The Historical Evolvement of Movement and Exercise Training in Patients with Severe Burns and Their Potential Effects on Grafts, Scars, and Function.

Exercise training for burn patients has become a major part of rehabilitation programs within the last decades. One of the main reasons for prolonged and long-term increased morbidity and mortality in this population is a persistent catabolic state with subsequent loss of lean body mass (LBM). A combination of resistance and aerobic exercises as well as stretching has shown to improve physical function by enhancing cardiopulmonary fitness, LBM, and strength and thus leading to ameliorated long-term outcomes of patients recovering from burns. In this literature review, we show an outline of the implementation of exercise training over the last decades into standardized care for patients with burns.

Key Exercise Concepts in the Rehabilitation from Severe Burns.

This article presents information on the benefits of exercise in counteracting the detrimental effects of bed rest, and/or severe burns. Exercise is key for maintaining physical function, lean body mass, metabolic recovery, and psychosocial health after major burn injuries. The details of an exercise training program conducted in severely burned persons are presented, as well as information on the importance of proper regulation of body temperature during exercise or physical activity. The sections on exercise and thermoregulation are followed by a section on the role of exercise in scarring and contractures. Finally, gaps in the current knowledge of exercise, thermoregulation, and contractures are presented.

Perceptions of patient disease burden and management approaches in systemic mastocytosis: Results of the TouchStone Healthcare Provider Survey.

BACKGROUND: Systemic mastocytosis (SM) is a rare clonal neoplasm driven by the KIT D816V mutation and has a broad range of debilitating symptoms. In this study, the authors evaluated SM disease perceptions and management strategies among US health care providers (HCPs). METHODS: Hematologist/oncologist (H/O) HCPs and allergist/immunologist (A/I) HCPs who were treating four or more patients with SM completed an online, 51-item TouchStone HCP Survey, which queried provider characteristics, perceptions of disease burden, and current management. Descriptive analyses by specialty and SM subtype were performed. RESULTS: Of 304 HCPs contacted, 111 (37%) met eligibility criteria, including 51% A/I specialists and 49% H/O specialists. On average, the HCPs had 14 years of practice experience and cared for 20 patients with SM. A/I HCPs saw more patients with nonadvanced SM (78%) compared with H/O HCPs, who saw similar proportions of patients with nonadvanced SM (54%) and advanced SM (46%). HCPs reported testing 75% of patients for the KIT D816V mutation and found an estimated prevalence of 47%. On average, HCPs estimated 8 months between symptom onset and SM diagnosis. HCPs reported that 62% of patients with indolent SM felt depressed or discouraged because of symptoms. In terms of treatment goals for SM, both types of specialists prioritized symptom improvement for nonadvanced SM and improved survival for advanced SM while also prioritizing improving patient quality of life. CONCLUSIONS: Both A/I and H/O specialists highlighted unmet needs for patients with SM. The HCPs surveyed reported a lower rate of KIT D816V mutations and a perceived shorter time between symptom onset and SM diagnosis compared with published estimates. LAY SUMMARY: Specialists treating systemic mastocytosis (SM) completed a 51-item questionnaire about their clinical practices and perceptions of disease impact. The study included 111 hematology, oncology, allergy, and immunology physicians. Physicians reported that most patients had nonadvanced disease, yet SM symptoms significantly disrupted their patients' lives. Physicians estimated that SM is diagnosed within months of symptom onset, in contrast with published reports of years' long delays reported by patients with SM. This study identified unmet needs that can inform educational and patient management priorities in this rare disease.

Patient-reported outcomes among patients with systemic mastocytosis in routine clinical practice: Results of the TouchStone SM Patient Survey.

BACKGROUND: Systemic mastocytosis (SM) is a rare clonal neoplasm driven by KIT D816V and other mutations. Data were collected from the patient perspective on disease burden and included an SM-specific symptom assessment tool. METHODS: US adults aged 18 years and older with a self-reported SM diagnosis completed an online TouchStone SM Patient Survey of 100 items, including the 12-item Short-Form Health Survey, the Indolent Systemic Mastocytosis Symptom Assessment Form, and the Work Productivity and Activity Impairment Questionnaire, as well as questions about SM diagnosis, the impact of SM on daily activities, work impairment, and health care use. The results were analyzed using descriptive statistics. RESULTS: Fifty-six individuals completed the survey (89% women; median age, 48 years; mean time since diagnosis, 6.7 years), reporting indolent SM (66%), aggressive SM (9%), smoldering SM (5%), and unknown SM subtype (18%). Over a 1-year recall, respondents reported seeking emergency care for anaphylaxis (30%) and taking three or more prescription medications (52%) for SM. Over one half of patients (54%) reduced their work hours because of SM, and 64% avoided leaving home because of symptoms. A majority of respondents (93%) had experienced ≥10 SM-related symptoms, noting that the most bothersome were anaphylactic episodes (18%), abdominal/stomach pain (16%), diarrhea/loose stools (13%), and fatigue (11%). Whereas an Indolent Systemic Mastocytosis Symptom Assessment Form-derived total symptom score of 28 is used to indicate moderate-to-severe symptoms, the mean total symptom score was 52.7. Mental and physical component summary scores from the 12-item Short-Form Health Survey were below population norms. CONCLUSIONS: Patients who were surveyed reported substantial symptom burden and unmet needs because of SM, as evidenced by seeking emergency care and reporting bothersome symptoms, poor quality of life, and reduced work hours and productivity. LAY SUMMARY: The objective of this research was to understand the burden and unmet needs in the rare disease of systemic mastocytosis (SM) to guide future care. Fifty-six patients completed an online survey containing questions about their diagnosis, medications, health care use, quality of life, and SM symptoms. The results demonstrated that SM is associated with severe and burdensome symptoms, anaphylactic events, emergency department visits, use of multiple medications, reduced ability to work, and poor physical and psychological quality of life. These findings suggest the need for future advances to address unmet needs in patients affected by SM.

Mast Cell Diseases in Practice and Research: Issues and Perspectives Raised by Patients and Their Recommendations to the Scientific Community and Beyond.

BACKGROUND: Since 2010, patients and physicians have collaborated to understand unmet needs of patients with mast cell diseases, incorporating mastocytosis and mast cell activation disorders, which include mast cell activation syndromes. OBJECTIVE: This Open Innovation in Science project aims to expand understanding of the needs of patients affected by mast cell diseases, and encourage global communication among patient advocacy groups, physicians, researchers, industry, and government. A major aim is to support the scientific community's efforts to improve diagnosis, management, therapy, and patients' quality of life by addressing unmet needs. METHODS: In collaboration with mast cell disease specialists, 13 patient advocacy groups from 12 countries and regions developed lists of top patient needs. A core team of leaders from patient advocacy groups collected and analyzed the data and proposed possible actions to address patient needs. RESULTS: Findings identified similarities and differences among participating countries in unmet needs between patients with mastocytosis and those with mast cell activation syndromes. Issues emphasized struggles relating to the nature and rarity of mast cell diseases, their impact on quality of life, the diagnostic process, access to appropriate care, more effective treatment, and the need for research. CONCLUSIONS: Solutions vary across countries because situations differ, in particular regarding the existence of and access to centers of excellence and reference centers. Multifaceted mast cell activation syndrome barriers necessitate innovative approaches to improve access to appropriate care. The outcomes of this project should greatly support scientists and clinicians in their efforts to improve diagnosis, management, and treatment of patients with mastocytosis and mast cell activation disorders.

Metal chelation reduces skin epithelial inflammation and rescues epithelial cells from toxicity due to thermal injury in a rat model.

BACKGROUND: One of the most pervasive complications of burn injury is wound progression, characterized by continuous tissue destruction in untreated wounds, which leads to wound infection, inflammation, oxidative stress and excessive scar formation. We determined whether additional tissue destruction could be attenuated with Livionex formulation (LF) lotion, which contains a metal-chelating agent and reduces inflammation in burn wounds. METHODS: We subjected male Sprague Dawley rats to a 2% total body surface area (TBSA) burn using a brass comb model and topically applied LF lotion (containing ethylenediaminetetraacetic acid and methyl sulfonyl methane) to the affected area every 8 hours over 3 days. Inflammatory cytokine levels, cell apoptosis and wound healing were compared in LF lotion-treated and untreated rats. Statistical analysis was performed using a one-way analysis of variance in conjunction with Tukey's post-hoc test. RESULTS: Serum inflammatory cytokines were not detectable after 3 days, suggesting that small burn wounds induce only an immediate, localized inflammatory response. Microscopy revealed that LF lotion improved burn site pathology. Deoxynucleotidyl transferase biotin-d-UTP nick-end labeling staining showed reduced cell death in the LF-treated samples. LF lotion prevented the spread of tissue damage, as seen by increased amounts of Ki-67-positive nuclei in the adjacent epidermis and hair follicles. Tumor necrosis factor-alpha, interleukin-6 and inducible nitric oxide synthase levels in LF-treated skin sections from burned rats were comparable to the levels observed in unburned control sections, indicating that LF lotion reduces inflammation in and around the burn site. CONCLUSIONS: These results establish LF lotion as a therapeutic agent for reducing inflammatory stress, cell death and tissue destruction when applied immediately after a burn injury. Further studies of LF lotion on large TBSA burns will determine its efficacy as an emergency treatment for reducing long-term morbidity and scarring.

Thermal injury initiates pervasive fibrogenesis in skeletal muscle.

Severe burn injury induces a myriad of deleterious effects to skeletal muscle, resulting in impaired function and delayed recovery. Following burn, catabolic signaling and myofiber atrophy are key fiber-intrinsic determinants of weakness; less well understood are alterations in the interstitial environment surrounding myofibers. Muscle quality, specifically alterations in the extracellular matrix (ECM), modulates force transmission and strength. We sought to determine the impact of severe thermal injury on adaptation to the muscle ECM and quantify muscle fibrotic burden. After a 30% total body surface area dorsal burn, spinotrapezius muscle was harvested from mice at 7 (7d, n = 5), 14 (14d, n = 4), and 21 days (21d, n = 4), and a sham control group was also examined (Sham, n = 4). Expression of transforming growth factor-ß (TGFß), myostatin, and downstream effectors and proteases involved in fibrosis and collagen remodeling were measured by immunoblotting, and immunohistochemical and biochemical analyses assessed fibrogenic cell abundance and collagen deposition. Myostatin signaling increased progressively through 21 days postburn alongside fibrogenic/adipogenic progenitor cell expansion, with abundance peaking at 14 days postburn. Postburn, elevated expression of tissue inhibitor of matrix metalloproteinase 1 supported collagen remodeling resulting in a net accumulation of muscle collagen content. Collagen accumulation peaked at 14 days postburn but remained elevated through 21 days postburn, demonstrating minimal resolution of burn-induced fibrosis. These findings highlight a progressive upregulation of fibrogenic processes following burn injury, eliciting a fibrotic muscle phenotype that hinders regenerative capacity and is not resolved with 21 days of recovery.

Adipose-derived stem cells improve grafted burn wound healing by promoting wound bed blood flow.

BACKGROUND: Researchers have explored the use of adipose-derived stem cells (ASCs) as a cell-based therapy to cover wounds in burn patients; however, underlying mechanistic aspects are not completely understood. We hypothesized that ASCs would improve post-burn wound healing after eschar excision and grafting by increasing wound blood flow via induction of angiogenesis-related pathways. METHODS: To test the hypothesis, we used an ovine burn model. A 5 cm2 full thickness burn wound was induced on each side of the dorsum. After 24 hours, the burned skin was excised and a 2 cm2 patch of autologous donor skin was grafted. The wound sites were randomly allocated to either topical application of 7 million allogeneic ASCs or placebo treatment (phosphate-buffered saline [PBS]). Effects of ASCs culture media was also compared to those of PBS. Wound healing was assessed at one and two weeks following the application of ASCs. Allogeneic ASCs were isolated, cultured and characterized from non-injured healthy sheep. The identity of the ASCs was confirmed by flow cytometry analysis, differentiation into multiple lineages and gene expression via real-time polymerase chain reaction. Wound blood flow, epithelialization, graft size and take and the expression of vascular endothelial growth factor (VEGF) were determined via enzyme-linked immunosorbent assay and Western blot. RESULTS: Treatment with ASCs accelerated the patch graft growth compared to the control (p < 0.05). Topical application of ASCs significantly increased wound blood flow (p < 0.05). Expression of VEGF was significantly higher in the wounds treated with ASCs compared to control (p < 0.05). CONCLUSIONS: ASCs accelerated grafted skin growth possibly by increasing the blood flow via angiogenesis induced by a VEGF-dependent pathway.

Standards in Biologic Lesions: Cutaneous Thermal Injury and Inhalation Injury Working Group 2018 Meeting Proceedings.

On August 27 and 28, 2018, the American Burn Association, in conjunction with Underwriters Laboratories, convened a group of experts on burn and inhalation injury in Washington, DC. The goal of the meeting was to identify and discuss the existing knowledge, data, and modeling gaps related to understanding cutaneous thermal injury and inhalation injury due to exposure from a fire environment, and in addition, address two more areas proposed by the American Burn Association Research Committee that are critical to burn care but may have current translational research gaps (inflammatory response and hypermetabolic response). Representatives from the Underwriters Laboratories Firefighter Safety Research Institute and the Bureau of Alcohol, Tobacco, Firearms and Explosives Fire Research Laboratory presented the state of the science in their fields, highlighting areas that required further investigation and guidance from the burn community. Four areas were discussed by the full 24 participant group and in smaller groups: Basic and Translational Understanding of Inhalation Injury, Thermal Contact and Resulting Injury, Systemic Inflammatory Response and Resuscitation, and Hypermetabolic Response and Healing. A primary finding was the need for validating historic models to develop a set of reliable data on contact time and temperature and resulting injury. The working groups identified common areas of focus across each subtopic, including gaining an understanding of individual response to injury that would allow for precision medicine approaches. Predisposed phenotype in response to insult, the effects of age and sex, and the role of microbiomes could all be studied by employing multi-omic (systems biology) approaches.

Early reduced bone formation following burn injury in rats is not inversely related to marrow adiposity.

OBJECTIVES: The objective of the study was to determine whether postburn reduction of bone formation occurred earlier than 2-3 weeks after burn injury and whether that reduction was inversely related to marrow adiposity. METHODS: Using a rat model of burn injury with sacrifice at 3 days postburn, we measured serum osteocalcin, a biomarker of bone formation, as well as a regulator of glucose metabolism, and counted tibial marrow adipocytes. RESULTS: Serum osteocalcin was reduced as early as 3 days postburn, coinciding with a trend toward decline in marrow adipocyte number rather than demonstrating an inverse relationship with adipocyte count. CONCLUSIONS: Factors that may be responsible for the dissociation include lack of circulating sclerostin, previously reported, increased energy demands following burn injury, increased sympathetic tone and perhaps oxidative stress. The relationship between bone formation and marrow adiposity is complex and subject to a variety of influences.

Effect of N-(2-aminoethyl) ethanolamine on hypertrophic scarring changes in vitro: Finding novel anti-fibrotic therapies.

Hypertrophic scars (HS) limit movement, decrease quality of life, and remain a major impediment to rehabilitation from burns. However, no effective pharmacologic therapies for HS exist. Here we tested the in vitro anti-fibrotic effects of the novel chemical N-(2-aminoethyl) ethanolamine (AEEA) at non-toxic concentrations. Scanning electron microscopy showed that AEEA markedly altered the structure of the extracellular matrix (ECM) produced by primary dermal fibroblasts isolated from a HS of a burn patient (HTS). Compression atomic force microscopy revealed that AEEA stiffened the 3D nanostructure of ECM formed by HTS fibroblasts. Western blot analysis in three separate types of primary human dermal fibroblasts (including HTS) showed that AEEA exposure increased the extractability of type I collagen in a dose- and time-dependent fashion, while not increasing collagen synthesis. A comparison of the electrophoretic behavior of the same set of samples under native and denaturing conditions suggested that AEEA alters the 3D structure of type I collagen. The antagonization effect of AEEA to TGF-ß1 on ECM formation was also observed. Furthermore, analyses of the anti-fibrotic effects of analogs of AEEA (with modified pharmacophores) suggest the existence of a chemical structure-activity relationship. Thus, AEEA and its analogs may inhibit HS development; further study and optimization of analogs may be a promising strategy for the discovery for effective HS therapies.

Calpain-mediated cleavage of p53 in human cytomegalovirus-infected lung fibroblasts.

Endogenous fragments of p53 protein were identified in human cytomegalovirus (HCMV)-infected human lung fibroblasts, particularly a 44-kDa N-terminal fragment [hereafter referred to as p53(ΔCp44)], generated via calpain cleavage. The fragment abundance increased in a biphasic manner, peaking at 6-9 hours and 48 hours post infection. Treatment of LU cells with calpain inhibitors eliminated most detectable p53 fragments. In cell-free experiments, exogenous m-calpain cleavage generated p53(ΔCp44). Attempts to preserve p53 proteins by treating cells with the calpain inhibitor E64d for 6 hours before harvesting increased the sensitivity of p53 to calpain cleavage. p53 in mock-infected cell lysates was much more sensitive to cleavage and degradation by exogenous calpain than that in HCMV-infected cells. The proteasome inhibitor MG132 stabilized p53(ΔCp44), particularly in mock-infected cells. p53(ΔCp44) appeared to be tightly associated with a chromatin-rich fraction. The abundance of p53ß was unchanged over a 96-h time course and very similar in mock- and HCMV-infected cells, making it unlikely that p53(ΔCp44) was p53ß. The biological activities of this and other fragments lacking C-terminal sequences are unknown, but deserve further investigation, given the association of p53(ΔCp44) with the chromatin-rich (or buffer C insoluble) fraction in HCMV-infected cells.

Buprenorphine-Sustained Release Alters Hemodynamic Parameters in a Rat Burn Model.

BACKGROUND: It has been previously shown that anesthesia and analgesia can affect outcomes in the rat burn model and that buprenorphine alleviated pain without drastically altering the outcomes of interest. Recently, the use of a sustained release (SR) formulation of buprenorphine has been promoted over conventional buprenorphine. In this study, we assessed whether buprenorphine-SR altered hemodynamic parameters in our rat model of severe burn injury. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were randomized to receive either conventional buprenorphine (0.05 mg/kg) or buprenorphine-SR (1 mg/kg). Buprenorphine-SR was administered 24 h before the experiment. Buprenorphine was administered on the day of experiment. These groups were further randomized to control or scald burn (60% of total body surface area). Systolic and diastolic blood pressure (SBP, DBP) and heart rate (HR) were measured using a noninvasive blood pressure system before receiving analgesia and after 72 h. RESULTS: As expected, HR was significantly higher after burn injury regardless of analgesic (P <0.0001). Both SBP and DBP were significantly decreased in burned animals receiving conventional buprenorphine (P < 0.0001), but neither was altered in the buprenorphine-SR-treated burned animals. However, SBP, DBP, and HR were significantly increased after 72 h in control animals receiving buprenorphine-SR (P < 0.0001). CONCLUSIONS: These data indicate that buprenorphine-SR alters the hemodynamic response to injury and may not be an appropriate choice for a model of severe burn injury. If this analgesic is used, investigators must cautiously form conclusions, especially in experimental conditions that would be expected to alter cardiac hemodynamics.

Effects of a restrictive blood transfusion protocol on acute pediatric burn care: Transfusion threshold in pediatric burns.

BACKGROUND: Blood transfusion is costly and associated with various medical risks. Studies in critically ill adult and pediatric patients suggest that implementation of more restrictive transfusion protocols based on lower threshold hemoglobin concentrations can be medically and economically advantageous. The purpose of this study was to evaluate the implications of a hemoglobin threshold change in pediatric burn patients. METHODS: We implemented a change in hemoglobin threshold from 10 g/dL to 7 g/dL and compared data from patients before and after this protocol change in a retrospective review. Primary endpoints were hemoglobin concentration at baseline, before transfusion, and after transfusion; amount of blood product administered; and mortality. Secondary endpoints were the incidence of sepsis based on the American Burn Association physiological criteria for sepsis and mean number of septic days per patient. All endpoint analyses were adjusted for relevant clinical covariates via generalized additive models or Cox proportional hazard model. Statistical significance was accepted at p less than 0.05. RESULTS: Patient characteristics and baseline hemoglobin concentrations (pre, 13.5 g/dL; post, 13.3 g/dL; p > 0.05) were comparable between groups. The group transfused based on the more restrictive hemoglobin threshold had lower hemoglobin concentrations before and after transfusion throughout acute hospitalization, received lower volumes of blood during operations (pre, 1012 mL; post, 824 mL; p < 0.001) and on days without surgical procedures (pre, 602 mL; post, 353 mL; p < 0.001), and had a lower mortality (pre, 8.0%; post, 3.9%; mortality hazard decline, 0.55 [45%]; p < 0.05). Both groups had a comparable incidence of physiological sepsis, though the more restrictive threshold group had a lower number of sepsis days per patient. CONCLUSION: More restrictive transfusion protocols are safe and efficacious in pediatric burn patients. The associated reduction of transfused blood may lessen medical risks of blood transfusion and lower economic burden. LEVEL OF EVIDENCE: Therapeutic, level IV.

Correlation between invasive and noninvasive blood pressure measurements in severely burned children.

INTRODUCTION: Accurate blood pressure monitoring is essential for burn management, with the intra-arterial line method being the gold standard. Here we evaluated agreement between cuff and intra-arterial line methods. METHODS: Data from burned children admitted from 1997 to 2016 were retrospectively reviewed. Simultaneously collected intra-arterial and cuff measurements were cross-matched and linear regression performed to assess agreement for systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP). RESULTS: We identified 9969 matches for SBP, DBP, and MAP in 872 patients (579 male) aged 8±5years with burns covering 52±20% of the total body surface area and a hospitalization lasting 33±31 days. Intra-arterial lines had a complication rate of 1%. The mean bias (95% CI) between methods was 1.3 (0.5, 2.1) mm Hg for SBP, -6.4 (-7.0, -5.7) mmHg for DBP, and -5.8 (-6.4, -5.3) mmHg for MAP. The standard deviation of the bias (95% limit of agreement) was 12.1 (-22.5, 25.1) mmHg for SBP, 9.9 (-25.8, 13.0) mmHg for DBP, and 8.7 (-22.8, 11.1) mmHg for MAP. CONCLUSIONS: Cuff measurements vary widely from those of intra-arterial lines, which have a low complication rate. Intra-arterial lines are advisable when tight control of the hemodynamic response is essential.

Reduced Postburn Hypertrophic Scarring and Improved Physical Recovery With Yearlong Administration of Oxandrolone and Propranolol.

BACKGROUND: Massive burns induce a hypermetabolic response that leads to total body wasting and impaired physical and psychosocial recovery. The administration of propranolol or oxandrolone positively affects postburn metabolism and growth. The combined administration of oxandrolone and propranolol (OxProp) for 1 year restores growth in children with large burns. Here, we investigated whether the combined administration of OxProp for 1 year would reduce scarring and improve quality of life compared with control. STUDY DESIGN: Children with large burns (n = 480) were enrolled into this institutional review board-approved study; patients were randomized to control (n = 226) or administration of OxProp (n = 126) for 1 year postburn. Assessments were conducted at discharge and 6, 12, and 24 months postburn. Scar biopsies were obtained for histology. Physical scar assessments and patient reported outcome measures of physical and psychosocial function were obtained. RESULTS: Reductions in cellularity, vascular structures, inflammation, and abnormal collagen (P < 0.05) occurred in OxProp-treated scars. With OxProp, scar severity was attenuated and pliability increased (both P < 0.05). Analyses of patient-reported outcomes showed improved general and emotional health within the OxProp-treated group (P < 0.05). CONCLUSIONS: Here, we have shown improvements in objective and subjective measures of scarring and an increase in overall patient-reported physical function. The combined administration of OxProp for up to a year after burn injury should be considered for the reduction of postburn scarring and improvement of long-term psychosocial outcomes in children with massive burns.

Contemporary Burn Survival.

BACKGROUND: The standard of burn treatment today reflects major advances. We sought to quantitate the impact of these advances on burn survival via age-stratified mortality ratios compared with other reported mortality analyses in burns. STUDY DESIGN: Age, percent of the total body surface area (TBSA) burned, presence of inhalation injury, length of stay, and survival status were recorded at admission and at discharge for all new burn admissions between 1989 and 2017. The expected mortality probability was calculated using historical multiple regression techniques and compared with observed data. We developed a prediction model for our observed data. RESULTS: Between 1989 and 2017, there were 10,384 consecutive new burn admissions, with 355 mortalities (median age, 13 years; median percent TBSA burn, 11%). We saw a significant decrease in our observed mortality data compared to historical predictions (p < 0.0001), and a 2% reduction per year in mortality during the 3 decades. The prediction model of mortality for the data is as follows: Pr(dying) = ex/(1 + ex) where x = -6.44 - 0.12 age + 0.0042 age2 - 0.0000283 age3 + 0.0499 TBSA + 1.21 Inhalation Injury + 0.015 third degree TBSA. CONCLUSIONS: The reduction in mortality over time may be attributed to successful changes in standard of care protocols in the burn center that improved the outlook for burned individuals, including protocols for management of inhalation injury, nutrition, resuscitation, and early excision and grafting.

ß-Adrenergic Receptor Trafficking, Degradation, and Cell Surface Expression Are Altered in Dermal Fibroblasts from Hypertrophic Scars.

Burn trauma elevates catecholamines for up to 2 years and causes hypertrophic scarring. Propranolol, a nonspecific ß1-, ß2-adrenergic receptor (AR) inverse agonist, counters the hypermetabolic response to elevated catecholamines and may decrease hypertrophic scarring by an unknown mechanism. We investigated the effect of burn injury on ß1-, ß2-, and ß3-AR expression, trafficking, and degradation in human dermal fibroblasts from hypertrophic scar [HSF], non-scar fibroblasts, and normal fibroblasts. We also investigated the modulation of these events by propranolol. Catecholamine-stimulated cAMP production was lower in HSFs and non-scar fibroblasts than in normal fibroblasts. ß1- and ß2-AR cell surface expression was lowest in HSFs, but propranolol increased cell surface expression of these receptors. Basal ß2-AR ubiquitination was higher in HSFs than non-scar or normal fibroblasts, suggesting accelerated receptor degradation. ß-AR degradation was mainly driven by lysosomal-specific polyubiquitination at Lys-63 in normal fibroblasts and HSFs, which was abrogated by propranolol. Propranolol also targeted ß-AR to the proteasome in HSFs. Confocal imaging showed a lack of ß2-AR-GFP trafficking to lysosomal compartments in catecholamine-stimulated HSFs. These data suggest that burn trauma alters the expression, trafficking, and degradation of ß-ARs in dermal fibroblasts, which may then affect fibroblast responses to propranolol.