Diabetic wounds are a significant healthcare problem with its  healing depends on many factors such as glycemic control, vascularity , bacterial load,  location of the wound, nutritional status of the patient (Calhoun et al., 2002; Younes et al., 2006). Many agents have been tried in wound healing, one such agent is phenytoin. Phenytoin (diphenylhydantoin) was introduced into therapy in 1937 for effective control of convulsive disorders (Meritt and Putnam, 1938; Silverman et al., 1988)  with a common side effect being gingival hyperplasia (Bethedsa, 2001). This stimulatory effect of phenytoin on connective tissue suggested possibility for its use in wound healing. The beneficial effect of phenytoin has been shown in promoting healing of decubitus ulcers (el Zayat, 1989; Rhodes et al., 2001), venous stasis ulcers (Simpson et al., 1965), traumatic wounds (Modaghegh et al., 1989; Pendse et al., 1993), burns (Lodha, 1991), leprosy trophic ulcers (Bansal and Mukul, 1993). The present study was conducted to assess the efficacy of topical phenytoin dressing as compared to conventional moist wound dressing in the healing process of diabetic ulcers and to check whether it is a better alternative in the management of diabetic ulcers.

 

This quasi-experimental study included 200 patients with diabetic ulcers admitted in our hospital from 2008 to May 2011 satisfying all the inclusion criteria mentioned below. The clearance from the ethical committee was obtained. All diabetic ulcers where conventional dressings are indicated were included in the study. 

 

The inclusion criteria were:

(1) Patients with chronic ulcers (ulcers of 8 weeks duration) with diabetes mellitus.

(2) Wound size <5% TBSA.
 

The exclusion criteria were：

(1) Chronic non-healing wounds of other etiology.

(2) Diabetes mellitus with gangrenous changes.

(3) Wounds with osteomyelitis.

(4) Wounds with poor vascularity determined by arterial Doppler study.

(5) Other co-morbid conditions like renal failure, generalized debility and other factors, which adversely affect wound healing.
 

The data was collected from 200 patients who were having diabetic ulcers satisfying all the inclusion criteria mentioned above. Selection of patients was done from consecutive series of prospective patients. The patients were allocated into the study and the control group based on their consent. The study group included the patients undergoing wound care with topical phenytoin therapy. Those who were not willing were subjected to conventional wound care and were included under the control group. We have included 100 patients in each group according to sample size calculation.  All patients underwent detailed clinical examination and relevant investigations including fasting and post-prandial blood sugar levels. The wounds were thoroughly debrided (surgically under anesthesia) and the ulcer dimensions as well as the surface area were assessed using vernier calipers, immediately after debridement and reassessed after 14 days in either type of dressings. Both the groups underwent wound dressings twice a day. A good glycemic control was obtained using regular insulin (Hg A1C levels were not assessed). Wound cultures were obtained using sterile culture swab on the day of initiation of treatment and on 14^th day of treatment. The patients were followed up on a daily basis for 14 days in both the study and the control groups.

 

A single 100 mg phenytoin sodium capsule was opened and placed in 5 ml of sterile normal saline to form a suspension. Sterile gauze was soaked in the suspension and placed over the wound at 20 mg/cm² TBSA. Conventional Dressing was done with 5% w/v povidone – iodine solution. Before applying the dressing, the wound was cleaned with normal saline. At the end of 14 days the wounds in both the groups were inspected and the wounds were compared based on the following parameters. They were:

(1) Rate of granulation tissue formation as percentage of the ulcer surface Area; 

(2) Quality of ulcer bed; 

(3) Present dimensions and surface area of the ulcer.

Once these parameters were assessed, both the groups were subjected to split thickness skin grafting. Both the groups were given the same systemic antibiotics (ceftriaxone 1 g intra-venous for 5~7 days with metronidazole 100 ml t.id. for 3 days) during the postoperative period. The wounds were reassessed at the end of the fifth postoperative day and wounds were compared based on the following parameters. They were:

(1) Skin graft take-up as a percentage of ulcer surface area,

(2) Number of days of hospitalization. 

 

The follow-up of these patients was done in the out patient department after one month of discharge to assess post skin grafting complications like contractures, itching, pain and infection, wound dimensions.

The results obtained were statistically evaluated based on the following parameters. They were:

(1) Rate of granulation tissue formation, 

(2) Graft survival and take up, 

(3) Duration of hospital stay. 
 

The mean rate of granulation tissue formation, graft survival and hospital stay was calculated and compared for both groups. The variables were compared using the Unpaired Student’s t-test. A “P” value <0.05 was considered significant.

 

The mean age in the study group was 50.11 (%)± 14.0 (SD) years and in the control group was 51.41 (%)± 13.4 (SD) years. In the study group, 65 patients were males and 35 were females. In the control group, males were 67 and females were 33 in number. Both the groups had comparable age and sex distribution. There was no statistical difference between the two groups in terms of gender. All the patients belonged to the middle and low socio economic groups.

                                                      

The efficacy of the dressing was assessed as the percentage of ulcer surface area covered by healthy granulation tissue after 14 days. The mean rate of granulation tissue formation in the study group was 87.94% ± 7.33 (SD) of total ulcer surface area and in the control group was 74.64% ± 8.04 (SD) of total ulcer surface area. The results were analyzed by Unpaired Student’s t-test which showed highly significant difference in rate of granulation tissue formation (p<0.0001) (Table 1).
 

Table 1 Rate of granulation tissue formation as percentage of ulcer surface area

The patients in both the groups were subjected to split thickness skin grafting as the final treatment modality. The graft take up was then assessed at the end of 5^th post operative day as the percentage of ulcer surface area is given below. The mean graft take up in the study group was 92.31% ± 3.94 (SD) and in the control group was 86.15% ± 6.93 (SD).  Analysis of the data by Unpaired Student’s t-test revealed highly significant difference in graft take up (p<0.0001) (Table 2).
 

Table 2 Graft take up as percentage of ulcer surface area

The total hospital stay (the total number of days of admission in the hospital) was assessed. The mean hospital stay in the study group was 36.26 ± 2.64 (SD) days and that in the control group was 40.97 ± 3.31 (SD) days. Analysis of the data showed highly significant difference in the hospital stay in both groups with a negligibly low p value(p< 0.0001) obtained in the Unpaired Student’s t-test (Table 3).

Table 3 Duration of hospital stay

The patients in both the groups were assessed for culture sensitivity at 14 days to determine the effect of topical agents on the bacterial load. 70% of the study group showed negative culture sensitivity at the end of 14 days, whereas in the control group it was 54%. In both the groups, no complications occurred during the application of dressings, skin grafting or in the post operative period. The patients were followed up after 1 month of discharge. The main post operative parameters noted in both the groups during follow up were: wound size, contractures, pain, infections. All these parameters were lower in the study group as compared to the control group.
 

Anstead G.M., Hart L.M., Sunahara J.F., and Liter M.E., 1996, Phenytoin in wound healing, Ann Pharmacol., 30:768-775

 

Bansal N.K., and Mukul, 1993, Comparison of topical phenytoin with normal saline in the treatment of chronic trophic ulcers in leprosy, Int. J. Dermatol., 34: 210-213

 

Bethedsa M.D., 2001, ASHP drug information 2001, American Society of Health System Pharmacists, 2081

 

Calhoun J.H., Overgaard K.A., Stevens C.M., Dowling J.P., and Mader J.T., 2002, Diabetic foot ulcers and infections: Current concepts, Adv. Skin Wound Care, 15: 31-42 (quiz 44-45)

 

Dill R.E., Miller E.K., Weil T., Lesley S., Farmer G.R., and La copino A.M., 1993, Phenytoin increases gene expression for platelet – derived growth factor in β chain in macrophages and monocytes, J peridontol., 64: 169-173

 

el Zayat S.G., 1989, Preliminary experience with topical phenytoin in wound healing in a war zone, Mil Med., 154: 178-180

PMid:2499825

 

Genever P.G., Cunliffe W.J., and Wood E.J., 1996, Influence of the extracellular matrix on fibroblast responsiveness to phenytoin using in vitro wound healing models, Br. J. of Dermatol., 133:231-235

 

Kimball O.P., and Horan T.N., 1939, The use of dilantin in the treatment of epilepsy, Ann. Intern. Med., 13: 787-793

 

Lodha S.C., 1991, New application of an old drug: topical phenytoin for burns, J. Burns care Rehabil., 12: 96

 

Lodha S.C., Lohiya M.L., Vyas M.C.R., Bhandari S., Goyal R.R., and Harsh M.K., 1991, Role of phenytoin in healing of large abscess cavities, Br. J. Surg., 78: 105-108

PMid:1998849

 

Meritt H.H., and Putnam T.J., 1938, Sodium diphenyl hydantoinate in the treatment of convulsive disorders, JAMA,111:1068-1073

 

Modaghegh S., Salchian B., Tavassoli M., Djamshidi A., and Rezai A.S., 1989, Use of phenytoin in healing of war and non war wounds, a pilot study of 25 cases, Int. J. Dermatol, 28: 347-350

PMid:2666326

 

Muthukumaraswamy M.G., Sivakumar G., and Manoharan G., 1991, Topical Phenytoin in diabetic foot ulcers, Diabetes Care, 14: 909-911

 

Pendse A.K., Sharma A., Sodani A., and Hada S., 1993, Topical phenytoin in wound healing, Int. J. Dermatol., 32: 214-217

PMid:8444538

 

Pai M.R., Sitaram N., and Kotian M.S., 2001, Topical pheytoin in diabetic ulcers: A double blind controlled trial, Indian J. Med Sci., 55: 593-599

PMid:12508631

 

Rhodes R.S., Heyneman C.A., Culbersten V.L., Wilson S.E., and Phatak H.M., 2001, Topical phenytoin treatment of stage II decubitus ulcers in the elderly, Ann Pharmaco therapy, 35: 675-681

 

Shapiro M., 1958, Acceleration of gingival wound healing in non-epileptic patients receiving diphenylhydantoin sodium, Exp. Med. Surg., 16: 41-53

PMid:13537920

 

Simpson G.M., Kunz E., and Slafta J., 1965, Use of diphenylhydantoin in treatment of leg ulcers, N Y State J Med., 65:886-888

PMid:14265330

 

Silverman A.K., Fairley J., and Wongs R.C., 1988, Cutaneous and Immunologic reactions to phenytoin, J. Am. Acad. Dermatol., 18: 721-741

 

Talas G., Brown R.A., and McGrouther A., 1999, Role of phenytoin in wound healing-a wound pharmacology perspective, Biochem Pharmacol, 57: 1085-1094

PMid:11265677

 

Younes N., Albsoul A., Badran D., and Obedi S., 2006, Wound bed preparation with 10 percent phenytoin ointment increases the take of split-thickness skin graft in large diabetic ulcers, Dermatol Online 1, 12: 5