Surface Area Partial-thickness Burn Research Articles

Abstract 128: A Translational Strategy Targeting Type I BMP Receptors to Prevent Heterotopic Ossification

PURPOSE: Trauma-induced heterotopic ossification (tHO) is the aberrant growth of ectopic bone in soft tissue, which develops in patients following severe musculoskeletal trauma. Much of HO literature focuses on a related pathology known as fibrodysplasia ossificans progressiva (FOP), which is caused by a hyperactivating mutation in the type I bone morphogenetic protein receptor (T1-BMPR) ACVR1 (ACVR1 R206H). Consequently, emphasis has been placed on developing inhibitors with improved specificity for ACVR1. However, patients who develop tHO do not harbor known ACVR1 mutations, and it is unclear whether emphasis on ACVR1-specific inhibition is beneficial for the treatment of tHO. Here investigate whether any single T1-BMPR is required for tHO, or whether these receptors perform overlapping roles during tHO development. We further evaluate the efficacy of the BMP ligand trap, Alk3-Fc, as a broad-spectrum inhibitor of T1-BMP receptors in the treatment and prevention tHO. METHODS: Wild-type, tamoxifen-inducible Acvr1 knockout (Acvr1 tmKO: Ub.creERT/Acvr1fl/fl), tamoxifen-inducible Bmpr1a knockout (Bmpr1a tmKO: Ub.creERT/Bmpr1afl/fl), and Bmpr1b knockout (Bmpr1b-/-) mice receivedhindlimb Achille’s tendon transection and dorsal 30% total body surface area partial-thickness burn. A second cohort of wild-type mice received daily i.p. injections of Alk3-fc (2 mg/kg) or saline for 6-weeks post-injury or during weeks 0–2 (inflammation), weeks2-4 (chondrogenesis), or weeks 4–6 (ossification) after injury. Mice receiving abbreviated treatment with Alk3-fc received intraperitoneal saline injections for the remainder of their 6-week treatment period. HO was quantified by microCT 9-weeks post-injury, and cartilage formation was assessed via pentachrome staining. RESULTS: Genetic loss of Acvr1 (p>0.05), Bmpr1a (p>0.05), or Bmpr1b (p>0.05) alone was unable to significantly or substantially reduce tHO after injury. However, genetic loss of both Acvr1 and Bmpr1a (Acvr1;Bmpr1a tmKO: Ub.creERT /Acvr1fl/fl;Bmpr1afl/fl) led to a substantial and significant reduction in tHO volume (16.7-fold decrease vs. wild-type; p<0.05). Based on these findings we studied the effect of Alk3-Fc, a BMP ligand trap which inhibits BMP receptor signaling capable of broadly T1-BMPR inhibition at different points during tHO development. Mice treated daily with Alk3-Fc for 6-weeks post-injury demonstrated a significant and substantial reduction in tHO volume (2.9-fold; p<0.05). Mice treated daily with Alk3-Fc from 0–2 weeks demonstrated similar reductions in tHO volume (2.3-fold; p<0.05). This was confirmed histologically, with diminished cartilage content in 6-week and 0–2 week treated groups when compared with controls. CONCLUSIONS: Here we demonstrate that although BMP signaling is required for tHO, no single T1-BMPR (ACVR1/ALK2, BMPR1a/ALK3, or BMPR1b/ALK6) alone is necessary for this disease. This suggests that, unlike with genetic forms of HO such as FOP, these receptors have functional redundancy in the setting of tHO. Based on these data we developed an approach based on broad-spectrum T1-BMPR blockade using the ligand trap Alk3-Fc to prevent tHO formation. Our findings suggest that Alk3-Fc treatment during the earliest period after injury is sufficient to block tHO and provides a translational approach to targeting this disease process.

Significant Chemical Burns Associated with Dermal Exposure to Laundry Pod Detergent

Concentrated laundry pods have been reported to cause significant clinical effects including oropharyngeal burns and respiratory distress requiring intubation. Dermal burns have been reported, but no incidents of serious isolated dermal injury have been published. We report a case of significant, isolated dermal injury as a result of dermal exposure to a concentrated laundry detergent pod. Total body surface area partial thickness burns in this case were estimated at approximately 2% with an additional 4-5% of total body surface area (TBSA) displaying superficial burns/chemical dermatitis. Health-care providers should be aware of this complication and should perform thorough dermal decontamination in the event of an exposure. Parents should be educated regarding the dangers associated with dermal exposure to laundry pod compounds and the need to secure these items away from children as well as proper decontamination techniques should an exposure occur.

Initial Assessment and Management of Thermal Burn Injuries in Children

1. Ramin Jamshidi, MD* 2. Thomas T. Sato, MD† 1. *The Pediatric Surgeons of Phoenix, Phoenix, AZ. 2. †Division of Pediatric Surgery, Children’s Specialty Group, Children’s Hospital of Wisconsin, and The Medical College of Wisconsin, Milwaukee, WI. Burns are a frequent cause of injury in children and adolescents. Clinicians should be familiar with initial assessment and management of burns and be capable of identifying burn injuries appropriate for referral to a regional burn center. After reading this article, readers should be able to: 1. List 3 types of burn injuries. 2. Describe the initial evaluation of a burned child in terms of burn depth, size, and associated injuries or medical conditions. 3. Describe appropriate burns for outpatient management. 4. Estimate initial fluid resuscitation requirements for the first 24 hours in children with large (>25% total body surface area) partial-thickness burns. 5. Describe 2 methods of dressing management for a 5% total body surface area partial-thickness burn. 6. Recognize indications for transfer of a burned child to a regional burn center. Death from fires and burn injuries is the third leading cause of fatal home injury and the third leading cause of unintentional death in children younger than 14 years in the United States. (1) In 2009, the Centers for Disease Control and Prevention estimated 437 deaths and 120,761 nonfatal burn injuries in children age 0 to 19 years. (2) Although hospitalization rates for children with burns appear to be decreasing in the past decade, annual cost estimates of approximately 10,000 inpatient hospitalizations for pediatric burn care exceeded $211 million in 2000. (3) Although it is difficult to estimate the global incidence rate, morbidity, and mortality of burn injuries, it is clear that burns are a major cause of injury in both developed and developing countries. (4) Burns are one of the most physiologically and psychologically stressful injuries that occur in children and adults. Given the …

Effectiveness of Biobrane for treatment of partial-thickness burns in children

Purpose Wound care for partial-thickness burns should alleviate pain, decrease hospital length of stay, and be readily applied to a variety of wounds. The effectiveness of Biobrane (UDL Laboratories, Rockford, IL) is compared with that of Beta Glucan Collagen (BGC; Brennan Medical, St. Paul, MN) in a retrospective cohort study. Methods A retrospective chart review of all children treated at a tertiary care pediatric hospital between 2003 and 2009 identified patients with partial-thickness burns treated with Biobrane. These patients were compared with historical controls treated with BGC. Results A total of 235 children between the ages of 4 weeks and 18 years with an average of 6.0% body surface area partial-thickness burns were treated with Biobrane. In a multivariate statistical analysis, patients treated with Biobrane healed significantly faster than those treated with BGC (Biobrane vs BGC: median, 9 vs 13 days; P = .019; hazard ratio, 1.68). In addition, patients who required inpatient treatment trended toward having shorter length of hospital stay in the Biobrane group (2.6 vs 4.1 days, P = .079). Conclusion Partial-thickness burn care consists of early debridement and application of a burn wound dressing. Biobrane dressings result in faster healing compared with BGC and may decrease hospital length of stay for patients requiring inpatient admission.

Local wound p38 MAPK inhibition attenuates burn-induced cardiac dysfunction

Topical inhibition of activated p38 MAPK within burn wounds attenuates the local and systemic inflammatory response. In this study, we investigated the effects of local activated p38 MAPK inhibition on burn-induced cardiac dysfunction. Using a standardized rat model of scald burn injury, rats were given a 30% total body surface area partial thickness burn or sham injury, and the wounds were treated with an activated p38 MAPK inhibitor (SB) or vehicle. Systemic blood pressure measurements were recorded in vivo followed by in vitro assessment of sarcomere contraction in single-cell suspensions of isolated cardiomyocytes. Systolic blood pressure or maximum left ventricular pressures in vivo and peak cardiomyocyte sarcomere contractility in vitro were significantly reduced after burn injury. These functional deficits were abolished 24 h after burn injury following local p38 MAPK inhibition. In vitro incubation of normal cardiomyocytes with homogenate from burned skin or burn serum resulted in a similar pattern of impaired cardiomyocyte contractility. These effects were reversed in normal cardiomyocytes exposed to burn skin homogenates treated topically with a p38 MAPK inhibitor. A Western blot analysis showed that cardiac p38 MAPK activation was not affected by dermal blockade of activated p38 MAPK, arguing against systemic absorption of the inhibitor and indicating the involvement of systemic cytokine signaling. Topical activated p38 MAPK inhibition within burned skin attenuates the release of proinflammatory mediators and prevents burn-induced cardiac dysfunction after thermal injury. These results support the inhibition of burn-wound inflammatory signaling as a new therapeutic approach to prevent potential postthermal injury multiorgan dysfunction syndrome.

TOPICAL p38MAPK INHIBITION REDUCES DERMAL INFLAMMATION AND EPITHELIAL APOPTOSIS IN BURN WOUNDS

Thermal injury induces dermal inflammatory and proapoptotic signaling. These phenomena extend burn wound size and trigger a systemic inflammatory response, factors known to adversely affect outcomes. p38MAPK is known to trigger inflammatory responses and induce epithelial proapoptotic genes. We hypothesize that topical p38MAPK inhibition will attenuate excessive inflammatory and apoptotic signaling and reduce dermal tissue loss. Rats were given a 30% total body surface area partial thickness burn or sham injury. Some of the animals were treated with a p38MAPK inhibitor or vehicle, which was applied directly to the wound. Dermal inflammation was investigated with enzyme-linked immunosorbent assay, reverse transcriptase polymerase chain reaction, myeloperoxidase assay, and Evans blue extravasation. Apoptotic changes were detected using terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and Caspase-3 in situ staining. Burn injury activated dermal p38MAPK and induced a significant rise in dermal IL-6, TNF-alpha, and IL-1beta expression. Neutrophil sequestration, microvascular damage, and hair follicle apoptosis were significantly elevated after injury. Topical p38MAPK inhibition significantly attenuated downstream dermal p38MAPK targets, proinflammatory cytokine expression, neutrophil sequestration, and microvascular injury. A significant reduction in hair follicle apoptosis was seen. This study demonstrates the attenuation of burn-induced cellular stress by topical application of p38MAPK inhibitors. Blunting early excessive inflammatory signaling may be an efficient strategy to improve patient outcomes after burn injury.

Protegrin-1 enhances bacterial killing in thermally injured skin.

Septic complications and the emergence of drug-resistant microbes represent serious risks to patients. Recently, naturally occurring peptides have been discovered that possess potent and broad-spectrum antimicrobial activity. Protegrin-1 is particularly attractive for clinical use in human wounds because, unlike defensins, protegrin-1 retains broad antimicrobial and antifungal activity at physiologic salt concentration and in the presence of serum. The objective of this study was to examine the efficacy of protegrin-1 in killing multiple drug-resistant microbes isolated from human burn patients. For thein vitroexperiment, bilayer radial diffusion was performed comparing standard antibiotics with protegrin-1 on multiple-drug-resistant microbial organisms isolated from infected burn wounds. In vivo, rats received a 20% total body surface area partial-thickness burn by immersion in 60 degrees C water for 20 secs followed by wound seeding with 106 colony forming units of Silvadene-resistant Pseudomonas aeruginosa. University of Michigan research laboratory. Adult, male Sprague-Dawley rats. Rats were randomized into three groups: those receiving synthetic protegrin-1, acetic acid (carrier), or gentamicin (positive control). Protegrin-1 was administered by topical application or intradermal injection. Wound tissues were harvested aseptically at different time points for quantitative bacterial counts. In vivo and in vitro experiments revealed rapid and significant decreases in bacterial counts for protegrin-1-treated groups compared with controls. This study shows that protegrin-1 potentially may be used as an alternative or adjunct therapy to standard agents used to treat wound infections.

Topical lidocaine in the treatment of partial-thickness burns.

The analgesic properties and systemic absorption of topical lidocaine in the treatment of partial-thickness burns were evaluated by applying a 5% lidocaine cream to the burn wound at a concentration of 1 mg/cm2. The plasma lidocaine level was measured in 24 patients 15, 30, 60, 120, and 240 minutes after application. Systemic analgesics were given 30 minutes before application of the lidocaine cream. The Visual Analog Scale was used to record pain intensity in 30 patients just before and 30 minutes after application of the lidocaine cream. The maximal area treated was 28% total body surface area partial-thickness burn with application of 4.5 gm of lidocaine, resulting in a plasma level of 5.8 micrograms/ml. The plasma lidocaine level was constant during the 4-hour experiment and was associated with a significant decrease in pain. No infectious, allergic, or cardiovascular complications were observed. Our results indicate that topical lidocaine cream offers significant pain relief of long duration without associated systemic side effects.