Split-thickness skin grafting is a frequently used reconstructive technique for management of traumatic and surgical wounds. In this technique, skin grafts (consisting of the epidermis and superficial dermis) are harvested from a remote healthy skin area of the body and transplanted to the wound area. In the process, a new partial-thickness wound is created at the donor site. Although typically the donor site is re-epithelialized within 2 weeks,1 it can occasionally be harder to heal than the primary wound. The donor site wound can be complicated by infection, excessive pain, pruritus, scarring, and patient comorbidities.2 There is a substantial need for an ideal donor site wound dressing that can promote healing and prevent infection.
In general, donor site wound dressings can be categorized as moist and dry dressings. Based on available data, moist dressings may be more effective than dry dressings in promoting healing and reducing pain.3–5 Various topical agents have been tested as moist dressings at donor sites. However, the results conflict, and no single dressing method has been established as most effective.3–6
Because of the antimicrobial and anti-inflammatory properties of some natural materials such as aloe vera and honey, the efficacy of these materials for wound healing has been of interest to researchers.7–9 However, the majority of previous studies are limited to burn wounds, and the data regarding the efficacy of these agents for skin graft management are still scarce. In this study, investigators aimed to evaluate the efficacy of a new natural ointment made of aloe vera, honey, and peppermint as a topical agent for skin graft donor site wound dressing.
This was a double-blind, placebo-controlled, randomized controlled trial (RCT) conducted at Razi Hospital, a referral dermatology center affiliated with the Tehran University of Medical Sciences. Between December 2017 and June 2018, patients referred for split-thickness skin graft after burns or surgical wounds in the scalp or face area were assessed for eligibility. Patients older than 25 years with a donor site wound size less than 15 cm were included. Based on medical history or physical examination, exclusion criteria were susceptibility to keloids and hypertrophic scarring, major underlying disease, current or previous history of scleroderma, history of radiation therapy, immunodeficiency, and pregnancy or breastfeeding.
The protocol of this study was reviewed and approved by the ethics committee of Tehran University of Medical Sciences (code: IR.TUMS.MEDICINE.REC.1396.2641). This trial is registered at the Iranian Clinical Trial Registry (IRCT.ir) with the IRCT identification code IRCT20161180026096N1. All patients signed a written informed consent before study enrollment. Individual participant data are available on request from the corresponding author.
A thin layer of skin with a depth of 0.04 mm and an approximate size less than 15 × 7 cm was harvested from the thigh of each participant by a plastic surgeon with an electric or manual dermatome. The donor sites were divided and randomized (using the permuted block randomization method with a block size of 4 generated with spreadsheet software) to receive either natural ointment or petroleum jelly as a topical agent (4-mm-thick layer). For concealed allocation, sealed envelopes were used. Peppermint essence was added to the petroleum jelly to make it smell like the natural ointment and ensure blinding. The ointments were kept in unlabeled containers. Both patients and physicians were blinded to treatment.
Under the supervision of a trained nurse, topical agents were applied as allocated on split-thickness donor site wounds on days 0, 4, 7, and 14 during patient visits to the facility. The wound dressings were changed only on the visiting days. Wound size, pain, erythema, pruritus, patient discomfort, complications (infection, discoloration, scarring, etc), and physician satisfaction were evaluated at each visit.
Natural Ointment Formulation
For the preparation of the peppermint essential oil, fresh peppermint leaves were collected and dried at room temperature. Then, peppermint essential oil was extracted using the Clevenger apparatus (Figure 1). Honey and aloe vera gel were prepared as described previously.7,10 A combination of these natural materials with the following proportions was used to make the ointment: 70% honey, 20% aloe vera, and 10% peppermint. The natural ointment used in this study was granted a patent (no. 89/34329).
Digital photography of the donor site wounds was performed at each visit to measure wound width and length. All photographs were taken at the same angle, distance, and in the same light. The anti-red-eye function was used. The wound surface area was measured by Digimizer software version 188.8.131.52 (MedCalc Software Ltd, Ostend, Belgium) on days 0, 4, 7, and 14. The healing rate was calculated according to the following formula:
Pain was assessed at each treatment site using the 100-mm visual analog scale. Based on physician opinion, wound erythema was scored on a scale of 0 to 3, where 0 represented no erythema and 3 represented severe erythema. Pruritus was assessed subjectively by the patient using a numeric rating scale (0–3), where 0 was no itching and 3 was severe itching. Patients also were asked to rate their discomfort on a scale of 0 to 3, where 0 represented no discomfort and 3, severe discomfort. Physician satisfaction with the treatment was rated on a 5-point Likert-type scale, with 5 indicating excellent satisfaction; 4, very good; 3, good; 2, fair; and 1, poor.
IBM’s SPSS version 25 (Armonk, New York) was used for statistical analyses. Quantitative variables were expressed as mean ± SD or mean (95% confidence interval). The repeated-measures analysis of covariance method was used for comparisons between the groups. P < .05 was considered significant.
A total of 28 patients were included. The mean age of patients was 54.7 ± 14.5 years, and 50% (14 patients) were male. The mean surface area of the wound was 48.21 ± 8.4 cm2 in the control group, and 43.36 ± 7.9 cm2 in the intervention group (P = .031). All analyses were adjusted accordingly for baseline wound surface area. No abnormal scarring, infection, or other adverse effect was observed in the study cohort.
Researchers observed a significant reduction in wound size over time at all donor sites (P < .001; Table). However, there was no significant difference between the two groups regarding the rate of wound healing (F = 0.675, P = .415; Figure 2).
Wound erythema decreased significantly during the study period (P < .001) and was completely resolved in all patients at day 14 (Table). The ointment was superior to petroleum jelly in reducing wound erythema during the study (F = 12.614, P = .001).
Pain at the donor site decreased significantly over the study period (P < .001; Table), and changes were comparable in both groups (F = 3.161, P = .081). However, no significant improvement in wound pruritus was achieved during the study period (P = .813; Table), and there was no significant difference between groups in terms of itch (F = 0.405, P = .527). Further, patient discomfort resolved completely during the 14 days of study (P = .047; Table), but this progress was indistinguishable between groups (F = 0.254, P = .616).
Physician satisfaction with treatment increased during the study (P = .009; Table). Physicians were significantly more satisfied with wound sites treated with the ointment compared with the sites treated with petroleum jelly (F = 32.692, P < .001).
During the 14-day study period, all aspects of donor site wounds, except for pruritus, improved significantly. There was no significant difference between groups in terms of wound healing, pain, and discomfort. However, wound erythema was significantly lower, and physician satisfaction was considerably higher, in the ointment group.
Aloe vera contains 75 potentially active components: vitamins, enzymes, minerals, sugars, lignin, saponins, salicylic acids, and amino acids.11 In vivo and in vitro studies have demonstrated that aloe vera has antibacterial, antiviral, antifungal, antidiabetic, and antitumoral properties and can promote wound healing and reduce inflammation.11–14 However, it may also act as an allergen and cause dermatitis in some sensitive individuals.15 Animal studies have shown that aloe vera can reduce skin irritation and itching by preventing histamine production.16,17 Moreover, some components of aloe vera such as mucopolysaccharides, amino acids, and zinc can improve skin hydration and integrity and reduce erythema.18,19 Therefore, it seems that aloe vera may have significant therapeutic potential for wound care. However, only a few RCTs have evaluated the efficacy of aloe vera in the management of skin graft donor sites.20,21
Khorasani et al21 assessed the efficacy of aloe vera cream compared with placebo cream and a dry dressing for the management of split-thickness skin graft donor site wounds. Compared with the aloe vera and placebo groups, complete re-epithelialization time was significantly longer in the dry dressing group, but there was no statistically significant difference between the aloe vera and placebo cream groups.21 The authors concluded that aloe vera gauze dressing enhances donor site wound healing by moisture maintenance, but it has no superiority to placebo cream.21 In another RCT by Burusapat et al,20 aloe vera and placebo creams were applied to divided split-thickness skin graft donor sites in 12 patients with 24 donor sites.20 In contrast to the previous study,21 accelerated wound healing was observed in aloe vera-treated sites compared with placebo-treated sites.20 However, visual analog scale scores did not differ significantly between the groups.20
Honey is another natural substance with antimicrobial, anti-inflammatory, and antioxidant properties, which could be helpful for wound care.22 The direct antimicrobial effects of honey are attributable to its viscosity, acidity, hydrogen peroxide, antioxidants, defensin-1, and other as yet unidentified components.22–24 It also has indirect antibacterial activity.25 The antimicrobial activity varies with different sources of honey; Manuka honey has the highest potency.26 Moreover, honey can effectively reduce wound odor.27 The clinical efficacy of honey as a wound dressing has been observed in patients with different types of acute and chronic wounds such as burns, diabetic foot ulcers, venous leg ulcers, and surgical site wounds.24,28–31 One RCT evaluated the effects of honey in split-thickness skin graft donor sites and found that, compared with the petroleum jelly gauze-treated group, wound healing was significantly faster among those treated with honey, but pain scores were similar among the groups.32 As in this study, abnormal scarring and infection were reported in neither group.32 However, the most recent Cochrane review included 26 RCTs that failed to prove the superiority of honey over alternative wound dressings in either acute or chronic routine wound care.33
Several in vitro studies have shown that peppermint has antibacterial effects, is a potent antioxidant, and has antitumor activity.34–36 The menthol component of peppermint has analgesic effects and is useful for controlling wound malodor.27,37–39 A limited number of studies have assessed the efficacy of peppermint oil in wound healing.40–42 Based on animal model studies of infected wounds, peppermint may accelerate wound healing by reducing inflammation and bacterial count.40,41 To the authors’ knowledge, the efficacy of peppermint for treating split-thickness skin graft donor site wounds has never been studied.
Study authors hypothesized that the combination of honey, aloe vera, and peppermint would be more effective than each agent separately. However, the present study failed to confirm this hypothesis. There is little known about the combined effect of aloe vera and honey on wound healing. Yari et al43 found that adding aloe vera to honey and nano zinc is not associated with accelerated wound healing in animal models with third-degree burns. Although this combination had no significant impact on the rate of wound healing in this study, it was superior to petroleum jelly for the management of wound erythema; this may be attributable to its anti-inflammatory properties.
Certain limitations to this study should be acknowledged. First, baseline wound area was not equal between the groups. Although investigators adjusted the subsequent analyses for baseline wound size, confounding could still persist. The small sample size and short follow-up period are other notable limitations.
Taken together, it seems that the topical ointment investigated in this study may be an alternative moist dressing in split-thickness skin graft donor site wounds. It can effectively promote wound healing, prevent infection and scarring, and reduce pain. Notably, it was more effective than petroleum jelly in reducing erythema and was associated with better satisfaction among physicians. However, the higher price and lower availability of the natural ointment should be considered during decision-making.
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