A Comparative Study of Efficacy of Topical Phenytoin vs Conventional Wound Care in Diabetic Ulcers  

Leo F.  Tauro , Prathvi Shetty , Nita T.  Dsouza , Saleem  Mohammed , Suresh   Sucharitha
Department of General Surgery, Fr. Muller Medical College Hospital, Kankanady, Mangalore - 575002 (D.K.), Karnataka, India
Author    Correspondence author
International Journal of Molecular Medical Science, 2013, Vol. 3, No. 8   doi: 10.5376/ijmms.2013.03.0008
Received: 08 May, 2013    Accepted: 02 Jun., 2013    Published: 29 Jul., 2013
© 2013 BioPublisher Publishing Platform
This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

A common side effect of phenytoin (diphenylhydantoin) treatment for epilepsy is gingival hyperplasia. This stimulatory effect of phenytoin on connective tissue suggested possibility for its use in wound healing. Aims: The objective of this study was to assess the efficacy of topical phenytoin compared to conventional wound care in improving the healing process and to prove it as a relatively low cost and easy to use option in the management of diabetic ulcers. Methods and Material: In this quasi-experimental study, the data from 200 patients with diabetic ulcers was collected, 100 patients underwent topical phenytoin dressing, remaining 100 patients underwent conventional wound care. The results were compared after 14 days. The variables compared were: rate of granulation tissue formation as percentage of ulcer area covered, percentage of graft take up and duration of hospital stay. Statistical analysis used: The categorical variable was compared by chi-square test and continuous variables by Student t-test. A "p" value <0.05 was considered significant. Results: In study group , the mean rate of granulation tissue formation was 87.94% , mean graft take up was 92.31% and mean hospital stay was 32.26 days with negative culture sensitivity was 70%. The control group showed, the mean rate of granulation tissue formation was 74.64%, the mean graft take was 86.15% of total ulcer surface area and mean hospital stay was 54 days with negative culture sensitivity was 54% Conclusions: Topical phenytoin helps in faster healing with better graft take up and reduces hospital stay.

Topical phenytoin; Wound dressing; Diabetic ulcers; Rate of granulation tissue formation; Graft take up

1 Introduction

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.
2 Subjects and methods
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 14th 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.
3 Results
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 5th 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.
4 Discussion
Phenytoin (diphenylhydantoin or Dilantin) has been investigated as a treatment for more than 100 diseases. Numerous allergy and proliferative, idiosyncratic cutaneous side effects have been reported with its use (Meritt and Putnam, 1938). A frequent observed and unwanted side effect of phenytoin, an anticonvulsant medication, is gingival hyperplasia, especially in children (Bethedsa, 2001). This side effect suggested that phenytoin can induce the growth of connective tissue, and may have the ability to promote wound healing. In 1939 Kimball and Horan first observed that gingival hyperplasia occurred in some patients treated with phenytoin. This stimulated the first controlled clinical trial in 1958, which found that the periodontal patients with surgical wounds who were pretreated with oral phenytoin had less inflammation, less pain, and accelerated healing when compared with controls (Shapiro, 1958). Phenytoin has been investigated to treat ulcers in epidermolysis bullosa and other inflammatory conditions. Since then, the effectiveness of topical phenytoin has been confirmed by several clinical trials for different types of wounds. The earliest clinical study of phenytoin in cutaneous wound healing used oral phenytoin sodium to treat venous stasis ulcers in 28 patients in a double-blind, placebo-controlled trial (Simpson et al., 1965).
Phenytoin promotes wound healing by following mechanisms. They are: stimulation of fibroblast proliferation, enhancing the formation of granulation tissue, decreasing collagenase activity, inhibition of glucocorticoid activity, direct or indirect antibacterial activity by affecting inflammatory cells, neovascularization (Muthukumaraswamy et al., 1991; Anstead et al.,1996; Talas et al., 1999; Genever et al., 1996), and phenytoin increases gene expression of the platelet derived growth factor β chain in macrophage and monocytes (Dill et al., 1993).
A number of clinical studies indicate that phenytoin decreases the bacterial load of wounds (Muthukumaraswamy et al., 1991; Pendse et al., 1993; Lodha et al., 1991). Topical phenytoin was reported to eliminate Staphylococcus aureus, E. coli, Klebsiella and Pseudomonas from wounds within 7~9 days (Modaghegh et al., 1989). In a guinea pig model of wound healing, it was found that phenytoin more readily cleared gram negative organisms than gram positive bacteria from wounds (Lodha et al., 1991). It is not known if phenytoin has intrinsic antibacterial activity, or whether the effect of phenytoin on the bacterial load of wounds is mediated indirectly by effects on inflammatory cells and neovascularization (Modaghegh et al., 1989). Local pain relief has also been observed with topical phenytoin therapy, which can be explained by its membrane-stabilizing action and the reduced inflammatory response (Rhodes et al., 2001; Talas et al., 1999). Facilitation of nerve regeneration has also been reported with phenytoin (Modaghegh et al., 1989). This explains why in our study, phenytoin (study) group had negative bacterial culture when compared to povidone iodine (control) group.
The prospective, controlled trial by Muthukumarswamy et al. (1991) examined the use of topical phenytoin versus control therapy in 100 non-insulin dependent diabetic patients with foot ulcers. In the control group (n=50), a sterile occlusive dressing was applied daily. In the phenytoin group (n=50), phenytoin powder was applied in a “thin layer” to the ulcer surface, and then dry dressing applied daily. Mean healing time was 21 days in the phenytoin group compared to 45 days in the control group (p<0.05%). A study conducted by Pai et al. (2001) showed good granulation tissue with topical phenytoin. Comparison of the present study to study by Muthukumarswamy et al.(1991) (M.K.M.G. et al) was done and it showed following similarities (Table 4).

Table 4 Comparison of present study to study by Muthukumaraswamy et al. (1991)

4.1 Reported Side Effects of Topical Phenytoin Preparations
Topical phenytoin used in wound therapy appears to be well tolerated. Its adverse effects are mild and infrequent. Some patients have a transient burning sensation when the powder is initially applied, but this can be prevented by using pure phenytoin powder instead of phenytoin sodium. A generalized rash that resolved when treatment was stopped has also been reported (Rhodes et al., 2001). Hypertrophic granulation tissue was noted in 10~36 percent of patients in two studies (Muthukumaraswamy et al., 199; Pendse et al., 1993). This is reversed by stopping treatment, and it is suggested that stopping treatment when the wound area is covered with a granulation base can prevent this effect. Systemic absorption of topical phenytoin is not significant. Most studies that have monitored serum phenytoin levels during topical application have shown the levels to be undetectable. Only one case report showed significant levels of serum phenytoin after topical phenytoin (Anstead et al.,1996).
4.2 Limitations of the study
The most important limitation of the present study is its sample size. Although a sample size of 200 patients is sufficient for statistical analysis, a randomized controlled comparative study with a much larger population may help to further substantiate the findings or reveal variations which were not observed in the present study. 
The cost burden on the patient is also not analyzed in this study as this can be influenced by various factors other than the cost of dressings. Phenytoin dressing was found to be less expensive compared to conventional moist dressings (Muthukumaraswamy et al., 1991). The quantitative assessment of the post operative parameters like wound contraction, pain and residual raw ulcer area was also not included in the present study, which might have given a much better analysis of the efficacy of topical phenytoin moist dressings as compared to conventional moist dressings.
Clinical progress of an ulcer varies according to the location of the ulcer  however we have not tabulated the location of the ulcers in the present study. From wound culture mixed bacterial flora was grown which was not included in this study.
We have not studied the type of infective organisms in this study. Skin graft take depends on lot of other inherent qualities of the ulcer, technical factors in skin grafting and the nutritional status of the patient which are not included in the present study. 
For a real controlled study, it would be best to treat two ulcers in the same patient using one as a control which was not considered in our study since this is not a controlled trial.
5 Conclusions
From our study, we conclude that topical phenytoin by decreasing bacterial load, forming healthy granulation tissue helps in better graft take up than the conventional dressing. Because of enhanced healing, overall hospital stay and post-operative complications were less in topical phenytoin dressing group. Thus, the topical phenytoin moist wound dressing can be considered as superior option in the management of diabetic ulcers. But further studies with larger population will be needed in the future before topical phenytoin dressing can be added to the wide spectrum of treatment modalities available in the management of diabetic ulcers and ulcers of other ethology.
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