounds — would be interesting to better understand. Synopsis of the Research: Corticosteroid hormones are widely used to treat a variety of diseases, but corticosteriods have been shown to impair wound healing, which has become a serious clinical problem. Researchers from the Suleyman Demirel University in Isparta, Turkey, designed a study to evaluate the efficacy of topical and systemic beta glucan administration on wound healing impaired by corticosteroids. Beta glucan is a complex carbohydrate that is found in the cell walls of yeast, fungi, and cereal plants, and is known as a potent macrophage stimulator. Macrophage cells play an important role in wound healing. Wistar albino rats were used for the incision and excision wound models. Percentage of wound contraction, epithelialization period, hydroxyproline level, histopathological examination, and tensile strength were evaluated. Although both systemic and local administration of beta glucan enhanced percentage wound contraction, improved epithelialization time, improved tensile strength, and elevated hydroxyproline level, systemic administration was found to be more effective. (See Figure 3.) Researchers concluded that these results indicate that systemic and topical beta glucan improve wound healing that has been impaired by corticosteroids, and that systemic administration is more effective than topical application. Source: Celal Cerci, MD; Mehmet Yildirim, MD; Murat Ceyhan, MD; Serkan Bozkurt, MD; Duygu Doguc, MD; Alpaslan Gokicimen, MD. The Effects of Topical and Systemic Beta Glucan Administration on Wound Healing Impaired by Corticosteroids. Wounds. December 2008. 20:341-346. Dr. Kirsner is Vice Chairman & Stiefel Laboratories Professor, Department of Dermatology & Cutaneous Surgery at the University of Miami Miller School of Medicine.
Skin & Aging’s sister journal Wounds is the nation’s leading wound care research journal, and it’s the major source of current research, treatment methodology, and current protocol in the field of wound care. In addition, this journal is the standard reference tool of those healthcare professionals who are leaders in establishing wound care programs and treatment centers both nationally and internationally. This month, we bring you the top 10 selections from the whole body of research published in Wounds in 2008. Dermatologist and wound care expert, Dr. Robert Kirsner, who is Section Editor for Wounds and an Editorial Advisory Board Member for Skin & Aging, selected the following research findings as the most relevant to dermatology. Read on for Dr. Kirsner’s commentary on the relevance of this research as well as synopses of these wound care findings.
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Oxygen is a Drug Dr. Kirsner’s Comments: A conceptual hurdle to understanding the role of oxygen is appreciating how hyperbaric oxygen helps to heal wounds when the wounds are without the treatment for 22 out of every 24 hours, even on the days patients receive the treatment. If these wounds are in need of oxygen, one would think that they would need oxygen all the time, not just a couple of hours daily. This, at first blush, is anti-intuitive until one begins to think of oxygen not as a nutrient but rather as a drug. The drug oxygen can be dosed similarly to more typical drugs like antibiotics. The drug oxygen is needed for a variety of critical functions ranging from antimicrobial activities such as nicotinamide adenine dinucleotide phosphate (NADPH) in leukocytes and bactericidal effect of superoxides as well as cross linking of collagen. Like any drug, delivery to tissue is critical, and while the majority of oxygen is carried on hemoglobin, more critical is partial pressure of oxygen in the blood, which leads to oxygen diffusion to wounded tissue. Thus, the high partial pressure of oxygen caused by hyperbaric treatment appears to be among the most effective ways to deliver the drug oxygen to tissue. Studying oxygen is often most easily accomplished in animal models. Myers and Gould highlight the most important and applicable animal models to study the effect of oxygen, hypoxia, and hyperbaric treatment. Using a variety of relevant models helps one gain a better understanding of how oxygen helps heal wounds, the effect of diminished oxygen, and the role of oxygen therapy to treat a variety of wounds. Synopsis of the Research: Effective and dependable influx and efflux of blood, fluid, and nutrient supply is essential for wound healing. The delicate balance between adequate oxygenation and hypoxia is an important aspect of this process. Due to the wide variety of wounds that occur in humans, along with multiple comorbidities, it is difficult to define, understand, and optimize treatments for chronic wounds. Although valuable for examining mechanisms at a molecular level, in vitro cell culture models cannot replicate the complex environment of a wound. A stable, reliable, and reproducible animal wound model that mimics the chronic wound state has yet to be found. Myers and Gould reviewed the current understanding of the effect of ischemia on wound healing and examined the features of currently available animal models that simulate ischemic wounds. Although it is not a chronic wound model, the authors believe that the ischemic bipedicle flap model has the potential to be a valuable tool for understanding the contribution of ischemia to impaired wound healing. This flap does not develop necrosis, yet, it remains ischemic for up to 2 weeks with markedly impaired wound healing. Although it is very flexible, by suturing to both the skin flap and to the dorsal muscle fascia, the silicone sheet also acts as a splint and can prevent wound contraction to some extent. This model was standardized so trained personnel with minimal surgical experience could perform the model with good reproducibility and flap survival. Rats tolerate the flap well and can be treated with systemic or topical agents. The wounds can be measured and excised, providing sufficient tissue for multiple biochemical analyses. The researchers noted that the Sprague-Dawley ischemic flap showed that hyperbaric oxygen (HBO) improves the rate of wound closure in ischemic wounds but has no effect on the wound closure rate in nonischemic wounds. According to the researchers, biochemical and histologic analyses demonstrated that apoptosis is attenuated by HBO treatment of ischemic wounds and that this effect is blocked by systemic administration of the free radical scavenger, N-acetylcysteine. Reduced inducible nitric oxide synthase, reduced 3-nitrotyrosine, and induction of copper/zinc superoxide dismutase, catalase, and glutathione peroxidase in the hyperbaric-treated ischemic wounds indicate modulation of the balance between reactive oxygen species and endogenous antioxidants. SOURCE: Wesley T. Myers, MD, and Lisa J. Gould, MD, PhD. Animal Models of Tissue Ischemia to Evaluate the Importance of Oxygen in the Wound Healing Environment. Wounds. January 2008;20:9-17.
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Ulceration is a Complication of Neuropathy, Not Diabetes Dr. Kirsner’s Comments: We are in the midst of an epidemic in diabetes. Within the United States and abroad, the prevalence of diabetes, by conservative estimates, is expected to increase 50% to 100% in the next 2 decades. As a consequence, complications of diabetes will increase as well. Of the 20 million Americans with diabetes, 15% will get a foot ulcer. The presence of a foot ulcer represents the most common risk factor for osteomyelitis, amputation, and increased mortality. Foot ulcers occur most commonly from neuropathy, and validated scales for both signs and symptoms for neuropathy exist. Testing for the signs and symptoms of neuropathy are simple, and no patient with diabetes should go untested for neuropathy. Bacarin and colleagues teach us a number of important lessons in their study of diabetics with and without foot ulcers. First is that signs of neuropathy were more commonly seen in those with diabetic foot ulcers compared with symptoms of neuropathy. Thus, examination of signs (physical examination) may be a better test for risk than merely asking about symptoms. Signs of neuropathy were more severe in those patients with ulcers than those without ulcers, suggesting the severity of neuropathy to be the critical component for those developing ulcers. Additionally, the duration of diabetes was not related to severity of neuropathy, suggesting that all patients with diabetes undergo neurologic assessment as opposed to only those with longstanding disease. Synopsis of the Research: Previous research has shown that patients with a plantar ulcer due to diabetes tend to have had diabetes for a longer duration and are older than those patients who have diabetes but no ulcers. It’s known that diabetic peripheral neuropathy (DPN), a common condition in patients with diabetes, causes loss of protective sensation, a major risk factor for ulceration in diabetic feet. Researchers from Brazil conducted a study to determine if patients with a history of plantar ulcers due to DPN have more symptoms, a longer duration of disease, and poorer foot sensitivity — parameters that previously had not been studied together in patients with ulcers who had diabetes. This study conducted by Bacarin et al compared the duration of disease, the prevalence of neuropathy symptoms, and plantar insensitivity among three groups — patients with diabetic neuropathy with a history of plantar ulcers (UDG), patients with diabetic neuropathy without a history of plantar ulcers (DG), and a nondiabetic group of patients (the control group [CG]). (See Table 1.) Investigators used the Michigan Neuropathy Screening Instrument (MNSI) to study the neuropathy symptoms. The evaluation of plantar sensitivity was composed of three sensory tests — sensitive chronaxie, and thermal and tactile sensitivities. Plantar sensitivity was investigated in five areas of the plantar surface of both feet, including the heel, mid-foot, lateral forefoot, medial forefoot, and hallux. Results showed the neuropathic groups did not differ in duration of diabetes, and, according to MNSI scores, presented a similar number of symptoms. Abnormal sensitivity was highest in the UDG. A delay in sensing the electrical stimulus was higher in the UDG. The number of areas with sensitive chronaxie values higher than 0.30 ms did not show any difference among groups (P = 0.593). However, the UDG had more areas with values higher than the threshold (2 areas for CG, 3 areas for DG; 5 areas for UDG). In terms of tactile sensitivity, the median number of areas with deficit of tactile sensitivity were no areas for CF, 2 areas for DG, and 6 areas for UDG — with five patients (55.5%) from UDG unable to feel the 10-g monofilament pressure in more than 5 areas of the feet. The medians for the number of areas with inability to discriminate hot and cold temperatures were: 0 areas for CG, 2 areas for DG, and 3 areas for UDG. The MNSI total score achieved a weak and insignificant correlation with sensitive chronaxie (r = -0.17; P > 0.05) and with thermal sensitivity (r = -0.11;P > 0.05) for all areas. The results of this study led the researchers to conclude that patients with diabetic neuropathic ulceration had decreased sensitivity in their feet, confirmed by the high number of insensitive plantar areas as well as by the high values of sensitive chronaxie. The authors wrote, “These findings were not related to the duration of diabetes onset, nor to the symptoms reported by the patients. However, the symptoms may be an indicator of decreased foot sensitivity, but the symptoms alone are not able to differentiate between groups with variation in progression of diabetic neuropathy.” Source: Tatiana de A. Bacarin, MSc, Dip PT; Paula M. H. Akashi, MSc, Dip PT; Prof. Isabel de C. N. Sacco, PhD. Duration of Disease, Neuropathic Symptoms, and Plantar Sensitivity in Patients With Diabetes With and Without Previous Plantar Ulceration. Wounds. February 2008;20:37-45.
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Charcot Foot Deformity: When Amputation May be Avoided Dr. Kirsner’s Comments: Neuropathy and vascular disease take many clinical forms. Neuropathy, for example, has effects not solely on the sensory nerves, leading to insensate feet; but also to the motor nerves, leading to atrophy of major muscle groups, as well as autonomic neuropathy, leading to the dry, scaling, and calloused skin seen in patients with diabetes. In an analogous fashion, both small and large vessel disease may occur in diabetics, leading to a variety of clinical presentations. One manifestation of diabetes — and less often of other conditions — is Charcot foot. While several theories have been proposed for why only a small subset of patients with diabetes develops this, the crux of the problem appears to be a bony collapse of the foot, leading to foot deformity. Once developed, repetitive trauma can worsen disease and lead to progression, so early recognition and prompt intervention may prevent complications. Thomas and Huffman teach us that the Charcot foot progresses through 3 stages, with the earliest stage of edema and inflammation often mimicking an active infection. Indium-labeled leukocyte scans may be the best technique to differentiate Charcot from infection and off loading is critical in hopes of preventing progression to stages 2 and 3. However, late presentation and development of ulcer formation may require more aggressive treatment, including a variety of surgical options leading to correction of the foot deformity and ulcer healing. Synopsis of the Research: Because patients with diabetes are living longer, studies have shown that there has been an increase in the number of Charcot arthropathy, a non-infective progressive process characterized by painless joint destruction, fracture, and eventual dislocation. Charcot arthropathy can have a significant impact on patients in terms of limb salvage and overall health. Its treatment has long been a topic of debate, with amputation being the most common surgical treatment for many years. However, with a better understanding of the disease and the development of new fixation and surgical techniques, it’s possible to avoid amputation. Thomas and Huffman note, “Proper preoperative evaluation, often by a multidisciplinary team of specialists, is critical as well as the assurance of the necessary vascular perfusion to achieve healing.” Surgical options include exostectomy and reconstruction, with or without various plastic surgical procedures, and amputation, which should only be considered for the nonsalvegable extremity. Using three case studies to demonstrate successful surgical treatment of Charcot foot, the authors found that surgical reconstruction is a viable option in selected patients, even when other specialists had recommended amputation. They found plastic surgical techniques and new fixation methods, such as external ring fixation (see Figure 1), seem to provide better outcomes and more flexibility. The keys to achieving and maintaining postoperative results include surgical planning, preoperative work-up with a multidisciplinary team, and proper orthotic management after surgery to avoid recurrence of ulcers. Source: James L. Thomas, DPM, FACFAS, and Lanie Huffman, DPM. Charcot Foot Deformity: Surgical Treatment Options. Wounds. March 2008; 20:67-73.
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Measuring Blood Flow Dr. Kirsner’s Comments: The performance of a vascular assessment is part of most algorithms of care of lower extremity wounds. This assessment is routine, as it is generally accepted that adequate blood flow is required for healing. While physical examination findings of good pulses and capillary perfusion are often used, there is a subset of patients with vascular disease who have normal physical examinations. A variety of methods have been developed and used to measure blood flow in the lower extremity. Most common perhaps is the ankle-brachial index, or ABI, which is a ratio of the systolic blood pressure in the leg compared with the arm. Normally, lower ABIs have correlated with worse vascular disease. Importantly, an ABI of less than 0.9 is an independent risk factor for cardiovascular disease. Limitations to the ABI exist, as the ABI is a measure of large vessel disease, and hardening of the vessels through glycosalation in patients with diabetes and calcification in the elderly can give false negative results. Tissue oxygen measures, by way of measuring transcutaneous oxygen (TcPO2), have also been used. Somewhat tedious to perform and requiring rigorous standardization of body temperature, measuring oxygen at the site of the wound is a more direct approach than measuring large vessel disease. TcPO2 is limited by things such as limb edema. More recently skin perfusion pressure (SPP) using laser Doppler directly measures skin perfusion at the site of the wound by slowing releasing pressure from blood pressure cuffs and measuring perfusion to the site. The fact that it is simple and fast to use makes SPP attractive. But the question remains about how well it works. Tsuji and colleagues teach us that SPP is, in fact, very good. In their study of consecutive lower limb wounds, the SPP was able to dichotomize healing from nonhealing wounds (60 mmHg vs. 31 mmHg), was shown to increase in patients who underwent revascularization and healed, and predicted the need for amputation in a patient who underwent revascularization but whose SPP did not change and whose wound did not heal. As this technology becomes more prevalent, it is likely SPP will become standard of care in wounds centers throughout the United States. Synopsis of the Research: In previous studies, SPP has been shown to be a reliable predictor of wound healing. The authors of this study wanted to determine if SPP measurements can be used to accurately predict wound healing in critical limb ischemia (CLI) and to select peripheral arterial reconstructive procedures. The authors measured SPP at the proximal margin of foot ulcers (not in the wound bed) in patients referred to the Wound Treatment Center at Shin-Suma General Hospital (Kobe, Japan) for the treatment of intractable foot ulcers, and compared it with the outcomes of treatment (healed or failed to heal). Foot ulcers that did not heal within 12 weeks after debridement or minor amputation or that required peripheral arterial reconstruction or more proximal amputation were evaluated as “failed to heal.” Those that demonstrated complete wound closure without additional surgery were evaluated as “healed.” Skin perfusion pressure was compared before and after peripheral arterial reconstruction. The effect of SPP elevation on wound healing was also evaluated. The study found the average SPP of patients with healed wounds was 60 mmHg, while the average SPP for patient with unhealed wounds was 31 mmHg. The data, analyzed to determine the optimal cutoff level for SPP, showed that SPP levels below the threshold gave a positive result and were predictive of healing failure, while SPP levels above the threshold gave a negative result and were predictive of healing success. The sensitivity, specificity, and the positive and negative predictive values of SPP measurement were calculated, and then the data was analyzed by the receiver operation characteristic (ROC) curve. According to the ROC curve, the optimal SPP lies at 35 mmHg. In contrast, at a threshold of 60 mmHg, the negative predictive value dropped to 62.8%, suggesting that peripheral arterial reconstruction may not always be necessary to facilitate an efficient wound healing process, or that a proximal amputation level is necessary. Based on these findings, the authors propose “that when the SPP value is not ≥ 35 mmHg, any surgical debridement should be secondary to the restoration of adequate skin blood flow to minimize invasive debridement. When the SPP is ≥ 35 mmHg, surgical debridement of necrotic tissue is feasible without any peripheral arterial reconstruction.” The study showed that SPP measurement is useful in accurately planning minimally invasive amputation and for predicting successful wound healing in CLI. Source: Yoriko Tsuji, MD; Terashi Hiroto, MD, PhD; Ikuro Kitano, MD, PhD; Shinya Tahara, MD, PhD; Daisuke Sugiyama, MD, MPH. Importance of Skin Perfusion Pressure in Treatment of Critical Limb Ischemia. Wounds. April 2008; 20:95-100.
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Improving the Quality of Healing Dr. Kirsner’s Comments: While, at times, just getting a chronic wound to heal is a major accomplishment, for many, excessive healing leads to excessive fibrosis, scarring, and even keloid formation. Additionally, fibrosis is a major medical problem, with protean manifestations ranging from keloids and scleroderma in the skin to arthritis affecting joints, cirrhosis affecting the liver, and other life-threatening fibrosis affecting the lungs and heart, as a result of pulmonary hypertension and myocardial infarction, respectively. Clearly, novel ways to reduce scarring are needed, and any general or gastrointestinal surgeon would also welcome ways to reduce adhesions and their accompanying complications. Recently, angiotensin II (ANG II) has become an attractive target to study in an effort to reduce fibrosis. This is partly because ANG II has been shown to stimulate collagen deposition and fibroblast proliferation, and inhibition of ANG II ameliorates this effect. Additionally, ANG II is produced locally in the skin, and pharmaceutical companies have already created drugs targeting the angiotensin-renin pathway to treat hypertension. Stemming from this rationale, Ardekani and colleagues studied the New Zealand White Rabbit to study the benefit of topical captopril to prevent scar formation. Creating two equal sized wounds on each ear, these investigators were able to demonstrate significant improvement in the scar index with a greater than 30% clinical benefit after 7 days. From a mechanistic standpoint, captopril reduced collagen organization typical of scar formation, but it did not have an effect on inflammation at a histologic level. This study opens the idea of addressing fibrosis through the use of ANG II inhibitors and for follow-up studies in humans, researchers might consider evaluating keloid formation among systemic captopril and non-captopril uses as well as performing trials comparing topical and systemic captopril with the aim of improved quality of healing. Synopsis of the Research: The extracellular matrix in tissues such as bone, cartilage, and skin, is primarily made up of collagen, which is known to play a major role in wound healing processes. Overproduction and/or decreased degradation of collagen fibers can lead to abnormal wound healing, which could result in hypertrophic scarring or keloid formation. According to the study authors, “Hypertrophic scar (HS) and keloid are two disfiguring and debilitating forms of wound healing that can cause serious psychological and functional complications.” Most of the available treatments for these conditions are inadequate or associated with adverse events and high recurrence. Recently, ANG II has been shown to be present in several cutaneous cells and to stimulate fibroblast proliferation and collagen synthesis, and to suppress matrix metalloproteinase activity. Ardekani et al conducted a study to examine the effect of topical captopril, an ANG II production inhibitor, against hypertrophic scar formation in six 3-month-old female New Zealand white rabbits. Under sterile conditions, two circular, 7-mm, full-thickness, dermal ulcers were created on the ventral surface of the ears of each rabbit, and the perichondrium was also removed. In each animal, one ulcer was made at the middle part of the left ear and another made at the same level on the right ear. The wounds on the left ears were treated with topical 5% captopril, and the wounds on the right ears were treated with the vehicle (70% ethanol/30% propylene glycol) alone. Daily topical applications were started at the time of wounding and were continued for 7 consecutive days. Applications were always performed by the same technician, who was blinded to the treatment identifications. The wounds were uncovered and exposed to air at day 28. At that time, researchers evaluated the scar elevation index (SEI) and the collagen organization. The SEI was reduced from 3.06 in the vehicle-treated wounds to 1.94 in the captopril-treated wounds (P < 0.05). An increase in collagen organization was achieved by captopril, and an 8.5% decrease in collagen organization scale was derived by captopril compared to vehicle. This study shows captopril is efficacious in preventing hypertrophic scars in an animal model. The authors note that more studies are needed to assess the minimal effective concentration and the optimal frequency of captopril application, and to verify if captopril exerts any significant therapeutic efficacy against HS and keloid formation in humans. Source: Gholamreza Safaee Ardekani, MD; Saeed Ebrahimi, MD; Mitra Amini, MD, MPH; Fatemeh Sari Aslani, MD; Farhad Handjani, MD; Gholamhossein Ranjbar Omrani, MD; Leila Safaee Ardekani, BS; Seyed Hamidreza Hosseini Alhashemi, MD; Behrooz Kasraee, MD. Topical Captopril as a Novel Agent Against Hypertrophic Scar Formation in New Zealand White Rabbit Skin. Wounds. April 2008; 20:101-106.
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Good News For Women Dr. Kirsner’s Comments: Disparities in health care and health services are a hot topic. At-risk populations based on race/ethnicity, socioeconomic status and gender all affect patient outcomes. For example, in a disease common in dermatology, blacks, Hispanics, lower socioeconomic groups, and women all have reduced quality of care as measured by late-stage melanoma diagnoses and worse survival compared to whites, higher socioeconomic status groups, and men, respectively. These differences in outcomes appear more likely related to health services than to biology, but active study to determine if biologic heterogeneity contributes to differential outcomes is underway. Related to wound care, do differences exists based on some of these same parameters? It is known, for example, that Hispanics have a very high prevalence of diabetes and resultant diabetic complications such as diabetic foot ulcers. Dinh and Veves contribute to our knowledge base by studying the prevalence of diabetic foot ulcers and parameters of neuropathy in both men and women. In a study of 248 patients, foot ulcers developed more frequently in men (40% vs. 19%), and men had greater neuropathy disability scores, higher plantar pressures, and reduced mobility. The reason for these differences in neuropathy and ulceration is not entirely clear, but it’s been hypothesized that there are more (longer) at-risk nerves in taller men, or that perhaps estrogen may play a protective role for women. In sum, as seen in the change in the workforce in recent months, it’s good to be a woman. Synopsis of the Research: There are numerous risk factors known for the development of foot ulceration, including peripheral neuropathy, high plantar foot pressures, limited joint mobility, and peripheral vascular disease. Studies also have found that socio-demographic factors, such as race, education level, and gender, appear to influence the likelihood of foot ulceration. In a previous large, prospective trial that the authors’ unit coordinated, 29% of all patients with diabetes, including men and women, were shown to ulcerate over a 30-month period. To try to determine if gender poses a significant risk factor, the authors of this study analyzed these same data separately for men and women. A total of 248 patients with diabetes were enrolled in a 30-month, multicenter, prospective study. There were 124 men and 124 women. Patient demographics were similar between men and women in terms of age, duration of diabetes mellitus, and body mass index. Neuropathy disability score (NDS), vibration perception threshold (VPT), Semmes Weinstein monofilament (SWM), plantar peak foot pressures, subtalar joint (STJ), and first metatarsal joint (MTJP) mobility risk factors were measured in both groups. Men had higher NDS (13 ± 8 versus 8 ± 7, P < 0.0001), VPT (36 ± 17 V versus 23 ± 16, P < 0.0001), SWM (5.9 ± 1.4 versus 5.9 ± 1.3, P < 0.0001), and plantar peak foot pressures (6.4 ± 3.4 kg/cm2 versus 5.0 ± 2.3, P < 0.0001), while women had higher MTPJ mobility (69 ± 24 degrees versus 77 ± 23, P < 0.0001) and STJ mobility (22 ± 10 degrees versus 26 ± 8, P < 0.0001). Plantar foot ulceration developed in 49 (40%) men compared to 24 (19%) women (P < 0.0001) during the study. When men and women were analyzed separately, univariate logistical regression analysis yielded similar odds ratios in both groups for high NDS (≥ 5, M 6.1, W 8.3), high VPT (≥ 25 V, M 6.0, W 8.9), SWM (M 6.6, W 3.7), high foot pressures (≥ 6 kg/cm2, M 2.7, W 3.0), and MTPJ mobility (M 0.97, W 0.98). This study showed that women have a lower risk than men for foot ulceration, but the lower risk appears to be the result of less severe neuropathy, increased joint mobility, and lower foot pressures. Once neuropathy or other risk factors are present, women were found to have the same risk of developing foot ulcerations as men, according the results. Source: Thanh Dinh, DPM, and Aristidis Veves, MD, DSc. The Influence of Gender as a Risk Factor in Diabetic Foot Ulceration. Wounds. May 2008;20:127-131.
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Optimal Treatment for Burns Dr. Kirsner’s Comments: Burn wound injury is a catastrophic event, at times life threatening or life altering. While advances in critical care have led to increased survival, there have been fewer advances in care of the actual burn wounds. One significant advance has been the appreciation that early debridement leads to faster healing of burn wounds due to the reversal of the healing lag typical of non-debrided burn wounds. Since major burns limit the reservoir of available autologous skin to graft, another major advance has been the use of skin substitutes. In addition to speeding the healing of the wounds, skin substitutes serve as mechanisms to prevent excessive fluid and electrolyte loss and as barriers to infection. The perfect skin substitute for burns would possess a number of important characteristics. It would be readily available and made of non-antigenic tissue that would serve as a permanent replacement applied in a single procedure. The result would be a rapidly healed wound that would result in little or no scarring. Unfortunately, the perfect skin substitute has not yet been developed for burn wounds. Paul reviews the currently available skin substitutes used for burn wounds and highlights the various characteristics, advantages, and limitations. This serves as an excellent resource until the perfect substitute is developed. Synopsis of Research: To gain a better understanding of the history on the use of graft material aside from skin for both partial- and full-thickness burns, Paul performed Medline and Google searches using the key words: skin graft, skin substitute, allograft, homograft, xenograft, heterograft, autograft, burn grafting, and burn coverage. Articles retrieved were visually scanned for applicability, and those thought to apply were reviewed. Appropriate references within the articles were also reviewed. Based on this review, the author concluded that although there have been numerous advances in the science of biological tissue engineering in the past few decades, an ideal skin replacement has not been found yet. There is no available product that fulfills all the criteria of an ideal skin replacement. The patient’s skin remains the best alternative to replace burned tissues, though the addition of dermal replacement alternatives has improved the long-term success of split-thickness skin grafts. The author noted, “Further progress will undoubtedly be made in the years to come. Unfortunately, ideal skin replacement remains an ephemeral goal that must be diligently pursued. Hopefully this replacement will be found sooner rather than later.” Source: Chester N. Paul, MD, FACS. Skin Substitutes in Burn Care. Wounds. July 2008; 20:203-205.
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Do Not Fear Fungi Dr. Kirsner’s Comments: Much scientific investigation has focused on why chronic wounds are refractory. Among the reasons why well-vascularized wounds in otherwise healthy nourished patients fail to heal include the presence of excessive or resistant bacteria, an inflammatory or proteolytic wound environment with reduced or unavailable growth factors, and senescent or unresponsive cells. These factors appear to be more common in nonhealing chronic wounds compared to those chronic wounds that are healing and represent potential therapeutic targets for clinicians. However, do other targets for intervention exist, whereby nonhealing wounds can be converted to healing wounds? Veraldi and co-workers sought to study the role of fungi in chronic non-healing wounds. Studying 149 patients with long-standing chronic wounds greater than 2 months duration and performing fungal culture twice in each patient, they were able to set our minds at ease regarding a major role of fungi in nonhealing wounds. Only 11 patients had any fungi detected in their wounds — all candida species, with C. albicans found in 7 patients, C. parapsilosis in 2 patients, and C. krusei and C. lipolytica (1 patient each). No other fungi (dermatophytes or molds) were isolated. Seven of the patients were treated with combination oral antifungal without clinical improvement of the ulcers. Synopsis of the Research: To date, the role of fungi in superinfection of chronic leg ulcers has been poorly studied. What has been published is typically based on either a small number of patients or single cases, and the study conclusions are conflicting. Veraldi et al conducted a study to evaluate the percentage of mycotic superinfections and their clinical importance in chronic leg ulcers. For this study, mycologic examinations were performed on 149 patients without diabetes who had chronic leg ulcers for at least 2 months. (See Table 2.) Two specimens were obtained from each ulcer. Mycologic examinations were positive in 11 patients (7.4%). Five of the 11 patients had venous ulcers, 2 had atherosclerotic ulcers, and 1 each had a post-traumatic, pressure, vasculitic, and neuropathic ulcer. The following fungal species were isolated: Candida albicans (7 patients), C. parapsilosis (2 patients), C. krusei (1 patient), C. parapsilosis and C. lipolytica (1 patient each). No other fungi (dermatophytes or molds) were isolated. Seven patients were treated with oral fluconazole (100 mg/day for 2 weeks) and 4 with oral itraconazole (200 mg/day for 2 weeks). No clinical improvement of the ulcers was observed with this therapy. This data shows that mycotic superinfections of chronic ulcers of the legs are rare; mycotic superinfections were exclusively caused by yeasts; clinical appearance of skin ulcers superinfected by fungi is not characterized by particular features; and oral antimycotic treatment did not provide clinical improvement for the ulcers with mycotic superinfection. Based on the results of this study, the authors concluded that mycologic examinations may be considered unnecessary in patients without diabetes who suffer with chronic leg ulcers. Source: Stefano Veraldi, MD; Anna Maria Tortorano, MD; Luisa Lunardon, MD; Maria Chiara Persico, MD; Claudia Francia, MD. Mycologic Evaluations in Chronic Leg Ulcers. Wounds. September 2008; 20:250-253.
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High Bacterial Counts Are Common But Are They Meaningful? Dr. Kirsner’s Comments: In non-healing wounds, bacteria have long been thought of as a potential target for intervention. For example, pressure ulcer guidelines recommend topical anti-microbial therapy for nonhealing wounds. In spite of this, most chronic wounds that heal do so with 3 or more bacteria present, and in acute partial-thickness wounds, faster healing with occlusive dressings is accompanied by increased bacterial numbers. So should we fear bacterial numbers? Ratliff and others from Virginia attempted to answer that question when they studied 30 clean wounds for the bacteria number and type. What they found was extremely interesting. First, they reported a majority (19 of 30, more than 60%) of these clean wounds had bacterial levels that were ≥ 105 ccfu/cm2 — the vast majority being aerobic bacteria. They also found that the number of bacteria did not correlate with wound reduction and worsening wounds in some cases had low numbers of bacteria. Several lessons can be drawn from this study. The first is that clinical signs and symptoms of infection should be the determinant of whether bacteria are causing delayed healing as opposed to sheer number. Additionally, we are learning that it is possible that a complex relationship between bacteria numbers, the virulence of the bacteria present as well as local and systemic host resistance may be more important than numbers alone. Finally, some data suggest the lifestyle in which bacteria exist in wounds, such as those living in a biofilm, may be more important in determining wound chronicity than the number of planktonic or free-floating bacteria present. Synopsis of the Research: Among wound care professionals, it is accepted that open, chronic wounds are colonized with bacteria, and most physicians have believed that it can be assumed that if a wound shows no signs of infection, the bacteria are not interfering with the healing process. However, new information is causing physicians to believe that high levels of bacteria may inhibit healing, even when there are no traditional signs of infection. The level of bacteria that inhibits wound healing but does not display the standard clinical signs of infection has been termed “critical colonization,” a situation that requires additional criteria to diagnose covert infection. Two previous studies assessed the validity of these additional criteria, including serous exudate, foul odor, discolored or friable granulation tissue, and delayed healing or wound deterioration using quantitative biopsies and a quantitative swab technique, respectively. Results of these studies caused the wound care plan to be altered to focus on reducing the level of bacteria in these wounds, which resulted in healing. Reseachers from the Department of Plastic Surgery Research, University of Virginia Health System, Charlottesville, VA, however, noted, “The use of quantitative bacteriology to direct a wound care program is limited by the technical difficulties and expertise required to process the samples.” They write that a simple diagnostic test to document if a clean, nonhealing wound contained ➢ 105 bacteria/g of tissue would be beneficial to wound care professionals. To develop such a test, it must be determined if anaerobic organisms play a significant role in the number of bacteria present in clean, nonhealing wounds, so these authors conducted a pilot study to quantitate the number of aerobic and obligate anaerobic organisms in a small number of clean, nonhealing wounds. Quantitative swabs were obtained from 30 clean, chronic wounds on 30 different patients. The number of organisms and the predominant organism were determined. All samples were processed under both aerobic and anaerobic conditions. Nineteen (63%) of the 30 clean wounds had bacterial levels that were ≥ 105 cfu/cm2. There was no correlation between ≥ 105 cfu/cm2 and delayed wound healing. The most frequently isolated predominant organism was Staphylococcus aureus. In these clean, chronic wounds, an obligate anaerobic organism was identified as predominant or co-predominant in only 2 (6.7%) of 30 wounds. The results indicated that the presence of obligate anaerobic organisms as the predominant organism in clean wounds is not frequent, which are in agreement with the results of those of much larger studies. Source: Catherine R. Ratliff, PhD, APRN-BC, CWOCN; Sandra I. Getchell-White, MT (ASCP), SM; George T. Rodeheaver, PhD. Quantitation of Bacteria in Clean, Nonhealing, Chronic Wounds. Wounds. October 2008. 20:279-283.
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Food for Thought Dr. Kirsner’s Comments: Impairment of healing occurs from a variety of sources ranging from age to comorbidities. One well-known cause of healing impairment is from the use of corticosteroids, a ubiquitous treatment for a variety of inflammatory conditions. Corticosteroids negatively affect all phases of wound healing, reducing inflammatory cell infiltration, granulation tissue formation and epithelial migration and collagen strength. For decades, attempts have been made to better understand reasons why steroids impair healing and to find potential treatments to reverse the healing impairment caused by steroids. Simplistically, steroids result in reduced growth factors and cytokines in the healing wound, which stagnate the healing cascade initiated by these key messengers. Among the treatments best studied and most utilized to reverse the healing impairment of steroids is the use of systemic and topical vitamin A and its derivative, retinoids. Cerci et al studied another compound to reverse the healing effects of corticosteroids — topical and systemic use of beta glucan. Four groups (control, steroid treated, and steroid treated plus either topical or systemic beta glucan) of 20 adult Wistar-albino rats each were studied after incisional and excisional wounding. As expected, steroids impaired healing, and as hypothesized, both topical and systemic beta glucan normalized healing and wound strength. Systemic beta glucan appeared superior to topical application. Easily tolerated, beta glucan may be beneficial for steroid-treated wounds. Whether systemic administration would also obviate the therapeutic effects is not known, but it does occur with systemic vitamin A administration. Additionally, whether the benefits of beta glucan extend beyond steroid-impaired wounds to a variety of other wounds that have difficulty healing — ranging from physiologic changes such as aging to diabetic or vascular wounds — would be interesting to better understand. Synopsis of the Research: Corticosteroid hormones are widely used to treat a variety of diseases, but corticosteriods have been shown to impair wound healing, which has become a serious clinical problem. Researchers from the Suleyman Demirel University in Isparta, Turkey, designed a study to evaluate the efficacy of topical and systemic beta glucan administration on wound healing impaired by corticosteroids. Beta glucan is a complex carbohydrate that is found in the cell walls of yeast, fungi, and cereal plants, and is known as a potent macrophage stimulator. Macrophage cells play an important role in wound healing. Wistar albino rats were used for the incision and excision wound models. Percentage of wound contraction, epithelialization period, hydroxyproline level, histopathological examination, and tensile strength were evaluated. Although both systemic and local administration of beta glucan enhanced percentage wound contraction, improved epithelialization time, improved tensile strength, and elevated hydroxyproline level, systemic administration was found to be more effective. (See Figure 3.) Researchers concluded that these results indicate that systemic and topical beta glucan improve wound healing that has been impaired by corticosteroids, and that systemic administration is more effective than topical application. Source: Celal Cerci, MD; Mehmet Yildirim, MD; Murat Ceyhan, MD; Serkan Bozkurt, MD; Duygu Doguc, MD; Alpaslan Gokicimen, MD. The Effects of Topical and Systemic Beta Glucan Administration on Wound Healing Impaired by Corticosteroids. Wounds. December 2008. 20:341-346. Dr. Kirsner is Vice Chairman & Stiefel Laboratories Professor, Department of Dermatology & Cutaneous Surgery at the University of Miami Miller School of Medicine.
