New Topical Agents for Treatment of Partial-thickness Burns in Children: A Review of Published Outcome Studies

Abstract: Evidence-based choices for treating burns in children are not well defined. Skin substitutes and contemporary dressings offer potential advantages over traditional treatment with topical antimicrobial agents in treating partial-thickness burns. Newer treatment modalities may reduce morbidity, financial burdens, and scarring by accelerating healing.      Reports of pediatric burn management from 1997 to 2007 were reviewed to compare agent performance with outcome measures such as healing time, pain moderation, cosmetic results, and hospital costs. Transcyte™ (Smith & Nephew, London), Biobrane® (Bertek Pharmaceuticals Inc, Morgantown, WV), beta-glucan collagen, and Mepitel® (Mölnlycke, Göteborg, Sweden) have been reported as superior to silver sulfadiazine (SSD) in achieving faster healing times and decreased pain in pediatric patients.      Initial reports describing the outcomes achieved with these new agents indicate that they may offer clinical advantages in the treatment of partial-thickness burns in children. Increased costs of the new products appeared to be offset by decreases in hospital stay, nursing care time and pain medications. The existing literature is not conclusive, and prospective trials with standardized outcome measures are needed to better define the role of these agents.

Address correspondence to: Wanda A. Dorsett-Martin, DVM Assistant Professor Division of Plastic Surgery University of Mississippi Medical Center 2500 N. State Street Jackson, MS 39216-4505 Phone: 601-815-1073 E-mail: wdorsett-martin@surgery.umsmed.edu


     Children, especially those younger than 2 years, are at high risk for burn injury.¹ Of 126,642 records of acute burn hospital admissions in the United States between 1995 and 2005, approximately 32% were younger than 20 years of age. ¹ In the 6-year period from 1997 to 2002, there was an annual average of 78,000 children (birth–4 years old) treated in US ambulatory settings for injuries resulting from contact with a hot object or substance. ² Natural curiosity, impulsiveness, lack of awareness of potential dangers, and limited ability to respond to a precarious situation in a prompt, appropriate manner, are factors leading to the high occurrence of burns in the pediatric population. ^3,4      Scalding is the leading cause of burns in children younger than 3 years, and fire is the major cause of burns in older children. ⁵ Scald injuries usually occur in the home as a result of cooking accidents or use of excessively hot water during bathing. ^6,7Accidental and neglect-related burns, although common, are not the only problem for the medical community; child abuse is the cause for many admissions. ⁵ Approximately 20% of pediatric burns are caused intentionally by a caregiver or parent. ⁸      The sheer volume of burn incidents, especially within a vulnerable population such as children, necessitates major medical resources dedicated to burn care. The ever-increasing financial pressures associated with health care also contribute to the need for effective, cost-efficient treatment options for burns. ⁹      Treatment of partial-thickness burns customarily involves early debridement of nonviable tissue. After debridement, the wound may be dressed with any of numerous dressings, which can be either biological, nonbiological, or a combination of these elements, in an effort to stimulate healing and provide protective covering for the wound. Pediatric burns traditionally have been treated with daily cleansing of the burn wound and application of topical antimicrobial agents. ¹⁰ Numerous carriers can be useful for burn treatment. According to Palmieri and Greenhalgh, ¹¹ such carriers include ointments, creams, biological and nonbiological dressings with the topical antimicrobials of choice being mafenide, neomycin, bacitracin, and silver sulfadiazine (SSD).      Coverage of the burn site with autografts is the optimum treatment for full-thickness or deep partial-thickness burns. Early treatment with skin grafts may not always be possible in a metabolically compromised patient or in large body surface area burns where adequate donor sites may not be available. Allografts (eg, cadaver skin) are useful as a temporary graft because they provide a protective barrier to a burn wound and can be supplied using skin banks. High cost, limited availability, and the possibility of disease transmission are all drawbacks of allografts. ¹² In most cases, skin grafting is unnecessary for the treatment of partial-thickness burns, unless the burn transitions to full thickness. While there is a need for a dressing and/or skin substitute that facilitates rapid healing of partial-thickness burns with minimal pain and scarring, this ideal dressing does not exist.      The objective for skin substitutes is complete restoration of both anatomical architecture and functional physiology of skin after wound treatment and healing. ¹³ Extra considerations for dressings specifically designed for pediatric patients include: 1) resistance to soiling of wounds with urine and feces in infants and toddlers; and 2) achieving adherence of dressings due to ever changing shear forces produced during play behavior of naturally active toddlers. ⁷ A large and increasing number of agents are available with varying claims of meeting these objectives.      The goals of this review are to provide a general overview of dressings and skin substitutes used in pediatric care of partial-thickness burns and if possible, to determine by the use of comparison studies, the most current, efficacious treatment of partial-thickness burns in children. Additionally, by reviewing the current practices, the authors will suggest possible directions for future research in this area.

Methods

     Articles comparing burn dressings over the past 10 years were reviewed using the scientific reference search engine of the National Library of Medicine (PubMed) by searching the following terms: pediatric burns, burn dressings, partial-thickness burns in children, and burn treatment. Articles comparing burn treatment products published in English between January 1997 and January 2007 were included.      Studies comparing innovative burn dressings to more traditional treatments, usually silver sulfadiazine (SSD), are listed in Table 1. The studies were examined for patient age, number of patients, burn size, mechanism of injury, and infection rate. Outcome assessments were analyzed to determine effectiveness of treatments, and to provide evidence-based practice recommendations. These assessments included healing/hospitalization times, pain scoring, aesthetic results, cost, and the need for grafting.

Results

     The following burn treatments were identified in our review of the literature conforming to the definition of this study.      Topical. Silver sulfadiazine ([SSD] Silvadene®, Monarch Pharmaceuticals, Bristol, TN; generic silver sulfadiazine, Watson Pharmaceuticals, Corona, CA; Thermazene™, Kendall, Mansfield, MA; Flamazine™, Smith & Nephew, London, UK) is a silver and sulfa drug cream used to prevent and treat infections of second- and third-degree burns. ¹⁴ Silver sulfadiazine is usually removed and applied once daily before covering with additional dressing materials to cover the burn injury.      Advanced dressing products. Duoderm® (ConvaTec, Skillman, NJ) is an occlusive hydrocolloid dressing that offers barrier protection producing a moist environment favorable to wound healing. ¹⁵      BGC (beta glucan) Matrix® (Brennen Medical, St. Paul, MN) combines beta glucan, a complex carbohydrate known to stimulate macrophages, with collagen in a meshed reinforced wound dressing. ⁴ Beta-glucan collagen is a semiocclusive wound covering, which decreases evaporative water and heat loss, and provides an effective bacterial barrier. ⁴      Mepitel® (Mölnlycke Health Care, Göteborg, Sweden) is a silicone-coated, nylon net dressing that contains no biological compounds or antimicrobials. ¹⁶       Skin equivalents. Biobrane® (Bertek Pharmaceuticals, Morgantown, WV) is a biocomposite dressing with a semipermeable silicone membrane mechanically bonded to a trifilament nylon fabric. ¹⁵ The nylon mesh is covered by porcine dermal collagen (porcine type 1) that provides a hydrophilic coating to facilitate ingrowth of fibrin. ^17–19 Blood and serum clot in the nylon matrix so that Biobrane adheres to the wound until epithelialization occurs, thus eliminating the need for daily dressing changes and debridment. ^15,20      Transcyte™ (Smith & Nephew, London, UK) a bioactive skin substitute consisting of a porcine collagen coated polymer membrane impregnated with human newborn fibroblasts. ⁹ Transcyte contains structural proteins, provisional matrix proteins, glycosaminoglycans, and growth factors synthesized by the fibroblasts during the time the tissue was grown. ²¹ Following freezing, cellular metabolic activity is stopped, but the tissue matrix and bound growth factors remain. ²¹      Age of patients. Research on partial-thickness burns in children included those age 18 and younger. It was found that various age limitations were included in the articles. Patients as young as 6 weeks were included in one study. ⁴ Noordenbos et al²² included both children and adults. Gotschall et al²³ limited their study to children 12 years and younger. ²³      Number in study. The number of subjects in the studies ranged from as few as 14 children²² to as many as 225. ⁴ Sometimes different treatments were used on separate burn sites on the same patient. For example, Kumar et al²⁴ studied 33 patients with 58 wound sites using Transcyte on 20 wounds, Biobrane on 17, and Silvazine™ (Smith & Nephew, Victoria, Australia) on 21 burns. ²⁴      Burn size/exclusions. Total burn surface area (TBSA) included in the studies ranged up to 35%. ⁴ Many of the studies did not include burns of the face, hands, or genitalia, and tended to include only noninfected, recently acquired wounds on flat surfaces of the body. Cassidy et al¹⁵ compared the depth of injury, defined as a superficial or mid-dermal, partial-thickness burn with < 10% TBSA. Their study excluded burns on the face, hands, feet, or perineum. Kumar et al²⁴ had patients with a mean of 5% TBSA. They studied partial-thickness burns < 24-hours-old that had no signs of infection. ²⁴ Lukish et al⁹ reviewed burn cases that were > 7% TBSA, and excluded hand burns. Delatte et al⁴ studied BGC on burns with a 1% to 35% TBSA and excluded burns that were several days old, on the face, hands, feet, joints, or genitalia. Lal et al⁷ reported on children with superficial partial-thickness, hot fluid scald burns covering 5%–25% TBSA admitted within 48 hours of injury and showing no infection, had no third-degree burns, and were not burned by grease. Barret et al¹⁰ studied patients who had a TBSA of 4%–13.8% and were admitted within 24 hours of injury with clean, noninfected wounds. ¹⁰ The study by Noordenbos et al²² studied patients with 4%–30% TBSA; wounds of the hand, face, buttocks, feet, and genitalia were excluded. Gotschall et al²³ studied partial-thickness scald burns covering ≤ 15% TBSA, and burns that only affected flat body surfaces. ²³ The study by Bugmann et al¹⁶ excluded patients with facial burns, burns older than 24 hours, and those > 10% TBSA.      Mechanism of injury. Scalds were the predominate mechanism of injury in the reviewed articles or the authors confined their study to scald injuries exclusively. In addition to scalds, contact burns, flames, and miscellaneous injuries were included in Cassidy et al. ¹⁵ Flame injuries and scalds were included in the Barret et al¹⁰ study. Noordenbos et al²² mention flash fire, as well as scald. Bugmann et al¹⁶ included thermal contact injuries, oil/melting plastic, flame, electrical burns, and scald injuries. ¹⁶      Infection rate. Many of the studies excluded wounds if they showed any signs of clinical infections or were more than 24 hours old. ^4,7,10,16,24 Kumar et al²⁴ found only one of the 20 patients treated with Transcyte required treatment for infection. Noordenbos et al²² did not document infection in the Transcyte group, while 6 patients were treated for infection in the SSD group. The Gotschall et al²³ study found no significant differences in wound infection rates between the use of Mepitel and SSD. Bugmann et al¹⁶ reported one infection in the SSD group, and none in the Mepitel group.      Healing times/hospitalization. Overall, no single study demonstrated sufficient evidence to establish specific product or treatment superiority; however, individual studies indicated that there might be some trends worthy of further well-designed studies.      More specifically, there was no significant difference in the time to complete healing seen between the use of Biobrane and Duoderm. ¹⁵ Silvazine took 11.2 days to heal burns, Biobrane 9.5 days, and Transcyte 7.5 days.24 Lukish et al⁹ observed a significant difference for length of stay for in-patients between the Transcyte group at 5.9 ± 0.9 days and standard therapy group at 13.8 ± 2.2 days. ⁹ Faster healing times were reported for use of BGC compared to SSD while it took 15 days to complete healing with 10 (23%) of the BGC patients not requiring hospitalization, 12 were hospitalized for < 24 hours; 4.1 days was the average length of stay (LOS) in the BGC group. ⁴ For patients receiving standard treatment with SSD, the burns were generally more severe, usually related to flame exposure, and averaged 14% TBSA.⁴ As predicted, the LOS was longer at 18.2 days and the time to complete wound healing was an average of 33.9 days. ⁴ Shorter hospital stays and faster healing times were associated with the use of Biobrane as compared to SSD. ^7,10Earlier healing times with a mean of 11.14 days to 90% epithelialization were reported in the Transcyte group verses 18.14 days for the SSD group. ²² Both Bugmann et al¹⁶ and Gotschall et al²³ reported that Mepitel had a shorter healing time than SSD; Mepitel had an epithelialization time of 7.58 ± 3.12 days versus 11.26 ± 6.02 days for Flamazine. ¹⁶      Pain scoring. Generally, patients treated with skin substitutes reported a decrease in pain versus those treated with SSD. Cassidy et al¹⁵ assessed the patients’ pain with either the Oucher Score or Visual Analogue Scale after initial debridement and dressing application, and subsequently before and after dressing changes. They reported no significant difference between Biobrane and Duoderm.¹⁵ Kumar et al²⁴ found that Transcyte- and Biobrane-treated patients required less pain medications than those in the Silvazine group. Lukish et al⁹ found that Transcyte appears to reduce pain compared to SSD. In the Delatte et al⁴ study, narcotics and anxiolytics were used, as needed, at dressing changes, and it was found that with the use of BGC, the sensory nerve terminals were covered and pain was diminished.⁴ In a study comparing Biobrane to SSD, the Biobrane group showed decreases in pain with superficial second degree burns without increased incidence of infection.⁷ Barret et al¹⁰ stated patients treated with Biobrane had a significant improvement in pain level (P < 0.001) compared to SSD treatment. ¹⁰ The prospective randomized study of Transcyte reported that the discomfort associated with repetitive dressing changes was eliminated and subsequently decreased the need for pain medication.²² Gotschall et al²³ reported patients experienced less pain with the use of Mepitel as compared to SSD.²³ Bugmann et al¹⁶ surmised that since less dressing changes were reported with Mepitel compared to SSD, consequently, there would be less associated pain.¹⁶      Aesthetic results. While many of the comparison articles focused on improved healing times, direct statements as to aesthetic outcome evaluations were often lacking. A better scar appearance was recorded for the use of BGC compared to SSD. ⁴ Noordenbos et al²² reported a significant decrease in scarring and less long-term pigmentation changes with the use of Transcyte compared to SSD. Noncomparison burn articles did remark on cosmetic results, such as the case report by Hassan et al, ²⁵ in which punctate scarring resulted from the use of porous Biobrane. Williams et al²⁶ reported longstanding pigmentary changes, and mesh imprinting was reported with the use of Mepitel on scalds in dark skinned children.      Cost. Cassidy et al¹⁵ concluded that Duoderm was more economical to use than Biobrane, and was equally effective. Kumar et al²⁴ reported faster healing times, less pain medications, and fewer dressing changes with Transcyte and Biobrane compared to SSD, but did not examine LOS to give a total picture of burn care costs. Lukish et al⁹ state that the significant decrease in LOS and use of less direct nursing care makes the use of Transcyte a significant economic benefit. ⁹ Delatte et al⁴ reports that the treatment of partial-thickness burns with BGC reduces the overall cost of the patient care. Cumulative material costs of treating a 5-in x 6-in, partial-thickness burn for 15 days with antimicrobial agents applied once daily is approximately $350 excluding labor time, but to treat the same size burn with BGC, costs are approximately $120, and requires only daily assessment, thus decreasing nursing time. ⁴ Lal et al⁷ and Barret et al¹⁰ reported that those treated with Biobrane had shorter hospital stays and faster healing times than those treated with SSD.      In a prospective trial comparing Biobrane with treatment containing 1% SSD, Barret et al¹⁰ showed significant reduction in pain medication requirements with the use of Biobrane. Noordenbos et al²² reported earlier healing with Transcyte versus SSD. Lower mean daily hospital charges and lower narcotics charges were reported with Mepitel versus SSD. ²³      As a point of reference, pricing for some of the products was secured from the University of Mississippi Pharmacy as of April 4, 2007: SSD (silver sulfadiazine), $1.72 for a 1% 20-g tube; Duoderm, $14.12 for a box of 5, 4-in x 4-in dressings; Mepitel, $36.07 for a box of 10, 2-in x 3-in dressings; and Biobrane, $210.91 for a box of 5, 5-in x 5-in sheets. Jones et al²⁷ state that Transcyte costs 16 times more than Biobrane.      Grafting. Kumar et al24 found that 5% of the Transcyte wounds required autografting, while 17% of the Biobrane and 24% of the Silvazine wounds needed grafts. ²⁴ Lukish et al⁹ reported 1 child in the Transcyte group and 7 children in the standard treatment group required autografting. Nine of the patients in the BGC group had the BGC matrix removed before healing because of nonadherence with 6 of these 9 BGC patients requiring skin grafting due to progression to a full-thickness burn injury. ⁴ Failure occurred in 5.9% of the Biobrane treated cases due to nonadherence.7 None of the patients in the Barret et al¹⁰ study needed autografting. Two of the SSD patients and none of the Transcyte patients needed grafts. ²²

Discussion

     Accumulating research data have shown that advanced products seem to decrease healing times with fewer dressing changes and decrease pain compared to SSD, but with increased costs. ^{4,7,9,10,16,22,23}Conversely, topical agents such as SSD are typically applied and removed once daily, which may result in the mechanical disruption of a newly epithelialized surface—this may account for the slower healing rates and increased pain when compared to skin substitutes that are applied and left in place for 3–5 days.      Overall, the studies reviewed here preclude drawing definitive conclusions because some of the studies were not well designed. The newer dressing products and/or skin substitutes offer some new options in the burn treatment armamentarium, which may advance therapy in terms of decreased healing times and reduced pain levels, but may not entirely replace well-documented products (eg, SSD) that have demonstrated efficacy controlling colonizing and infecting bacteria in burns.      A lack of rigorous multicenter, prospective clinical burn trials across product types and class leads to divergent, institutional-based methods of burn care that do not always agree on methods or philosophies, and creates individual practice patterns. ²⁸      Mandal²⁹ reports that Biobrane is one of the most widely used, modern biosynthetic dressings in the treatment of partial-thickness burns due to scalds in pediatric medicine. The authors concur with Mandal that further randomized controlled trials with long-term follow up are needed, since in at least one study¹⁵ no difference was found between Biobrane, a skin substitute, and Duoderm, an advanced dressing product. ²⁹ The authors agree with Cassidy et al¹⁵ in stating that with technological progression, it would be of great benefit to evaluate more advanced burn wound care products in direct comparison with the current standard of care.      Children have a low tolerance for pain, poor cooperation because of anticipated pain, and thus, the care of pediatric patients can be more challenging than for the same TBSA percentage in an adult patient. ^6,30 These pediatric studies should be approached with caution, and in an effort to prevent unnecessary risk, should be conducted initially in those pediatric patients with smaller body burns before being adapted as the standard of care in larger burns.

Conclusion

     Any addition to the already extensive body of burn care products is useful only if careful consideration is given to the ultimate cost of the product, patient comfort, ability to restore functionality, and appearance. Future products must closely imitate uninjured skin and lead to lower overall cost.      Myriad possibilities exist for healing products to incorporate single or combinations of growth factor gradients; it has been found that epidermal growth factor, transforming growth factor-beta, insulin-like growth factor, platelet-derived growth factors, and fibroblast growth factors, play a significant role in wound healing. ³¹

Acknowledgment

Thanks to Marie Phillips and Beth Mitchell for their editorial assistance.