Necrotizing soft tissue infections developing from pressure ulcers

Aim of the studyNecrotizing soft tissue infections (STIs) are serious complications that may arise from pressure ulcers. However, there are few studies on this important issue. In addition, diagnostic criteria for necrotizing STIs developing from pressure ulcers and infected pressure ulcers are not well established.MethodsWe defined necrotizing STIs developing from pressure ulcers based on clinical findings. Based on the definition, we retrospectively analyzed the medical records of 24 elderly patients with this condition to determine patient age, gender, comorbid disease, laboratory findings, wound location, bacteriology, and treatment outcomes.ResultsIn the examined population, necrotizing STIs developed primarily from pressure ulcers over the sacrum. Dementia and diabetes mellitus were also frequently observed in patients with necrotizing STIs. The average Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score was relatively low. Bacterial cultures from the debrided deep tissues exhibited mixed infections of gram-positive cocci and gram-negative bacilli, except 1 case. Anaerobic pathogens were isolated from 18 patients (72%), and 7 patients (29%) developed bacteremia. None of the cases were preceded by wounds dominated by granulation tissue. Surgical intervention, combined with antibacterial therapy involving intravenous carbapenem or cephem, was successfully used in most cases.ConclusionNecrotizing STIs arising from pressure ulcers are generally caused by mixed pathogens and exhibit symptoms that are milder than those of necrotizing fasciitis caused by group A Streptococcus.     

Autologous suction blister grafting for chronic leg ulcers

Background Non‐healing leg ulcers represent a treatment problem. Objective Investigate grafting of autologous suction blister roofs as treatment. Methods Twenty‐nine chronic, non‐healing leg ulcers of various aetiologies in 18 inpatients were treated by autologous epidermal grafting using the roofs of suction blisters. Results 55% of ulcers completely healed 2 to 6 weeks after grafting. A 50–90% reduction in size was documented in 34% and no change was observed in 11% of ulcers. Twelve weeks after grafting, 89% of ulcers were healed completely. In most ulcers, we observed a stimulation of reepithelialization from the wound edge (‘edge effect’) and an accelerated formation of healthy granulation tissue. During a follow‐up period of 12 months, 90% of the ulcers remained healed. Conclusion Grafting of autologous suction blister roofs is an effective treatment option for non‐healing leg ulcers. The advantages of the method are its lack of pain, low costs and immediate availability.     

Double-blind placebo-controlled study with topical 2% ketanserin ointment in the treatment of venous ulcers

Previous animal and human data have shown that ketanserin, the first specific serotonin2 antagonist, may have beneficial effects on peripheral vascular diseases and on the healing of ulcers. In this double-blind study a 2% ketanserin ointment in a polyethylene glycol base was used to treat 23 patients with venous ulcers (13 ketanserin, 10 placebo). Classical wound care measures were maintained in both groups; therefore, conventional ulcer therapy (with placebo in a polyethylene glycol base) was in reality compared with conventional ulcer treatment plus ketanserin. The most important parameter for evaluation in this study was the development of granulation tissue (first sign of successful wound healing). The evolution of granulation was significantly better with ketanserin than with placebo (p less than 0.05, Mann-Whitney U test). According to the investigator's evaluation, ketanserin showed a response in 10 out of 11 patients as opposed to 5 out of 10 placebo patients at the end of the study. This first double-blind placebo-controlled study suggests that topically applied ketanserin promotes the healing of venous ulcers.     

Short-contact topical tretinoin therapy to stimulate granulation tissue in chronic wounds

BACKGROUND: The use of retinoids in wound healing is increasing. It has been shown that retinoic acid reverses the inhibitory effects of glucocorticoids on wound healing and accelerates the formation of healthy granulation tissue. Pretreatment with tretinoin before epidermal injury such as chemical peeling and dermabrasion has shown accelerated wound healing. Enhanced healing of full-thickness skin wounds has also been demonstrated in early wound healing studies. However, tretinoin therapy can be quite irritating. OBJECTIVE: Our purpose was to observe the clinical and histologic effects of topical tretinoin solution 0.05% applied directly to the wound beds of chronic leg ulcerations. METHODS: We report on the cases of 5 patients with long-standing leg ulcerations. All were treated with topical tretinoin solution 0.05% applied directly to the wound bed. The tretinoin solution was left in contact with the ulcer bed for a maximum of 10 minutes daily and then rinsed with normal saline. Punch biopsy specimens were obtained from the wound beds at baseline and mid therapy. Standard wound care was continued throughout the study. RESULTS: In this study we found that as early as 1 week after treatment with topical tretinoin solution 0.05%, there was increased granulation tissue first noted at the wound's edge. After 4 weeks of therapy with tretinoin, there was further stimulation of granulation tissue, new vascular tissue, and new collagen formation. CONCLUSION: Short-contact tretinoin therapy is a novel modality in which to treat chronic ulcers and stimulate the formation of granulation tissue.     

Allogeneic cultured epidermal grafts heal chronic ulcers although they do not remain as proved by DNA analysis

To investigate whether allogeneic cultured keratinocytes are rejected or not, and to find out how beneficial their effect on wound healing could be, patients with chronic ulcers were grafted with allogeneic cultured human keratinocytes. In order to examine the epidermal origin of the healed wound, DNA analysis was performed and compared to donor and recipient blood-cell DNA. Healing was observed in 84% of the grafted ulcers by granulation tissue stimulation and would edge effect. In little time 60% of the grafted chronic ulcers healed completely. Although no rejection was observed, DNA analysis revealed that the grafted allogeneic keratinocytes were finally replaced by the patient's own epidermis. This study confirmed that cultured allogeneic keratinocytes that have been grafted on ulcers, play an important role in the wound healing process.     

Negative-pressure dressings in the treatment of pressure ulcers

Applying negative pressure to wounds may speed the formation of granulation tissue, decrease the amount of localized edema, increase blood flow, and accelerate healing. In the present study, we treated ten patients with stage IV chronic pressure ulcers using this negative pressure dressing technique. The long (A) and short (B) diameters of each ulcer were measured to determine size, and the vertical distance from the skin to the deepest point of the ulcer was measured to determine depth. Lesions were measured initially and at weekly intervals. The area of each lesion was taken to be 3.14 x A/2 x B/2 (cm(2)). When we compared the area of ulcer before and after the treatment, the area had been reduced in all cases, and the average reduction was 55.1%. The depth of ulcer also decreased in all cases, and the average reduction was 61.2%. Over the period of evaluation, the method was considered markedly effective in reducing the size and depth of ulcers.     

Treatment of leg ulcers with cryopreserved allogeneic cultured epithelium. A multicenter study.

BACKGROUND--In the past few years, several authors have described the usefulness of cultured allogeneic epidermal sheets in promoting wound healing of burns, leg ulcers, and donor sites. This study reports clinical results obtained by different departments in the treatment of chronic leg ulcers by cryopreserved cultured allogeneic epithelium. The freezing procedure and the assessment of viability of the cryopreserved epithelium are also described. A total of 30 ulcers were treated using 138 cryopreserved allografts. OBSERVATIONS--Twenty ulcers (66.6%) healed completely within 12 weeks. Four ulcers showed a 30% to 84.4% reduction in size by 3 weeks but did not heal completely; the remaining six ulcers did not show any improvement. A strong stimulation of granulation tissue formation and of reepithelialization from the wound edge were observed. RESULTS--The results indicate that frozen cultured epidermis, stored in a skin bank, is a valid and generally applicable alternative therapy for the treatment of chronic ulcers.     

Epithelial tissue-type plasminogen activator expression, unlike that of urokinase, its receptor, and plasminogen activator inhibitor-1, is increased in chronic venous ulcers

BACKGROUND: The plasminogen activation system represents a potent mechanism of extracellular proteolysis and is an essential component of normal wound healing. It has also been implicated in the pathogenesis of chronic, nonhealing ulcers. Traditionally, urokinase-type plasminogen activator (uPA) has been associated with pericellular proteolytic activity involved in tissue remodelling processes, and tissue-type plasminogen activator (tPA) mainly with intravascular fibrinolysis. OBJECTIVES: The present study was conducted to characterize the spatial distribution of the various plasminogen activation system components in chronic ulcers and acute, well-granulating wounds. METHODS: The expression of uPA, tPA, urokinase receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1), and vitronectin was investigated by immunohistochemical staining, in addition to uPA, tPA and PAI-1 expression by in-situ hybridization, in samples from eight chronic venous ulcers, five decubitus ulcers, five well-granulating acute wounds and five normal skin samples. RESULTS: In chronic venous leg ulcers tPA mRNA was detected in basal and suprabasal keratinocytes at the leading wound edge, while in well-granulating wounds and in decubitus ulcers tPA mRNA was expressed only in a few keratinocytes. However, tPA was widely expressed in fibroblast- and macrophage-like cells in the stroma of well-granulating wounds, while less tPA was detected in the granulation tissue of chronic ulcers. tPA mRNA and protein were localized in the superficial granular layers in normal skin. Although no qualitative differences in expression of uPA, PAI-1 or uPAR in the wound edge keratinocytes in chronic ulcers vs. normally granulating wounds were found, their expressions were more pronounced in the granulation tissue of well-granulating wounds. CONCLUSIONS: These results suggest that in poorly healing venous leg ulcers, the pattern of tPA expression is altered in keratinocytes at the leading edge of the wound, and the patterns of tPA, uPA and PAI-1 expression are altered in the granulation tissue.     

Topical therapy of ulcers

Therapy of ulcers includes both treating the ulcer itself and the underlying disease. Local or surgical wound therapy depends on the phase of the wound healing. Physiological wound healing can be divided into three phases: the cleansing phase, the granulation phase and the epithelialization phase. The choice of the optimal therapy also depends on degree of secretion, bacterial contamination and anatomical location, as well as size and depth of the wound. While dry wound therapy was performed years ago, moist wound therapy is well-established today. There are a large number of modern wound dressings for local, phase-dependent or phase-independent ulcer therapy, making the optimal treatment of each kind of chronic wound possible.     

Human recombinant transforming growth factor-beta 1 modulation of biochemical and cellular events in healing of ulcer wounds.

The effects of recombinant human transforming growth factor beta 1 (rhTGF-beta 1) on wound healing were examined in a rabbit ear ulcer model in which rhTGF-beta 1 was applied to full-thickness biopsy ulcers on the ears. The influence of perichondrium on healing was studied by comparing ulcers with and without perichondrium on 1) formation of total healing wound area (HWA, the newly formed connective and granulation tissues within the ulcer) over time and 2) the amount of collagen synthesized by the wound tissue at day 5. The HWA of ulcers with intact perichondrium increased sharply with time and reached a plateau at day 7, whereas a slower healing occurred in the perichondrium-free model where maximal HWA appeared at day 14. Topical application of 100 ng of rhTGF-beta 1 per wound accelerated healing by increasing HWA in both models. The enhancement of healing by rhTGF-beta 1 was associated with increased collagen synthesis. The percent collagen synthesis in the rhTGF-beta 1 was doubled in the perichondrium-intact ulcers and increased 40% in the perichondrium-free ulcers. DNA synthesis in the perichondrium-intact ulcers was not altered by rhTGF-beta 1 when measured at day 5 by in vitro labeling with [3H]thymidine ([3H]TdR). Autoradiography indicated that the primary cells labeled in the wound tissue were epithelial cells and rhTGF-beta 1 enhanced the migration of these cells from the wound margin towards the center. To evaluate the effects of rhTGF-beta 1 on fibroblasts derived from the granulation tissue of the wound, cells were treated with increasing concentrations of rhTGF-beta 1 and DNA and collagen synthesis were determined. rhTGF-beta 1 elicited a biphasic change in percent collagen synthesis with a maximal increase of 50% at 20 pM followed by a decline. A twofold increase in [3H]TdR incorporation that plateaued at 1 nM was also observed. Our results indicate that the cellular responses to rhTGF-beta 1 differ in vivo and in vitro. The perichondrium-intact ulcers contain more wound tissue and have larger responses to rhTGF-beta 1 stimulation, which allows better examination of biochemical and cellular events. The in vivo mechanisms are multi-factorial, which may involve cell migration and recruitment as results of numerous cell/cell and cell/matrix interactions.     

Mechanisms and Clinical Applications of the Vacuum-Assisted Closure (VAC) Device

The use of sub-atmospheric pressure dressings, available commercially as the vacuum-assisted closure (VAC) device, has been shown to be an effective way to accelerate healing of various wounds. The optimal sub-atmospheric pressure for wound healing appears to be approximately 125 mm Hg utilizing an alternating pressure cycle of 5 minutes of suction followed by 2 minutes off suction. Animal studies have demonstrated that this technique optimizes blood flow, decreases local tissue edema, and removes excessive fluid from the wound bed. These physiologic changes facilitate the removal of bacteria from the wound. Additionally, the cyclical application of sub-atmospheric pressure alters the cytoskeleton of the cells in the wound bed, triggering a cascade of intracellular signals that increases the rate of cell division and subsequent formation of granulation tissue. The combination of these mechanisms makes the VAC device an extremely versatile tool in the armamentarium of wound healing. This is evident in the VAC device's wide range of clinical applications, including treatment of infected surgical wounds, traumatic wounds, pressure ulcers, wounds with exposed bone and hardware, diabetic foot ulcers, and venous stasis ulcers. VAC has also proven useful in reconstruction of wounds by allowing elective planning of the definitive reconstructive surgery without jeopardizing the wound or outcome. Furthermore, VAC has significantly increased the skin graft success rate when used as a bolster over the freshly skin-grafted wound. VAC is generally well tolerated and, with few contraindications or complications, is fast becoming a mainstay of current wound care.     

Location-dependent depth and undermining formation of pressure ulcers

Aim of the studyWe examined the location-specific properties of pressure ulcers, focusing on depth and undermining formation, which are often unfavorable factors for ulcer healing.MethodsWe conducted a retrospective observational study of 2 independent databases on pressure ulcers. Databases from a 200-bed hospital (database A) and a 300-bed hospital (database B) were collected during different time periods. Relationships between ulcer location, ulcer depth, and undermining formation were analyzed. All pressure ulcers were accurately diagnosed and classified according to their locations.ResultsA total of 282 pressure ulcers in 189 patients from database A and 232 pressure ulcers in 154 patients from database B were analyzed. It was found that pressure ulcers primarily developed over the sacrum. Ratio of stages III and IV pressure ulcers was high in pressure ulcers of the foot, ankle, and crus on the lower leg. Among the deep pressure ulcers, undermining formation was frequently observed on the greater trochanter, ilium, and sacrum. In contrast, pressure ulcers of the foot, ankle, and crus did not exhibit undermining formation.ConclusionOur results revealed marked differences in pressure ulcer properties depending on their location. Factors affecting depth and undermining of pressure ulcers appear to be related to anatomical and physical properties of the bone and subcutaneous tissue.     

Mixture of sugar and povidone-iodine stimulates healing of MRSA-infected skin ulcers on db/db mice

The topical application of a mixture of sugar and povidone-iodine (PI) has been reported to accelerate the healing of cutaneous wounds and ulcers by promoting reepithelialization and granulation tissue formation, as well as by having an anti-microbial effect. In order to clarify the efficacy of a 70% sugar and 3% PI paste (U-PASTA™)(SP) on infectious skin ulcers, we made a bacterial infection model using methicillin-resistant Staphylococcus aureus (MRSA) on the skin of diabetic db/db mice, and investigated the effect of the paste on the healing process of wounds. Full-thickness wounds were made on the backs of female diabetic mice, (C57BL/ksJ db/db) and inoculated with S. aureus. SP was applied to the closed wounds for 8 days. The degree of repair was evaluated using three histological parameters: The degree of reepithelialization was given a percentage value of 0–100%; the amount of granulation tissue was quantified by measuring the area of granulation (mm²); and the number of capillary lumens in the granulation tissue was counted in the complete wound cross-section at 100× magnification. In addition, the colony-forming units (CFU) of MRSA on the wounds were counted. Continuous MRSA infection in the wounds of db/db mice was demonstrated with macroscopic and histopathological images. Wounding and infection caused by MRSA on the back of the diabetic mice significantly induced delayed reepithelialization, granulation tissue formation with inflammatory cell infiltrate and increased CFU on wounds (P < 0.01, respectively) compared to those of the MRSA-infected normal mice. Application of SP significantly accelerated reepithelialization (P < 0.01) and decreased CFU (P < 0.05) of the ulcers in the MRSA-infected wounds, compared to the non-treated group. Histopathological evaluation and CFU on this animal model revealed no significant difference between Methicilin-sensitive Staphylococcus aureus and MRSA infection. These results indicate that wounding on db/db mice provides a useful animal model of bacterial skin infections, and that SP is an effective topical agent for the treatment of diabetic skin ulcers.     

Use of topical ketanserin in the treatment of skin ulcers: a double-blind study

The use of a 2% ointment formulation of ketanserin, an S2-serotoninergic blocking agent, was investigated in a randomized double-blind clinical trial for its effect on the healing of wounds of patients with decubitus, venous, and ischemic skin ulcers. The result demonstrates a significant difference in favor of the ketanserin-treated group (35 patients) versus the placebo-treated group (37 patients) on the basis of two factors: formation of granulation tissue and epithelialization. In addition, a significant difference of 150% in the initial velocity of wound closure was observed in favor of the patients treated with ketanserin. This effect was persistent during the entire study period.     

Wound bed preparation with 10-percent phenytoin ointment increases the take of split-thickness skin graft in large diabetic ulcers

Healing of large diabetic foot ulcers may be difficult, particularly if the blood supply and chronic infection do not allow primary suturing. Split-thickness skin graft is a simple reconstructive technique used to close large wounds. Phenytoin is known to promote healing mainly by increasing granulation tissue formation. The effectiveness of topical phenytoin in wound-bed preparation (WBP) for split thickness skin grafting has been examined in 16 patients with large diabetic foot ulcers. All patients were treated with standard wound bed preparation including debridement of necrotic tissue. Topical phenytoin (10 % w/w ointment) was applied for 2-8 weeks prior to performance of autografting. Clinical and histologic evaluations were performed. The graft survival was 100 percent In twelve patients, 80-90 percent in three patients take and 60 percent in one patient. Neither local nor systemic side effects were observed. The authors conclude that phenytoin ointment is a safe and efficacious treatment to enhance the survival of split-thickness skin grafts in large chronic diabetic ulcers.     

Frequency rhythmic electrical modulation system in the treatment of chronic painful leg ulcers

Electrical current has been recommended for use on chronic wounds; however, the ability of this modality to improve healing of various types of chronic ulcers, arterial, venous, mixed arterial and venous ulcers, diabetic, and pressure ulcers is not well established. The purpose of this study was to examine the effect of frequency rhytmic electrical modulation system (FREMS) on healing of chronic painful leg ulcers.Thirty-five patients with 43 chronic painful leg ulcers participated in the study. The subjects were separated into two random groups, one treated with FREMS and the control group. Our investigation focused on the control of the parameter changes important for ulcer healing: wound surface area, wound appearance (fibrin accumulations, exudation, granulation, and epithelization), ulcer surroundings and associated symptoms. All the parameters were monitored clinically at the beginning, after first, second, and third week, and at the end, after 1 and 2 months of administered therapy, when the scores were determined. Pain intensity was evaluated with visual analog scale (VAS). FREMS therapy was administrated through the device model Aptiva Ballet into sessions and several stages. Comparing the findings of decrease leg ulcer surface, pain, leg ulcer score, score of vicinity (statistically significant at the level P < 0.05) with the controls, it was established that FREMS system accelerated ulcer healing, reduced pain and demonstrated better effects compared to the control group. The results of the study indicate that FREMS therapy accelerates wound closure and depresses the pain of chronic leg ulcers.     

The tension biology of wound healing

Following skin wounding, the healing outcome can be: regeneration, repair with normal scar tissue, repair with hypertrophic scar tissue or the formation of keloids. The role of chemical factors in wound healing has been extensively explored, and while there is evidence suggesting the role of mechanical forces, its influence is much less well defined. Here, we provide a brief review on the recent progress of the role of mechanical force in skin wound healing by comparing laboratory mice, African spiny mice, fetal wound healing and adult scar keloid formation. A comparison across different species may provide insight into key regulators. Interestingly, some findings suggest tension can induce an immune response, and this provides a new link between mechanical and chemical forces. Clinically, manipulating skin tension has been demonstrated to be effective for scar prevention and treatment, but not for tissue regeneration. Utilising this knowledge, specialists may modulate regulatory factors and develop therapeutic strategies to reduce scar formation and promote regeneration.     

Suction blister transplantation for leg ulcers.

Application of suction blister transplants to leg ulcers is an alternative symptomatic treatment to split-skin grafting, i.e. "pinch-grafting". Blisters are produced by the suction device Dermovac at a suction pressure of 250-300 mmHg for 1-2 hours. The blister-roofs are cut off at the periphery and placed on the granulation tissue of the ulcer. The healing time for leg ulcers was 10-14 days. Excellent epithelialization was seen in 10 out of 12 ulcers. The advantages of the method are, that it is easy to perform, no scarring is produced, and the procedure is painless.     

Detection of undegraded fibrin and tumor necrosis factor-alpha in venous leg ulcers.

The pathogenesis of venous leg ulcers is based on the leakage of fibrinogen leading to pericapillary fibrin cuff and plugging of capillaries by white blood cells. Eight patients with venous leg ulcers have been studied with a panel of antibodies reactive for fibrinogen, fibrin, fibrin degradation products, and various cell-associated markers for polymorphonuclear cells, monocytes, and B and T lymphocytes. Our results showed that pericapillary fibrin cuff was mainly composed of undegraded fibrin and that, in the granulation tissue, tumor necrosis factor-alpha and elastase activities were detectable in monocytes and polymorphonuclear cells, respectively. Only few activated lymphocytes were present. On the basis of these results, it is assumed that inflammation generated by activated white blood cells that accumulate under unrelieved pressure is the key event. Tumor necrosis factor-alpha synthesized by activated monocytes may therefore induce the formation of pericapillary fibrin cuffs. Pericapillary fibrin cuffs and toxic metabolites released by polymorphonuclear cells may explain the absence of wound repair.     

Comparison of IL-10 levels in chronic venous insufficiency ulcers and autologous donor tissue

Abstract In previous immunohistochemical studies, chronic venous insufficiency (CVI) ulcers have been shown to display positive staining for interleukin-10 (IL-10), while other wounds (including autologous donor wound tissue) show a reduced staining level. IL-10 inhibits the synthesis of many proinflammatory cytokines, while also inhibiting antigen presentation by antigen-presenting cells. It is possible that abnormally high amounts of IL-10 in chronic wounds may be related to the failure of these wounds to progress to final wound healing. The purpose of this study was to quantify the levels of IL-10 in CVI ulcers and autologous donor tissue using Western blotting. Extracts were prepared from frozen wound tissue samples and equal amounts of protein were concentrated by immune-precipitation for Western blot analysis. Densitometric analysis was performed on nonsaturated chemilumigraphs and normalized to an IL-10 standard run on each gel. The quantity of IL-10 in CVI ulcers was found to be 490% of the quantity in autologous donor tissue. This study provides confirmatory quantitative data which supports previous immunohistochemical findings showing elevated levels of IL-10 in CVI ulcers. Received: 29 June 1998 / Received after revision: 20 July 1998 / Accepted: 21 August 1998