Dermatology Online Journal

Wound bed preparation with 10 percent phenytoin ointment increases the take of split-thickness skin graft in large diabetic ulcers
Nidal Younes¹, Abla Albsoul², Darwish Badran³, Salwan Obedi¹
Dermatology Online Journal 12 (6): 5

1. Department of Surgery and Faculty of Medicine, University of Jordan. niyounes@ju.ed
2. Department of Clinical Pharmacyand Faculty of pharmacy, University of Science and Technology
3. Department of Anatomy Faculty of Medicine, University of Jordan, Amman, Jordan

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Abstract

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.

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Introduction

Patients with diabetes are at increased risk for foot ulcers [1]. The prevalence of foot ulcers among patients with diabetes is 12 percent [2]. These ulcers are associated with high financial cost, long term morbidity, and sometimes even mortality. Diabetic foot ulcers are associated with slow wound healing and an increased susceptibility to infection. Primary closure of the ulcer is often difficult. Wound closure by split thickness skin graft (STSG) is often the simplest and most versatile method of wound management. Development of granulation tissue in the wound is important requirement for successful skin grafting. Granulation tissue has a high level of vascularity resulting from abundance of new capillary formation. This degree of vascularity enables granulation tissue to accept skin grafts [3].

Phenytoin has been used topically for many years to enhance the healing of chronic wounds [4]. Its wound healing promoting effect has been attributed to many mechanisms, including increasing fibroblast proliferation, inhibiting collagenase activity, promoting collagen disposition, enhancing granulation tissue formation, decreasing bacterial contamination, reducing wound exudate formation, and up-regulating growth-factor receptors [4, 5, 6, 7, 8, 9, 10].

Chronic diabetic foot ulcers remain difficult to manage. Topical application of phenytoin has been used successfully in the management of diabetic foot ulcers [11, 12]. It stimulates the development of granulation tissue formation within 2 to 7 days after beginning treatment and is associated with non-detectable serum phenytoin levels [13, 14]. Almost all of the reports on phenytoin and wound healing used the powder form. Because of its dry nature, wound treatment with phenytoin powder is limited to wet wounds. Moisture is important for granulation tissue formation 15].

The purpose of this study was to evaluate the effect of phenytoin ointment on the rate of split thickness skin autograft survival in patients with large diabetic foot ulcers.

Patients and Methods

Figure 1
Prominent granulation tissue formation 4 weeks after phenytoin application

Sixteen patients with large ulcers underwent wound bed preparation with phenytoin ointment followed by split-thickness skin graft (STSG) application. There were twelve males and four females. The average age was 57.8 years (range 30-65 years). Six patients had dorsal foot ulceration, five patients had post mid-tarsal amputation ulcers, two patients had plantar foot ulceration, two patients had forefoot ulceration, and one patient had left heel ulceration. The grafts were taken from the ipsilateral thigh and the donor site was covered by nitrofurazone soluble dressing ointment (Bactazon™).

The patients' characteristics are shown in Table 1. Exclusion criteria included small ulcers (<20cm²), severe sepsis, or a history of contact allergy to phenytoin. Two patients who were excluded from the study on the basis ulcer size (<20 cm²) served as controls for histological evaluation.

Phenytoin powder BP was obtained from (Well Worth medicines, India). It was compounded with white petrolatum BP (Vaseline, Al-Eman for cosmetic products, Jordan) at a ratio of 10 percent (w/w).

The ulcers were debrided initially to remove necrotic tissue, cleansed with saline and dried with sterile gauze. A thin layer of phenytoin ointment was applied after which the ulcer was covered with a dry, sterile, non-occlusive gauze-pad dressing. Standard wound-bed preparation measures were maintained during treatment with phenytoin ointment. Patients continued to receive phenytoin treatment for 2-8 weeks (see Table 1). The following parameters were monitored in each patient: presence of bleeding at the time of dressing, quality of granulation tissue, the presence or absence of discharge, local skin reaction, and the size of the ulcer. Once the volume of granulation tissue was considered adequate (Fig. 1), a biopsy was taken and processed for histopathological study. The wound was then covered by STSG taken from the front of the thigh (Fig. 2). The graft was fixed to the underlying surface using skin staples. A sterile nitrofurazone dressing (Arab Center for Pharmaceuticals and Chemicals, Jordan) was applied on the immediate surface of the graft and then wrapped with several layers of gauze bandage. The foot was kept immobilized by a backslap of plaster of Paris for 1-2 weeks. Inspection of the graft for the first time was done on the third or fourth postoperative day. The graft take was declared as successful when the grafted skin attached completely and epithelization was apparent by inspection at the edges (Fig. 3).

Figure 2	Figure 3
Figure 2. Application of split thickness skin graft to the recipient site and fixation with skin staples
Figure 3. The mid-tarsal wound 14 days after grafting showing fixed donor skin with hyperemia reflecting complete take

Results and Discussion

Preparing the ulcer bed with 10 percent phenytoin was associated with a high rate of STSG acceptance. The take was 100 percent in twelve of the sixteen patients. Three patients had 90 percent take, and one patient (heel ulcer) had 60 percent take. Of the four patients with incomplete take, one patient had an active infection at the edge of the ulcer at the time of grafting (the patient with the heel ulcer), and the other three had an early mobilization. Rapid closure of associated smaller ulcers was noticed after grafting of the major ulcer in three patients treated with phenytoin and STSG.

No patients had bleeding at the time of dressing. Two patients suffered from a burning sensation at the start of phenytoin treatment; this decreased with continued use of the phenytoin ointment. These two patients had ulcers on the dorsum of the foot extending to the anterior aspect of the ankle joint. None of the patients reported the dressing changes to be painful except on the donor sites, which continued to be painful for several weeks. Phenytoin skin allergies were not elicited in any of the study patients.

Figure 4A	Figure 4B
Histopathology: Ulcer beds prepared by phenytoin showed edematous and highly vascular granulation tissue (Fig. 4A) compared to the control beds (Fig. 4B).

Biopsies taken from ulcer beds prepared by phenytoin showed more edematous and much highly vascular granulation tissue formation (Fig. 4A) compared to the control beds (Fig. 4B).

Soft tissue coverage of chronic diabetic ulcers has been viewed as troublesome because of the lack of adequate blood supply available from the bed of the ulcer attributed to inadequate granulation tissue formation. The introduction of growth factors in the management of chronic wounds resulted in increased reports documenting good results, especially with chronic small ulcers (< 40cm²) treated with platelet-derived growth factors [16, 17].

In our study, an ointment form of phenytoin (prepared in our lab using petrolatum (Vaseline) at a ratio of 10 percent w/w) was applied once daily to the wound area; this preparation maintained the hydration of the wound and increased granulation tissue formation. It enhanced the take of STSG and closure of large diabetic foot ulcers (>20 cm² ). Comparing our results to those of other groups using various growth factors was not possible because of different methodologies, and different ways of measuring outcomes.

Phenytoin wound bed preparation is not without potential risks. Because of the presence of soft tissue infection in most of these ulcers, it is not uncommon for some patients to develop foot sepsis proximal to the site of ulceration. To minimize this problem, adequate surgical debridement and broad spectrum antibiotics are recommended before initiation of any wound therapy.

Diabetic patients with associated peripheral arterial disease have poorer healing of foot ulcers and they are at a higher risk for amputation. The use of phenytoin ointment to enhance the development of granulation tissue and then coverage with STSG offers a good alternative to prolonged hospital stay and repeated debridement or amputation of the limb.

Conclusion

Preparing Large diabetic ulcers with phenytoin ointment enhances the survival of STSG. Almost complete take (90 percent and above) was noticed in 90 percent of the cases after a period of preparation of 2-8 weeks. However, this is a preliminary study and further controlled studies are needed. This study demonstrates the efficacy of phenytoin used in an ointment form in wound bed preparation for skin grafting with no local or systemic side effects. Phenytoin ointment is a cheap, available, and safe; it may be beneficial in the management of large diabetic ulcers and it appears to increases the survival of STSG in difficult cases and large ulcers.

Acknowledgments: This work was supported in part by the Faculty of Medicine, and Hamdi Mango Center for Scientific Research at The Jordan University, their support is gratefully acknowledged.

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