Clinical trials of a biosynthetic temporary skin replacement, Dermagraft-Transitional Covering, compared with cryopreserved human cadaver skin for temporary coverage of excised burn wounds.

Human cadaver allograft skin (HCAS) is widely used for covering excised burn wounds when limited available skin donor sites or the overall patient condition does not permit immediate grafting with autologous skin. However, recurring problems are associated with HCAS including limited supply, variable quality, ultimate immune rejection, and the potential for bacterial and viral disease transmission. These problems speak for the need for development of a dependable substitute for HCAS. We evaluated the ability of a biosynthetic analogue of human skin to temporarily close excised burn wounds in humans. Dermagraft-TC (Advanced Tissue Sciences, Inc.) (DG-TC) is composed of human neonatal fibroblasts cultured on a synthetic dressing (Biobrane; Dow Hickam, Inc.) that consists of nylon mesh fabric covered with a thin layer of silicone rubber membrane, which provides an epidermal "barrier." The material is stored frozen and thawed immediately before use. DG-TC is semitransparent, thus facilitating continuous observation of the underlying wound surface. Burn wounds in 10 patients (mean age 33.5 years, mean burn size 39.9% total body surface area) were surgically excised. Two variants of the DG-TC skin analogs were tested: a material that was cryopreserved to maintain fibroblast viability (DG-TC Red) and a material that was frozen without efforts to maintain fibroblast viability (DG-TC Blue). A control site on each patient received cryopreserved HCAS. Each study site was approximately 1% total body surface area. When clinically indicated, patients were returned to the operating room where the skin replacements were removed, the wound bed was evaluated and prepared for grafting, and the wounds were closed with meshed split-thickness autograft skin. The results showed that adherence to the wound and subsequent autograft "take" were excellent with both DG-TC variants and were at least equivalent to HCAS. No evidence of immune rejection of DG-TC was seen, whereas in four patients evidence of epidermal sloughing/rejection was noted in the HCAS control sites, which limited persistence of those grafts on the wound. Further clinical trials with this skin analogue are in progress.

A multicenter clinical trial of a biosynthetic skin replacement, Dermagraft-TC, compared with cryopreserved human cadaver skin for temporary coverage of excised burn wounds.

This multicenter study compared the use of a biosynthetic human skin substitute with frozen human cadaver allograft for the temporary closure of excised burn wounds. Dermagraft-TC (Advanced Tissue Sciences, Inc.) (DG-TC) consists of a synthetic material onto which human neonatal fibroblasts are cultured. Burn wounds in 66 patients with a mean age of 36 years and a mean burn size of 44% total body surface area (28% total body surface area full-thickness) were surgically excised. Two comparable sites, each approximately 1% total body surface area in size, were randomized to receive either DG-TC or allograft. Both sites were then treated in the same manner. When clinically indicated (> 5 days after application) both skin replacements were removed, and the wound beds were evaluated and prepared for grafting. DG-TC was equivalent or superior to allograft with regard to autograft take at postautograft day 14. DG-TC was also easier to remove, had no epidermal slough, and resulted in less bleeding than did allograft while maintaining an adequate wound bed. Overall satisfaction was better with DG-TC.

A metabolically active human dermal replacement for the treatment of diabetic foot ulcers.

Tissue engineering, the science of growing living human tissues for transplantation, promises to revolutionize aspects of medical care. Ulcers of the skin of the feet of diabetic patients are a serious health problem and a major cause of amputations. Dermagraft, a tissue-engineered, living human dermal tissue, which provides normal growth factors and matrix proteins, has been implanted to replace a patients' destroyed dermises and heal these ulcers. Large-scale clinical studies and in vitro experiments have demonstrated the importance of controlling specific product parameters, especially the metabolic activity of the tissue, to provide, upon implantation into the wound bed, a living tissue that facilitates healing. Implanting tissue within a defined therapeutic range of metabolic activity dramatically improves healing of diabetic foot ulcers, with significantly more ulcers healed completely in a shorter time. In this new, rapidly moving science, such elucidation of the mechanism of action is vital to ensure that tissues will provide their intended benefit.

Use of dermagraft, a cultured human dermis, to treat diabetic foot ulcers.

OBJECTIVE: To assess the effect of a tissue-engineered human dermis (Dermagraft) in healing diabetic foot ulcers. RESEARCH DESIGN AND METHODS: This controlled prospective multicenter randomized single-blinded pilot study evaluated healing over a 12-week period in 50 patients with diabetic foot ulcers. These patients were randomized into four groups (three different dosage regimens of Dermagraft and one control group). All patients received identical care except for the use of Dermagraft tissue. Ulcer healing was assessed by percentage of wounds achieving complete or 50% closure, time to complete or 50% closure, and volume and area measurements. RESULTS: Ulcers treated with the highest dosage of Dermagraft, one piece applied weekly for 8 weeks (group A), healed significantly more often than those treated with conventional wound closure methods; 50% (6 of 12) of the Dermagraft-treated and 8% (1 of 13) of the control ulcers healed completely (P = 0.03). The percentage of wounds achieving 50% closure was also significantly higher (75 vs. 23%; P = 0.018), and the time to complete or 50% closure was faster (P = 0.056). The group A regimen was more effective than other treatment regimens. All three were better than the control, however, and a dose-response was observed. There were no safety concerns. After a mean of 14 months of follow-up (range 11-22 months), there were no recurrences in the Dermagraft-healed ulcers. CONCLUSIONS: Dermagraft was associated with more complete and rapid healing in diabetic foot ulcers. The recurrence data may indicate an improved quality of wound healing.

Electrical stimulation to heal dermal wounds.

BACKGROUND: Numerous human and animal efficacy studies have demonstrated that electrical stimulation of the correct charge, density and total energy causes dramatically improved healing of dermal wounds. The investigations of biological actions (in vitro, animal, and human) demonstrate several effects that go a long way to explaining why electrical stimulation works. OBJECTIVE: To discuss recent research and advances in electrical stimulation of wound healing. RESULTS: Based on the latest scientific understanding of the wound healing process, one would expect a beneficial outcome from a therapy what decreases edema, debrides necrotic tissue, attracts neutrophils and macrophages, stimulates receptor sites for growth factors, stimulates growth of fibroblasts and granulation tissue, increases blood flow, stimulates neurite growth, induces epidermal cell migration, prevents post-ischemic oxygen radical-mediated damage, inhibits bacteria, and reduces numbers of mast cells. CONCLUSION: Taken together, the efficacy studies and the "mechanism of action" studies provide compelling, scientific evidence that electrical stimulation is safe and effective for promoting the healing of dermal wounds.

Electrical stimulation for dermal wound healing.

The investigations of biologic actions (in vitro, animal, and human) demonstrated several effects that help explain why electrical stimulation works. Based on the latest scientific understanding of the wound healing process, one would expect that a therapy that decreases edema, debrides necrotic tissue, attracts neutrophils and macrophages, stimulates receptor sites for growth factors, stimulates growth of fibroblasts and granulation tissue, increases blood flow, stimulates neurite growth, induces epidermal cell migration, prevents postischemic oxygen radical-mediated damage, inhibits bacteria, and reduces numbers of mast cells ought to be beneficial for wound healing. Numerous human and animal efficacy studies confirm that electrical stimulation of the proper charge, density, and total energy causes dramatically improved healing of dermal wounds. As of this writing, no devices have yet been approved by the FDA for use in wound healing, although several devices approved for other indications are being used for this purpose. One device (the Staodyn Dermapulse) has undergone controlled animal and human testing, and an application requesting approval for treating dermal ulcers has been submitted to FDA. Taken together, the efficacy studies and the "mechanism of action" studies provide compelling, scientific evidence that electrical stimulation is safe and effective for promoting the healing of dermal wounds.

Chronic dermal ulcer healing enhanced with monophasic pulsed electrical stimulation.

The purposes of this randomized, double-blind, multicenter study were to compare healing of chronic dermal ulcers treated with pulsed electrical stimulation with healing of similar wounds treated with sham electrical stimulation and to evaluate patient tolerance to the therapeutic protocol. Forty-seven patients, aged 29 to 91 years, with 50 stage II, III, and IV ulcers were randomly assigned to either a treatment group (n = 26) or a control (sham treatment) group (n = 24). Treated wounds received 30 minutes of pulsed cathodal electrical stimulation twice daily at a pulse frequency of 128 pulses per second (pps) and a peak amplitude of 29.2 mA if the wound contained necrotic tissue or any drainage that was not serosanguinous. A saline-moistened nontreatment electrode was applied 30.5 cm (12 in) cephalad from the wound. This protocol was continued for 3 days after the wound was debrided or exhibited serosanguinous drainage. Thereafter, the polarity of the treatment electrode on the wound was changed every 3 days until the wound progressed to a stage II classification. The pulse frequency was then reduced to 64 pps, and the treatment electrode polarity was changed daily until the wound was healed. Patients in the control group were treated with the same protocol, except they received sham electrical stimulation. After 4 weeks, wounds in the treatment and control groups were 44% and 67% of their initial size, respectively. The healing rates per week for the treatment and control groups were 14% and 8.25%, respectively. The results of this study indicate that pulsed electrical stimulation has a beneficial effect on healing stage II, III, and IV chronic dermal ulcers.

Classification by type of ventricular arrhythmia predicts frequency of adverse cardiac events from flecainide.

Antiarrhythmic therapy is known to be associated with a significant risk of adverse cardiac reactions, including a proarrhythmic response. This study assessed in 1,330 patients followed up for 292 +/- 393 days the predictive value for cardiovascular safety of a system by which patients were classified according to ventricular arrhythmias on entry, presence or absence of organic heart disease and drug dose for flecainide acetate. Baseline arrhythmia subgroups included patients with premature ventricular complexes only, nonsustained ventricular tachycardia, and sustained ventricular tachycardia. Proarrhythmic events occurred in 6.8% of patients overall and were serious in 2.3% and lethal in 1.0%. However, proarrhythmia was highly dependent on arrhythmia class on entry: serious nonlethal proarrhythmic events occurred in 6.6% of patients with sustained ventricular tachycardia, only 0.9% with nonsustained ventricular tachycardia and 0% with premature ventricular complexes (p less than 0.01). Proarrhythmic death occurred in 3.1% of patients with sustained ventricular tachycardia, 0.2% with nonsustained ventricular tachycardia and 0% with premature ventricular complexes only (p less than 0.01). Proarrhythmia was also influenced by the presence of structural heart disease: serious nonlethal proarrhythmia occurred in 2.6% of patients with versus 0.4% of those without organic heart disease, and death occurred in 1.2 versus 0%, respectively. These adverse events were also dependent on dosing regimen. Flecainide caused premature discontinuation due to new or worsened heart failure in 1.4% of patients, all with underlying organic heart disease; however, heart failure was not clearly related to dose or type of arrhythmia. Symptomatic conduction disturbances occurred in 2.2%, and were predicted by preexistent sinus node disease but not by other baseline features.(ABSTRACT TRUNCATED AT 250 WORDS)

Extracardiac adverse effects of flecainide.

The results of a well-controlled multicenter shortterm safety and efficacy study, supported by results from several long-term studies, indicate that therapeutic doses of flecainide are well tolerated by most patients. The most frequently reported extracardiac adverse experiences were dizziness (30%) and visual disturbances (28%), often occurring in tandem. Headache, nausea, dyspnea and chest pain occurred at incidences of 6 to 9%; other adverse experiences occurred at incidences of greater than or equal to 5%. Because of study design, it is likely that these figures are overestimates; they include all reports, whether or not they were caused by flecainide. Extracardiac adverse experiences were given as reasons contributing to discontinuation of therapy in 10% of patients in the short-term and 6% of patients in the long-term studies. In most cases the inability to tolerate flecainide became evident early in therapy. No new adverse experiences indicative of any chronic toxic effect of flecainide were reported during the long-term studies. Side effects tended to be intermittent and to decrease over time.

Bretylium tosylate as initial treatment for cardiopulmonary arrest: randomized comparison with placebo.

To evaluate the therapeutic effectiveness of intravenous bretylium tosylate as a first-line drug for patients in cardiopulmonary arrest, a randomized, double-blind study was conducted, comparing bretylium with a normal saline placebo. Fifty-nine patients presenting to the emergency department with cardiopulmonary arrest due mainly to ventricular fibrillation or asystole initially received either bretylium (10 mg/kg) or placebo in a rapid intravenous bolus and were then otherwise treated according to standard American Heart Association guidelines. If ventricular fibrillation or asystole persisted, a second bolus of bretylium or normal saline was given after 20 minutes. Thirty-five percent of patients presenting with ventricular fibrillation or asystole who received bretylium were successfully resuscitated, whereas 6% of patients who received placebo survived (P less than 0.05). These findings serve to suggest that the early use of bretylium tosylate in cardiopulmonary arrest improves survival.