Abstract
Introduction
Regular dressing of traumatic wounds is of paramount importance for healing. Phenytoin, an anticonvulsant, is thought to promote wound healing through multiple mechanisms, including fibroblast proliferation, granulation tissue formation, antibacterial activity, and pain alleviation.
Aim
To assess the effect of topical phenytoin on traumatic wound healing in terms of granulation tissue formation, pain alleviation, and time taken for wound healing.
Methodology
Fifty patients with traumatic wounds were divided into equal and comparable groups. After cleaning the wound, phenytoin dressing was done in the study group and saline dressing in the control group. Thereafter, regular dressings of the wounds were done, and healing was assessed on day 14 and day 21.
Results
On day 14, the wound surface area, percentage of granulation tissue, VAS score amongst cases was 39.4 ± 29.75 cm2, 82.12 ± 9.71%, 4.52 ± 1.08, and that of controls was and 51.28 ± 25.33 cm2, 62.72 ± 9.01%, 6.52 ± 1.22, respectively. On day 21, the wound surface area, percentage of granulation tissue, VAS score amongst cases were 29.4 ± 29.88 cm2, 92 ± 4.46%, 2.8 ± 0.94, and that of controls were 38.92 ± 23.24 cm2, 78.56 ± 8.19%, and 4.88 ± 1.17, respectively. The time taken for wound healing was 21.76 ± 5.28 days amongst cases and 31.64 ± 8.31 days amongst controls. Staphylococcus aureus was the commonest organism isolated in both the groups. On day 14,18(72%), wounds in the study group showed negative culture, whereas, in the control group, it was negative in 12 (48%) patients. The rate of granulation tissue formation was higher in cases when compared to controls amongst smokers and diabetics. The difference in all these parameters between the groups was statistically significant (P-value <0.05).
Discussion and conclusion
We observed a considerable increase in granulation tissue formation, pain alleviation, and reduction in time taken for wound healing. Topical phenytoin is a safe, effective, readily available, and frugal agent that can accelerate wound healing through its multimodal action, thus reducing patient morbidity and economic burden.
MeSH terms
Phenytoin, Wound healing, Topical, Ulcer, Anticonvulsant, Granulation Tissue, Saline dressing.
Keywords: Topical phenytoin, Traumatic wounds, Wound healing
1. Introduction
Traumatic wounds are a common health problem and is a frequent challenge faced by orthopaedic surgeons. The management of traumatic wounds is crucial, especially when associated with a fracture, as the condition of the soft tissue has a significant bearing on the fracture union. A definitive bony fixation can be done only when the surrounding soft tissue condition is favourable.
A healthy wound with good granulation tissue and absence of infection are favourable prognostic indicators.1 On the other hand, an unhealthy wound indicates poor tissue vascularity and is detrimental to fracture union. Additionally, if the wound is infected, it can spread to the bone and further complicate the treatment. These traumatic wounds are associated with an increased cost of medical care, prolonged morbidity, and, if extensive, can lead to mortality. Regular wound dressing is of paramount importance for healing. Various topical agents have been used to promote healing, and the quest for a better topical agent is a time immemorial challenge.
Phenytoin is an anticonvulsant which belongs to the hydantoin group of drugs. In 1939, Kimball observed that nearly half the patients who used oral phenytoin developed gingival hyperplasia as a side effect.2 In 1958, Shapiro studied the effects of oral phenytoin pre-treatment on the healing of surgically created gingival wounds in patients with periodontal disease.3 This apparent stimulatory effect on connective tissue has prompted its use in wound healing.
Subsequently, various studies have been conducted to assess the effects of topical phenytoin in various wounds such as diabetic ulcers,4,5 decubitus ulcers,6 venous stasis ulcers,7 leprosy trophic ulcers,8 and traumatic wounds.9,10 It is thought to promote wound healing through multiple mechanisms.11, 12, 13, 14, 15 Its efficacy has also been found to extend to pain alleviation via its membrane-stabilizing action and anti-bacterial action via direct and indirect mechanisms.4,10
Modaghegh S et al. conducted a pilot study on the effects of topical phenytoin where 19 cases of war wounds were included.9 Similarly, Pendse et al. included 7 patients of traumatic wounds in their study on heterogeneous wounds.10 However, there is dearth of studies on the effect of topical phenytoin in traumatic wounds.
1.1. Aims and objectives
Our aim was to compare the efficacy of topical phenytoin with conventional saline wound dressings in the healing of traumatic wounds in terms of rate of reduction of wound size, percentage of granulation tissue formation, number of days required for wound healing and, pain alleviation.
1.2. Patients and methods
This is a prospective case-control study consisting of 50 patients. The sample size was calculated using the WHO calculator, the level of significance was 5%, and the power of the test was 90%. The duration of the study was one year, from January 2019 to December 2019. Ethical Committee clearance was obtained from the institutional ethics committee, and the study conforms to the standards of the declaration of Helsinki (IEC/2019/010). Our inclusion criteria were adult patients between the ages of 18 and 60 years, with full-thickness traumatic wounds (i.e., involving skin and subcutaneous tissue) and patients willing to participate in the study. We excluded patients with co-morbid conditions that affect wound healing, such as hepatic and renal disease, patients on steroids, uncontrolled diabetes, vascular impairment, immunocompromised patients, history of oral phenytoin intake, and allergic to phenytoin.
Informed written consent was obtained from all the patients. The patients who fulfilled the inclusion and exclusion criteria were randomised into two equal and comparable groups based on the flip coin method. Cases and controls were comparable with respect to age, smoking, and diabetic history. Culture of the wounds was done. 1 g of intravenous ceftriaxone infusion was given twice a day for 5 days and 5 mg/kg body weight/day of intravenous gentamycin infusion in three divided doses were given for 5 days to all the patients in both the groups. Wound debridement was done as and when necessary. Wound measurements using tissue paper tracing and, pain assessment using Visual Analogue Scale (VAS) were done on day 0.
Dressings were done daily, followed by on alternate days depending upon the wound soakage in both the groups. The dressings were continued until the wound healed or was healthy enough to carry out closure using secondary suturing/split skin graft/flap cover. The wound was cleaned with normal saline, and moist dressings were done in the control group. In the study group, phenytoin suspension was used instead. The amount of phenytoin needed was determined on the surface area of the wound as follows.4 Up to 5 cm: 100 mg, 5–9 cm: 150 mg, 10–15 cm: 200 mg, >15 cm: 300 mg. The phenytoin tablets were crushed and mixed with 5 ml of normal saline for every 100 mg of the drug. The suspension so prepared was uniformly applied over the surface of the wound. Healing was assessed at the end of every week in terms of percentage of granulation tissue formation, pain alleviation as measured by VAS, the percentage reduction of the wound size by serial measurements, number of days required for complete wound healing or wound bed ready for grafting/secondary closure. The patients in both groups were assessed for culture sensitivity on day 14 to determine the antibacterial effect.
1.3. Observation and results
The data was analyzed using SPSS 22 version software (IBM SPSS Statistics, Somers NY, USA). Categorical data was represented in the form of frequencies. Continuous data were represented as mean and standard deviation. Mann-Whitney U test was used as a test of significance to identify the mean difference between two quantitative variables. MS Excel and MS word were used to obtain various types of graphs. P-value (Probability that the result is true) of <0.05 was considered statistically significant after assuming all the rules of statistical tests.
The mean age of the patients in the study group was 44.56 ± 13.54 years, and that of the control group was 43.6 ± 14.47 years. The difference between them was not found to be statistically significant (P 0.81). Similarly, the surface area and Visual Analogue Score on day 0, among cases were 60.16 ± 35.99 cm2 and 8.4 ± 1.12 and, that of in controls was 60.12 ± 26.64 cm2 8.28 ± 1.02 respectively. The difference in these parameters between the groups was also not statistically significant (P 0.72 and 0.69, respectively).
The percentage of granulation tissue covering the wound surface area was measured on day 14 and day 21. On day 14, it was 82.12 ± 9.71 among cases and was 62.72 ± 9.01 in controls. The difference between both groups was statistically significant, with a P-value of 0.01. On day 21, the value was 92 ± 4.46 in cases and was 78.56 ± 8.19 in controls, as shown in Fig. 1. The difference between both groups was statistically significant, with a P-value of 0.001.
Fig. 1.
Graph showing the percentage of granulation tissue formation.
Pain alleviation was measured on day 14 and day 21 using the Visual Analogue Scale. On day 14, VAS amongst cases was 4.52 ± 1.08, and that of in controls was 6.52 ± 1.22. On day 21, it was 2.48 ± 0.92 in cases and 4.88 ± 1.17 in controls. The difference among the groups was found to be statistically significant, with a P-value of 0.02. It is graphically represented in Fig. 2.
Fig. 2.
Graph showing Visual Analogue Score.
The wound surface area was measured serially to assess the reduction in size. On day 14, it was 39.4 ± 29.75 cm2 among cases and 51.28 ± 25.33 cm2 among controls. On day 21, the surface area was 29.4 ± 29.88 cm2 among cases and 38.92 ± 23.24 cm2 among controls, as shown in Fig. 3. Thus, the percentage reduction of wound surface area on day 21 was 51.13 among cases and 35.26 among controls.
Fig. 3.
Graph showing reduction in wound surface area.
There was no statistically significant difference between cases and controls with respect to the number of patients with history of smoking and diabetes(p > 0.05), as shown in Table 1 below.
Table 1.
Table showing the number of smokers and diabetics in each group.
| Cases |
Controls |
P value | ||||
|---|---|---|---|---|---|---|
| N | % | N | % | |||
| Smoking | No | 14 | 56.0% | 17 | 68.0% | 0.382 |
| Yes | 11 | 44.0% | 8 | 32.0% | ||
| Diabetic | No | 17 | 68.0% | 18 | 72.0% | 0.758 |
| Yes | 8 | 32.0% | 7 | 28.0% | ||
The healing of the wounds amongst the smokers was assessed using percentage of granulation tissue formation on day 14 and day 21 in both the groups. There was a statistically significant difference in granulation tissue formation between the groups. Similarly, healing was also calculated among the diabetics and the difference was found to be statistically significant. The results are as shown in Table 2.
Table 2.
Table showing difference of granulation tissue formation between the groups.
| Percentage of granulation tissue formation | Cases |
Controls |
P value | |
|---|---|---|---|---|
| Mean (SD) | Mean (SD) | |||
| Smokers | Day 14 | 83 ± 10.51 | 63.54 ± 8.96 | 0.005a |
| Day 21 | 92.33 ± 5.35 | 79.18 ± 8.38 | 0.004a | |
| Diabetics | Day 14 | 81.375 ± 9.43 | 62.875 ± 7.56 | 0.006a |
| Day 21 | 91.75 ± 4.38 | 78.125 ± 7.28 | 0.004a | |
Statistically significant at p < 0.05.
The microbiological evaluation of the wounds revealed that Staphylococcus aureus was the commonest organism in both the groups. The other organisms isolated from cases and controls are as shown in Fig. 4. The patients in both groups were assessed for culture on day 14 to determine the antibacterial effect. 18(72%) wounds in the study group showed negative culture, whereas it was negative in 12 (48%) patients in the control group.
Fig. 4.
Graph showing the growth of various organisms obtained from wounds on day 0.
Of the 25 wounds in the study group, 11 healed spontaneously, and 14 wounds were managed by a secondary procedure for coverage. Among the controls, 7 wounds healed spontaneously, and 18 wounds required an additional procedure. The number of days taken either for complete wound healing or the wound bed ready for further procedures was also measured. It was 21.76 ± 5.28 days among controls and 31.64 ± 8.31 days among cases. The difference was statistically significant, with a P-value of 0.01.
Progression of healing of a traumatic amputation wound that received regular phenytoin dressing is shown in Fig. 5. (a)on day 0, (b)- Wound on day 14, (c)- Wound on day 21, (d)- Wound on day 28.
Fig. 5.
Serial photographs of wound healing with phenytoin dressings: (a) - Wound on day 0, (b)- Wound on day 14, (c)- Wound on day 21, (d)- Wound on day 28.
2. Discussion
Wound dressings have progressed from providing mechanical protection and controlling local infection to the level of providing an environment that promotes wound healing. It has evolved from simple moist dressings to using various agents like aloe vera, honey, papaya, betadine, collagen impregnated sheets, hydrocolloid, silver sulfadiazine, mercurochrome, insulin, oxygen therapy, and negative pressure wound therapy. Not only is the quality of wound healing taken into consideration while comparing these agents, but also the cost-effectiveness, ease of availability, and applicability. Hence, the quest for a newer agent that is effective, as well as frugal, is an ongoing research.
Phenytoin has been investigated in the management of wounds. The mechanism responsible for this action remains unclear, and hence its wound-related pharmacology is being investigated. It acts through multiple mechanisms. It is thought to increase the expression of platelet-derived growth factor B in macrophages and monocytes, thus increasing neovascularization .11 Other mechanisms include fibroblast proliferation enhancing granulation tissue formation, anti-collagenase activity facilitating collagen deposition, competitive glucocorticoid antagonism, pain alleviation by membrane-stabilizing action, and antibacterial activity.4,12, 13, 14, 15, 16 Topical phenytoin is reported to be antibacterial against Staphylococcus aureus, Escherichia Coli, Klebsiella and, Pseudomonas species.17, 18, 19, 20 It is unclear whether the antibacterial activity is intrinsic or is mediated indirectly by its effects on the inflammatory cells and neovascularization. The best method of delivery of topical phenytoin is not known. Some authors have used phenytoin powder and have reported the development of white eschar like coating. This can be prevented by using phenytoin suspension.6 We have chosen suspension for the same reason.
Carneiro et al.21 compared the effects of topical phenytoin with silver sulfadiazine for the treatment of acute burns. There was a statistically significant increase in the number of negative wound cultures, and pain was significantly reduced in the phenytoin group. There was also a trend for accelerated healing in the phenytoin group although this was not statistically significant. Similarly, Meena K et al. have compared effects of topical phenytoin and silver sulfadiazine on burn wound healing in rats.22 The phenytoin group showed significant improvement in wound contraction and improved epithelialization in comparison to sulfadiazine group. Rhodes et al. compared effect of topical phenytoin in ulcers in the elderly with collagen dressing and antibiotic ointment.6 Healthier granulation tissue appeared earlier in the phenytoin group and there was evidence of reduced bacterial contamination. Lodha et al. investigated the role of topical phenytoin in the healing of large gluteal abscesses compared with EUSOL dressings.23 By day 20, a statistically significant reduction in mean wound area was reported in the phenytoin group compared with controls. Although, there are a few studies which have shown the effect of phenytoin in wounds of varied etiology, studies related exclusively to traumatic wounds are lacking to the best of our knowledge.
In our study, topical phenytoin was more effective compared to normal saline dressings. The percentage of granulation tissue formation was significantly higher among cases (92%) as compared to 78.56% among controls. Tauro et al. reported similar results with a significant improvement in granulation tissue formation between cases and controls.24 The rate of reduction in the mean surface area of the wounds at the end of 3 weeks was faster in the study group than in the control group. Muthukumarasamy et al., reported a similar result where the mean duration of wound healing in diabetic ulcers was 21 days in the phenytoin group and 45 days in saline dressings.19 Pain alleviation, as measured by VAS, was lower in the phenytoin group. Although not quantified in this study, we also observed that the wounds which received phenytoin dressings had reduced wound exudation. Carneiro et al. compared topical phenytoin with EUSOL dressings and showed a reduction in pain and clearance of ulcer discharge.25 Reduction of pain also reduces the need for analgesics. In our study, on day 14, 72% of the phenytoin treated wounds had negative culture compared to 48% among the controls. The antibacterial action of phenytoin was also shown by a study conducted by Pendse et al.20 Histopathological studies have shown increased neovascularization and lymphocyte infiltration in the phenytoin-treated wounds, which is responsible for its anti-bacterial action.22
Also, the granulation tissue formation was significantly higher among the cases than controls in patients with history of smoking and diabetes. Phenytoin improves wound healing even in these subsets of patients due to its multimodal action. The improved wound healing using topical phenytoin amongst diabetic ulcers is elaborated in a study conducted by Kodela et al.26
Topical phenytoin is well tolerated with minimal side effects. Some patients have a transient burning sensation when it is applied. It is thought to be due to the sodium content in the tablet. This can be minimized by using phenytoin only instead of phenytoin sodium.6,26,27 Hypertrophic granulation tissue was reported in two studies.19,20 This can be prevented by stopping the treatment when the granulation tissue covers the wound bed. Many studies have shown systemic absorption of phenytoin to be negligible, and the levels were undetectable in serum.27,28 We did not notice any case of hypersensitivity reaction to phenytoin.
2.1. Limitations of the study and future trends
We have attempted to show the beneficial effects of phenytoin in traumatic wounds as the relevant literature is lacking. However, the present study consists of a small sample size. Certain confounding factors like malnutrition, and the location of the wound were not taken into consideration. In this regard, double-blind placebo-controlled trials are needed to prove its efficacy, determine the optimum dose and method of delivery in traumatic wounds. Also, larger studies to compare the effect of topical phenytoin with more established agents will be helpful to validate its clinical use.
3. Conclusion
Our study demonstrated better-wound healing among the patients treated with topical phenytoin than normal saline in traumatic wounds. The rate of granulation tissue formation, pain alleviation as measured by the visual analogue scale, and percentage reduction of wound surface area showed a statistically significant difference between the groups. The time taken for wound healing is also decreased, thereby reducing the costs further. Hence, topical phenytoin is a safe, effective, readily available, applicable, and a frugal agent which can be used to treat traumatic wounds.
Patient declaration statement
“The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.”
Sources of funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Presentation at a meeting
None.
Declaration of interest
None.
Acknowledgement
None.
CRediT authorship contribution statement
C Shyam Kumar: Conceptualization, Design and Methodology, Investigation, Resources, Data acquisition, Writing - review & editingManuscript editing and review, Supervision. Nagashree Vasudeva: Conceptualization, Design and Methodology, Investigation, Literature search, Resources, Data acquisition, Data analysis, Writing - original draftManuscript preparation- original, Writing - review & editingManuscript editing and review, Supervision. D Venkateswara Rao: Design and Methodology, Resources, Data acquisition, Writing - original draftManuscript preparation- original, Writing - review & editingManuscript editing and review, Supervision. Ch R S Ayyappa Naidu: Conceptualization, Investigation, Resources, Data acquisition, Writing - review & editingManuscript editing and review.
Contributor Information
C Shyam Kumar, Email: drcsk61067@gmail.com.
Nagashree Vasudeva, Email: drnagashreev@gmail.com.
D Venkateswara Rao, Email: d_yenkee@yahoo.com.
Ch R S Ayyappa Naidu, Email: ayyappanaidudr@gmail.com.
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