Pediatric Annals

ISSUES IN TOPICAL THERAPY FOR CHILDREN 

New Developments in Wound Care for Infants and Children

Isabel C Valencia, MD; Anna F Falabella, MD; Lawrence A Schachner, MD

Abstract

This article focuses on wound care practices and wound outcomes in certain situations where healing is of crucial importance in pediatrics.

WOUND HEALING IN THE FETUS

In contrast to children and adults, the embryo and the early-gestation fetus (during the second and early third trimesters) have the unique ability to heal a potentially scarring injury, without scar formation, by regenerating epithelial and mesenchymal tissues to restore perfect tissue architecture. The process of fetal wound healing without scar formation is not completely understood, but several mechanisms have been implicated. Resurfacing of the wound appears to occur by contraction of actin fibers rather than by keratinocyte migration across the wound (as in child and adult epidermal healing). Also, the relatively small amount of transforming growth factor ß-1 (a scar-promoting cytokine) and the abundance of metalloproteinases (which may prevent scar formation) in fetal wounds may be responsible for this phenomenon.

Once the biology of fetal wound healing is fully determined, it is hoped that wounds in children and adults will be able to be manipulated to improve repair and reduce scarring.1 Although it has been shown that there are both qualitative and quantitative differences in wound healing between young and old animals, few studies have specifically addressed this issue in humans.2

WOUND HEALING IN CHILDREN AND ADULTS

Wound healing is a process that involves a complex interaction among many cell types, their cytokines and mediators, and the extracellular matrix. Wound healing is divided into three phases - inflammatory, proliferative, and remodeling - that overlap in time. The inflammatory phase is characterized by platelet accumulation, hemostasis, and the formation of a provisional extracellular matrix for cell migration. The proliferative phase begins within hours of the initial injury and is marked by re-epithelialization, neovascularization, fibroplasia, and wound contraction. The remodeling phase takes place during a period of months and consists of reorganization of the extracellular matrix. Scars never attain the same strength as uninjured skin (a scar is only 70% as strong as normal skin).3,4

Clinically, wounds can be categorized as acute or chronic, based on the timeliness of healing. However, the exact duration of healing and the distinction between acute and chronic is arbitrary and often based on variables such as the site and cause of the wound and the age and physical condition of the patient.3

Transitional or overlapping cases are recognized clinically, and it is widely believed that these two disorders are related and may represent varying expressions of a single entity. Toxic epidermal necrolysis is an acute, life-threatening, systemic disease in which large areas of skin and mucous membranes are denuded of overlying epithelium. Children with toxic epidermal necrolysis die of sepsis, and the mortality rate has been reported to be as high as 70%.12,13

The optimal management for Stevens-Johnson syndrome and toxic epidermal necrolysis is controversial, particularly regarding the use of systemic corticosteroids and intravenous immunoglobulins.14 Multidisciplinary treatment with a strategy emphasizing biologic wound closure, intensive nutritional support, continuous ophthalmologic evaluation, and early detection and treatment of septic foci is necessary.

The aim of local wound care is prevention of wound desiccation and superinfection. Gentle cleansing with saline or Burow's solution (aluminum acetate) compresses, topical antibiotic ointments such as polymyxin-bacitracin or mupirocin, and sterile nonadherent dressings such as gauze impregnated with petrolatum are generally recommended. Silver nitrate 0.5% has also been a useful topical agent, but creams containing sulfa are not indicated because sulfonamides have been implicated in the etiology of these disorders and may cause further toxicity through percutaneous absorption. Hydrogel dressings can be applied over denuded areas.12 Porcine xenografts have been used successfully in children. Whether early debridement…

This article focuses on wound care practices and wound outcomes in certain situations where healing is of crucial importance in pediatrics.

WOUND HEALING IN THE FETUS

In contrast to children and adults, the embryo and the early-gestation fetus (during the second and early third trimesters) have the unique ability to heal a potentially scarring injury, without scar formation, by regenerating epithelial and mesenchymal tissues to restore perfect tissue architecture. The process of fetal wound healing without scar formation is not completely understood, but several mechanisms have been implicated. Resurfacing of the wound appears to occur by contraction of actin fibers rather than by keratinocyte migration across the wound (as in child and adult epidermal healing). Also, the relatively small amount of transforming growth factor ß-1 (a scar-promoting cytokine) and the abundance of metalloproteinases (which may prevent scar formation) in fetal wounds may be responsible for this phenomenon.

Once the biology of fetal wound healing is fully determined, it is hoped that wounds in children and adults will be able to be manipulated to improve repair and reduce scarring.1 Although it has been shown that there are both qualitative and quantitative differences in wound healing between young and old animals, few studies have specifically addressed this issue in humans.2

WOUND HEALING IN CHILDREN AND ADULTS

Wound healing is a process that involves a complex interaction among many cell types, their cytokines and mediators, and the extracellular matrix. Wound healing is divided into three phases - inflammatory, proliferative, and remodeling - that overlap in time. The inflammatory phase is characterized by platelet accumulation, hemostasis, and the formation of a provisional extracellular matrix for cell migration. The proliferative phase begins within hours of the initial injury and is marked by re-epithelialization, neovascularization, fibroplasia, and wound contraction. The remodeling phase takes place during a period of months and consists of reorganization of the extracellular matrix. Scars never attain the same strength as uninjured skin (a scar is only 70% as strong as normal skin).3,4

Clinically, wounds can be categorized as acute or chronic, based on the timeliness of healing. However, the exact duration of healing and the distinction between acute and chronic is arbitrary and often based on variables such as the site and cause of the wound and the age and physical condition of the patient.3

Figure 1. (A) Acute wound secondary to aplasia cutis congenita. A 1 -week-old infant with a large denuded area involving the circumference of the distal left leg and the dorsum of the foot. (B) The same patient 2 weeks after treatment with tissue-engineered skin. The acute wound was healed by graft take.

Figure 1. (A) Acute wound secondary to aplasia cutis congenita. A 1 -week-old infant with a large denuded area involving the circumference of the distal left leg and the dorsum of the foot. (B) The same patient 2 weeks after treatment with tissue-engineered skin. The acute wound was healed by graft take.

APLASIA CUTIS CONGENITA

Aplasia cutis congenita is a congenital absence of skin. It can occur anywhere on the body, but typically involves the scalp (more than 80% are there) at the midline vertex (Fig. 1A). Other developmental abnormalities and chromosome aberrations may coexist with aplasia cutis congentia. Most wounds caused by aplasia cutis congenita are small (< 2.5 cm), are superficial to the skull, and heal with local wound care.5 However, 20% of patients can have defects that are larger or that extend through the skull, exposing the underlying brain and superior sagittal sinus. If these are left untreated, an eschar quickly forms, predisposing the individual to sudden lethal hemorrhage and infection.

Several treatment modalities have been suggested for aplasia cutis congenita. Two options, conservative versus surgical management, are usually considered. The choice is influenced by the severity of the defect. Conservative management includes the application of dressings soaked with saline and antibiotics 2 to 3 times daily, as well as the use of systemic antibiotics when indicated. Surgical treatments include full-thickness and split-thickness grafts and scalp rotation flaps, with closure of bone defects for protection of the underlying soft tissues. Large but more superficial wounds can be treated with the application of tissue-engineered skin, which heals the wound either by graft take or by accelerating the healing process (Fig. IB). Most authors recommend early surgical intervention for extensive defects overlying the sagittal sinus before the most common major complication, hemorrhage, develops.5-7

EPIDERMOLYSIS BULLOSA

Epidermolysis bullosa is composed of a group of genetically determined skin fragility disorders characterized by blistering of the skin and mucosae following mild mechanical trauma. Most forms of inherited epidermolysis bullosa are characterized by a lifetime of blister and wound formation. Currently, wound treatment of epidermolysis bullosa is only supportive.8 For example, any dressing routine for the patient with epidermolysis bullosa must mirdmize further damage to the skin. Dressings should be soaked off of the wound and never forcibly removed. Only nonadherent dressings should be used, and they should be secured with soft, roller gauze bandages or elastic tube dressings. Large blisters should be opened with a sterile needle to avoid the accumulation of fluid and the build up of pressure, while keeping the blister roof in place. Rotating different topical antibiotics every 2 to 3 months is recommended because prolonged use of the same agent encourages the emergence of resistant organisms.9

What type of dressing works best? A hydrocolloid dressing was compared with paraffin gauze and a nonadherent dressing in a controlled clinical trial of 3 pediatric patients (44 wounds) with recessive dystrophic epidermolysis bullosa. Advantages of the hydrocolloid dressing over the paraffin gauze and nonadherent dressing included faster re-epithelialization, less scar tissue formation, decreased pain and discomfort, and less frequent dressing changes.10

Falabella et al. first described the use of tissueengineered skin for the treatment of a newborn with a subtype of epidermolysis bullosa (Fig. 2). Tissue-engineered skin is a bilayered equivalent of human skin derived from neonatal foreskin. It is approved by the Food and Drug Administration for the treatment of venous and diabetic foot ulcers. In this patient, tissue-engineered skin was applied to more severely eroded areas and kept in place with gauze impregnated with petrolatum, nonadherent pads, and elastic gauze bandages, without sutures or staples. The areas treated with this tissue-engineered skin healed faster than areas treated with conventional therapy (gauze impregnated with petrolatum).11

The same authors conducted an open-label, uncontrolled study of 15 patients with 78 acute and chronic wounds. In this group, the tissueengineered skin induced rapid healing, mostly by clinical graft take. It was not clinically rejected and was devoid of side effects. Patients and their families felt that tissue-engineered skin was more effective than conventional dressings for wounds caused by epidermolysis bullosa.8 Controlled studies, a larger patient population, and longer follow-up are necessary before widespread use of tissue-engineered skin can be advocated.

STEVENS-IOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS

Stevens-Johnson syndrome and toxic epidermal necrolysis are both severe bullous disorders of the skin, occurring as adverse reactions to a spectrum of drugs and infectious agents.

Figure 2. Acute wound secondary to epidermolysis bullosa. Painful, large, or slow-healing wounds due to epidermolysis bullosa can be treated with tissue-engineered skin to accelerate the healing process.

Figure 2. Acute wound secondary to epidermolysis bullosa. Painful, large, or slow-healing wounds due to epidermolysis bullosa can be treated with tissue-engineered skin to accelerate the healing process.

Transitional or overlapping cases are recognized clinically, and it is widely believed that these two disorders are related and may represent varying expressions of a single entity. Toxic epidermal necrolysis is an acute, life-threatening, systemic disease in which large areas of skin and mucous membranes are denuded of overlying epithelium. Children with toxic epidermal necrolysis die of sepsis, and the mortality rate has been reported to be as high as 70%.12,13

The optimal management for Stevens-Johnson syndrome and toxic epidermal necrolysis is controversial, particularly regarding the use of systemic corticosteroids and intravenous immunoglobulins.14 Multidisciplinary treatment with a strategy emphasizing biologic wound closure, intensive nutritional support, continuous ophthalmologic evaluation, and early detection and treatment of septic foci is necessary.

The aim of local wound care is prevention of wound desiccation and superinfection. Gentle cleansing with saline or Burow's solution (aluminum acetate) compresses, topical antibiotic ointments such as polymyxin-bacitracin or mupirocin, and sterile nonadherent dressings such as gauze impregnated with petrolatum are generally recommended. Silver nitrate 0.5% has also been a useful topical agent, but creams containing sulfa are not indicated because sulfonamides have been implicated in the etiology of these disorders and may cause further toxicity through percutaneous absorption. Hydrogel dressings can be applied over denuded areas.12 Porcine xenografts have been used successfully in children. Whether early debridement of blistered areas should be performed is still controversial, because the blister roof frequently provides excellent coverage during re-epithelialization. We believe that debridement should not be routinely performed in children. Tissue-engineered skin may turn out to have a potential role in the treatment of toxic epidermal necrolysis.

The extensive skin loss in toxic epidermal necrolysis has prompted an analogy to partialthickness thermal wounds, and several authors have advocated treatment of these patients in specialized burn units.15

ULCERATED HEMANGIOMAS

Hemangiomas are tumors composed of proliferated endothelial cells, and represent the most common soft tissue tumors of infancy. They are clinically heterogeneous, with their appearance dictated by the depth, location, and stage of evolution. Despite the benign course of most cutaneous hemangiomas, they may cause functional compromise or permanent disfigurement.

Ulceration is the most common complication of deep, rapidly proliferative hemangiomas. They can be excruciatingly painful, and carry a risk of infection, hemorrhage, loss of function, and scarring. Hemangiomas of the anogenital region are at high risk for ulceration and secondary infection.16 Uncomplicated, superficial ulcerations can be treated with saline compresses and topical antibiotic ointments. Zinc oxide paste or petrolatum ointment may be used as protective agents. Open-air therapy is effective for lesions in the diaper area. Leaving the diaper off for an hour or so after each change is also recommended.17 Flash-lamp pulsed dye laser treatment18 with or without nonadhesive hydrocolloid wound dressings may facilitate healing of ulcerated superficial hemangiomas.

When the ulcer is deep or comes in close contact with the anus or with the genitalia in girls, the hydrocolloid dressing cannot adhere in the midline and cannot protect the wound from being soiled. In these cases, it is useful to put a thick layer of hydrocolloid paste on the wound until sufficient re-epithelialization of the boundaries is attained, thereby allowing for subsequent placement of the hydrocolloid dressing. When the ulceration is deep or becomes infected, oral antibiotics may be helpful, sometimes in combination with intralesional corticosteroids, oral corticosteroids, or both.19 The role of interferon-a2 in the treatment of ulcerated hemangiomas is controversial.

LEG ULCERS IN SICKLE CELL DISEASE

Leg ulcers are the most common skin complication in sickle cell anemia. They usually occur in patients between the ages of 10 and 35 years. Sickle cell ulcers are frequently initiated by minor trauma, commonly develop secondary infections, and tend to be painful. Most ulcers occur in the ankle area. They vary in size, and typically appear punched out with raised margins and a deep base. Ulcers recur in 25% to 50% of patients, so patient education about the risks of this, methods of prevention, and the need for repeated therapy should be emphasized.20

Once the diagnosis is established, classic management of leg ulcers related to sickle cell anemia includes bed rest with leg elevation, gentle debridement, control of local edema, and treatment of infections. Saline wet-to-dry dressings applied 2 or 3 times a day or conservative surgical debridement are good initial therapy for most ulcers with necrotic debris. However, these procedures are painful and have the risk of removing viable, newly formed tissue. Nonpainful autolytic debridement can be effectively achieved using occlusive dressings such as hydrocolloids. Elastic or inelastic compression bandages should be initiated immediately, in combination with any debridement technique, to control edema in ambulatory patients. Topical treatment with antibiotics might be beneficial, but systemic antibiotics should be reserved for patients with evidence of cellulitis.20 The prevalence of infections with Staphylococcus aureus and Pseudomonas aeruginosa in the patient population should be used to aid in the selection of antibiotics.21

Skin grafts are advocated for ulcers that are resistant to more conservative therapy.22 Several treatment modalities have been used for sickle cell ulcers with variable success, including blood transfusions, oral supplementation with zinc sulfate,23 hydroxyurea alone24,25 or in combination with erythropoietin,26 pentoxifylline,27 hyperbaric oxygen,28 and a synthetic topical extracellular matrix.29 Large, placebo-controlled trials are needed to further evaluate the role of these approaches in the management of sickle cell ulcers.

TRAUMATIC WOUNDS

Lacerations are common in children and represent 30% to 40% of all pediatric injuries seen in emergency departments.30 The cyanoacrylatebased adhesives are topical glues that bond to the outermost layer of skin to form a seal over the apposed edges of a laceration. These adhesives allow normal wound healing. Local anesthesia is not necessary for their application and they can be used for most children.

In a recent study, 83 pediatric patients presenting to an emergency department for laceration repair were randomized to receive either the tissue-adhesive 2-octy ley anoacry late (2-OCA) or nonabsorbable sutures or staples. The length of time for laceration repair was decreased and parents' assessment of the pain felt by their children was less in the group treated with the tissue adhesive. Cosmesis scores were slightly lower in the group treated with the tissue adhesive, although differences were not statistically or clinically significant. Complications included one wound infection in the group treated with 2-OCA. This was treated successfully with antibiotics but developed a hypertrophic scar.30,31 The authors concluded that 2-OCA is an acceptable alternative to conventional wound repair and has comparable cosmetic outcomes.

Puncture wounds account for 3% to 5% of all traumatic injuries presenting to pediatric emergency departments.32 They are usually innocuous and medical care is seldom required. Most puncture wounds involve the plantar surface of the foot and are caused by nails, although they can be located at other sites and caused by wood, metal, plastic, or glass. The history should help determine the time and mechanism of injury, the degree of contamination with foreign matter, and whether the penetrating object could have broken off in the wound. If there is any doubt about the possibility of a retained foreign body, diagnostic imaging should be requested. Erythema, swelling, or persistent pain in the area suggests a wound infection, with or without a foreign body. Determination of immunization status and appropriate immunization for patients with wounds that are susceptible to tetanus is necessary.

If the dermis of the puncture site is exposed, the area and surrounding skin should be irrigated superficially with saline. High-pressure irrigation of deep wounds should be avoided because this may cause tissue damage and push bacteria or foreign bodies deeper into the wound. Similarly, aggressive surgical debridement is not indicated. Uncomplicated wounds can be managed with rest, elevation of the foot, and intermittent soaking in warm water. For children who have a delayed presentation, or for those with signs of infection, the possibility of retained foreign material should be considered. Appropriate imaging studies should be ordered and oral antibiotics should be started.32

SKIN NECROSIS FROM EXTRAVASATION OF INTRAVENOUS FLUIDS

Peripheral intravenous fluid therapy is usually innocuous, but serious consequences can result when gross extravasations occur. Children are at particular risk for skin necrosis and account for most reported cases. Extravasation of fluids may cause full-thickness skin loss above the affected area. Where there is little subcutaneous tissue, the agent may also precipitate scarring around tendons, nerves, and joints. The volume and toxicity of the fluid, the site of extravasation, and the general nutrition of the patient can all influence the severity of injury.33 Intravenously induced skin injury can be produced by several different chemicals. These include nutrients, electrolytes (calcium, potassium, sodium salts, and bicarbonate), chemotherapeutic agents, and vasoconstrictors.34 Damage may be due to a direct toxic effect, pressure of the accumulated drug causing collapse of small vessels, changes in the osmotic equilibrium between the extracellular and the intracellular fluids, adverse changes in pH, and induced vasospasm.33

The most important way to avoid necrosis secondary to intravenous therapy is to prevent extravasation of fluids. Particular care should be taken when administering substances known to have a high incidence of skin necrosis. Selecting larger veins and avoiding sites with little subcutaneous tissue (eg, the dorsum of the hand, sites over joints, and bony prominences) is recommended.34 When extravasation occurs, there is no certain way of predicting which cases will result in significant tissue damage or whether the onset of damage will be delayed.33

Early recognition and proper treatment are important to rninimize the morbidity of this complication. Stopping the infusion is mandatory. Different treatment modalities from simple observation35 to aggressive early surgical debridement and skin grafting36 have been proposed. Some modalities include the use of specific antidotes, hyaluronidase to promote drug absorption,37 injections of saline to dilute the drug,38 or ice or steroid creams to minimize the inflammatory reaction.39 Early liposuction or saline flush out have also been recommended as alternatives to surgical excision because they remove extravasated materials while conserving the overlying skin.33

BURNS

Scalding by hot water or other liquids is one of the most common causes of pediatric burns. Superficial partial-thickness burns that involve less than 20% of the body surface can typically be treated with dressing changes twice a day. The burns are cleansed, a topical antibiotic ointment is applied, and the wounds are wrapped with sterile nonadherent gauze.40 The topical antibiotic ointment silver sulfadiazine is used by most burn centers in the United States to control wound infections. The cleansing of the wound with removal of the ointment, adhesion of the gauze or cotton dressings, or debridement of the eschar can be painful.

Because most children have a low tolerance for discomfort, a high anticipation of pain and poor cooperation are common.40,41 In addition, topical antibiotics may cause sensitization of the wound, and can promote the formation of an eschar.40 In a prospective, randomized clinical trial, 63 children with partial-thickness scald burns were assigned treatment with either a silicone mesh dressing or silver sulfadiazine. The authors found that burns treated with the silicone mesh dressing exhibited less eschar formation. Children also experienced less pain at dressing changes, and had significantly lower mean daily hospital charges. No significant difference in the rate of wound infection was noted.40

Similar results were obtained when comparing a bilaminar temporary skin substitute with silver sulfadiazine in the treatment of 20 pediatric second-degree burns. Pain, requirements for pain medication, duration of wound healing, and length of hospital stay were significantly reduced in the group treated with the bilaminar temporary skin substitute.42 In this study, no patient had an infection. However, infection rates from 5% to 22.6% have been reported in other studies using a bilaminar temporary skin substitute.41 Wounds older than 24 hours and deeper wounds are at risk for infection and may not be suitable for treatment with a bilaminar temporary skin substitute.41,42

KELOIDS AND HYPERTROPHIC SCARS

Keloids and hypertrophic scars may result from both major and minor trauma. They rarely occur in infants, and are more common in black children. The most prevalent sites for keloid formation in children and adults are the earlobes, sternum, back, shoulders, and upper arms. Varicella lesions may also heal with hypertrophic scars.

Currently, three methods are acceptable for the treatment of keloids and hypertrophic scars: intralesional steroid injections, silicone gel sheeting, and surgical excision. Silicone gel sheeting is the most accepted in the treatment of children. It is noninvasive, painless, easy to apply, and almost free of side effects. Flattening of the scar is seen after continuous use for several weeks. The mechanism of action of silicone gel sheeting remains speculative.43,44

Several studies have shown an inhibitory effect of interferons on dermal fibroblast growth, collagen production, or both with the formation of these scars. Intralesional injection of recombinant human interferon-a-2b or interferon-γ in keloids has given promising, albeit variable, results.45,46 Further controlled studies are required before recommending these agents for the treatment of keloids in the pediatric population.

TISSUE EXPANSION AS A SURGICAL ALTERNATIVE IN CHILDREN

Tissue expansion of regional skin flaps is a surgical alternative for reconstruction in pediatric cases when there is insufficient regional tissue available to treat significant deformities. Examples include congenital melanocytic nevi, sebaceous nevi, hemangiomas, burn scars, and large defects of aplasia cutis congenita. Cutaneous surgical reconstruction in the head and neck may be difficult in children due to insufficient elasticity or subsequent scar spread. Also, adjacent tissues in children are not rotated or advanced as easily as in older individuals.47 Although the effect of tissue expansion on developmental structures is not completely known, clinical experience suggests that the careful use of tissue expansion under the scalp of neonates and infants is safe.48

Although tissue expansion is a good alternative for some children, procedure tolerance, risks and complications, insufficient adjacent skin of like quality, and issues about the durability of the reconstruction and its ability to grow along with the child are some of the particular issues in these patients. Expanded donor site (from the groin and lower abdomen) full-thickness skin grafts maintain all of the characteristics of non-expanded full-thickness skin flaps and offer a good reconstructive alternative.49

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