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.

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.

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.

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.

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.

Inhalation Injury in the Burned Patient.

Inhalation injury causes a heterogeneous cascade of insults that increase morbidity and mortality among the burn population. Despite major advancements in burn care for the past several decades, there remains a significant burden of disease attributable to inhalation injury. For this reason, effort has been devoted to finding new therapeutic approaches to improve outcomes for patients who sustain inhalation injuries.The three major injury classes are the following: supraglottic, subglottic, and systemic. Treatment options for these three subtypes differ based on the pathophysiologic changes that each one elicits.Currently, no consensus exists for diagnosis or grading of the injury, and there are large variations in treatment worldwide, ranging from observation and conservative management to advanced therapies with nebulization of different pharmacologic agents.The main pathophysiologic change after a subglottic inhalation injury is an increase in the bronchial blood flow. An induced mucosal hyperemia leads to edema, increases mucus secretion and plasma transudation into the airways, disables the mucociliary escalator, and inactivates hypoxic vasocontriction. Collectively, these insults potentiate airway obstruction with casts formed from epithelial debris, fibrin clots, and inspissated mucus, resulting in impaired ventilation. Prompt bronchoscopic diagnosis and multimodal treatment improve outcomes. Despite the lack of globally accepted standard treatments, data exist to support the use of bronchoscopy and suctioning to remove debris, nebulized heparin for fibrin casts, nebulized N-acetylcysteine for mucus casts, and bronchodilators.Systemic effects of inhalation injury occur both indirectly from hypoxia or hypercapnia resulting from loss of pulmonary function and systemic effects of proinflammatory cytokines, as well as directly from metabolic poisons such as carbon monoxide and cyanide. Both present with nonspecific clinical symptoms including cardiovascular collapse. Carbon monoxide intoxication should be treated with oxygen and cyanide with hydroxocobalamin.Inhalation injury remains a great challenge for clinicians and an area of opportunity for scientists. Management of this concomitant injury lags behind other aspects of burn care. More clinical research is required to improve the outcome of inhalation injury.The goal of this review is to comprehensively summarize the diagnoses, treatment options, and current research.

Inducible satellite cell depletion attenuates skeletal muscle regrowth following a scald-burn injury.

KEY POINTS: Severe burns result in significant skeletal muscle cachexia that impedes recovery. Activity of satellite cells, skeletal muscle stem cells, is altered following a burn injury and likely hinders regrowth of muscle. Severe burn injury induces satellite cell proliferation and fusion into myofibres with greater activity in muscles proximal to the injury site. Conditional depletion of satellite cells attenuates recovery of myofibre area and volume following a scald burn injury in mice. Skeletal muscle regrowth following a burn injury requires satellite cell activity, underscoring the therapeutic potential of satellite cells in the prevention of prolonged frailty in burn survivors. ABSTRACT: Severe burns result in profound skeletal muscle atrophy; persistent muscle atrophy and weakness are major complications that hamper recovery from burn injury. Many factors contribute to the erosion of muscle mass following burn trauma, and we have previously shown concurrent activation and apoptosis of muscle satellite cells following a burn injury in paediatric patients. To determine the necessity of satellite cells during muscle recovery following a burn injury, we utilized a genetically modified mouse model (Pax7CreER -DTA) that allows for the conditional depletion of satellite cells in skeletal muscle. Additionally, mice were provided 5-ethynyl-2'-deoxyuridine to determine satellite cell proliferation, activation and fusion. Juvenile satellite cell-wild-type (SC-WT) and satellite cell-depleted (SC-Dep) mice (8 weeks of age) were randomized to sham or burn injury consisting of a dorsal scald burn injury covering 30% of total body surface area. Both hindlimb and dorsal muscles were studied at 7, 14 and 21 days post-burn. SC-Dep mice had >93% depletion of satellite cells compared to SC-WT (P < 0.05). Burn injury induced robust atrophy in muscles located both proximal and distal to the injury site (∼30% decrease in fibre cross-sectional area, P < 0.05). Additionally, burn injury induced skeletal muscle regeneration, satellite cell proliferation and fusion. Depletion of satellite cells impaired post-burn recovery of both muscle fibre cross-sectional area and volume (P < 0.05). These findings support an integral role for satellite cells in the aetiology of lean tissue recovery following a severe burn injury.

The metabolic stress response to burn trauma: current understanding and therapies.

Major burns provoke a profound stress response, which is unrivalled in terms of its magnitude and duration. Evidence suggests that the pathophysiological stress response to severe burn trauma persists for several years after injury. Thus, there is a pressing need for novel strategies that mitigate this response and restore normal metabolic function in patients with burns. This is the first in a Series of three papers about the care of people with burns. In this paper, we review the current knowledge of the stress response to burn trauma, with a focus on hypermetabolism, muscle wasting, and stress-induced diabetes. We highlight recent developments and important knowledge gaps that need to be pursued to develop novel therapeutic strategies to improve outcomes in burn survivors.

Hypertrophic scarring: the greatest unmet challenge after burn injury.

Improvements in acute burn care have enabled patients to survive massive burns that would have once been fatal. Now up to 70% of patients develop hypertrophic scars after burns. The functional and psychosocial sequelae remain a major rehabilitative challenge, decreasing quality of life and delaying reintegration into society. Approaches to optimise healing potential of burn wounds use targeted wound care and surgery to minimise the development of hypertrophic scarring. Such approaches often fail, and modulation of the established scar is continued although the optimal indication, timing, and combination of therapies have yet to be established. The need for novel treatments is paramount, and future efforts to improve outcomes and quality of life should include optimisation of wound healing to attenuate or prevent hypertrophic scarring, well-designed trials to confirm treatment efficacy, and further elucidation of molecular mechanisms to allow development of new preventive and therapeutic strategies.

Co-administration of vancomycin and piperacillin-tazobactam is associated with increased renal dysfunction in adult and pediatric burn patients.

BACKGROUND: Burn patients are prone to infections which often necessitate broad antibiotic coverage. Vancomycin is a common antibiotic after burn injury and is administered alone (V), or in combination with imipenem-cilastin (V/IC) or piperacillin-tazobactam (V/PT). Sparse reports indicate that the combination V/PT is associated with increased renal dysfunction. The purpose of this study was to evaluate the short-term impact of the three antibiotic administration types on renal dysfunction. METHODS: All pediatric and adult patients admitted to our centers between 2004 and 2016 with a burn injury were included in this retrospective review if they met the criteria of exposition to either V, V/IC, or V/PT for at least 48 h, had normal baseline creatinine, and no pre-existing renal dysfunction. Creatinine was monitored for 7 days after initial exposure; the absolute and relative increase was calculated, and patient renal outcomes were classified according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria depending on creatinine increases and estimated creatinine clearance. Secondary endpoints (demographic and clinical data, incidences of septicemia, and renal replacement therapy) were analyzed. Antibiotic doses were modeled in logistic and linear multivariable regression models to predict categorical KDIGO events and relative creatinine increase. RESULTS: Out of 1449 patients who were screened, 718 met the inclusion criteria, 246 were adults, and 472 were children. Between the study cohorts V, V/IC, and V/PT, patient characteristics at admission were comparable. V/PT administration was associated with a statistically higher serum creatinine, and lower creatinine clearance compared to patients receiving V alone or V/IC in adults and children after burn injury. The incidence of KDIGO stages 1, 2, and 3 was higher after V/PT treatment. In children, the incidence of KDIGO stage 3 following administration of V/PT was greater than after V/IC. In adults, the incidence of renal replacement therapy was higher after V/PT compared with V or V/IC. Multivariate modeling demonstrated that V/PT is an independent predictor of renal dysfunction. CONCLUSION: Co-administration of vancomycin and piperacillin-tazobactam is associated with increased renal dysfunction in pediatric and adult burn patients when compared to vancomycin alone or vancomycin plus imipenem-cilastin. The mechanism of this increased nephrotoxicity remains elusive and warrants further scientific evaluation.

Body Composition Changes in Severely Burned Children During ICU Hospitalization.

OBJECTIVES: Prolonged hospitalization due to burn injury results in physical inactivity and muscle weakness. However, how these changes are distributed among body parts is unknown. The aim of this study was to evaluate the degree of body composition changes in different anatomical regions during ICU hospitalization. DESIGN: Retrospective chart review. SETTING: Children's burn hospital. PATIENTS: Twenty-four severely burned children admitted to our institution between 2000 and 2015. INTERVENTIONS: All patients underwent a dual-energy x-ray absorptiometry within 2 weeks after injury and 2 weeks before discharge to determine body composition changes. No subject underwent anabolic intervention. We analyzed changes of bone mineral content, bone mineral density, total fat mass, total mass, and total lean mass of the entire body and specifically analyzed the changes between the upper and lower limbs. MEASUREMENTS AND MAIN RESULTS: In the 24 patients, age was 10 ± 5 years, total body surface area burned was 59% ± 17%, time between dual-energy x-ray absorptiometries was 34 ± 21 days, and length of stay was 39 ± 24 days. We found a significant (p < 0.001) average loss of 3% of lean mass in the whole body; this loss was significantly greater (p < 0.001) in the upper extremities (17%) than in the lower extremities (7%). We also observed a remodeling of the fat compartments, with a significant whole-body increase in fat mass (p < 0.001) that was greater in the truncal region (p < 0.0001) and in the lower limbs (p < 0.05). CONCLUSIONS: ICU hospitalization is associated with greater lean mass loss in the upper limbs of burned children. Mobilization programs should include early mobilization of upper limbs to restore upper extremity function.

Satellite cell activation and apoptosis in skeletal muscle from severely burned children.

KEY POINTS: Severe burns result in profound skeletal muscle atrophy that hampers recovery. The activity of skeletal muscle stem cells, satellite cells, acutely following a severe burn is unknown and may contribute to the recovery of lean muscle. Severe burn injury induces skeletal muscle regeneration and myonuclear apoptosis. Satellite cells undergo concurrent apoptosis and activation acutely following a burn, with a net reduction in satellite cell content compared to healthy controls. The activation and apoptosis of satellite cells probably impacts the recovery of lean tissue following a severe burn, contributing to prolonged frailty in burn survivors. ABSTRACT: Severe burns result in profound skeletal muscle atrophy; persistent muscle loss and weakness are major complications that hamper recovery from burn injury. Many factors contribute to the erosion of muscle mass following burn trauma and we propose that an impaired muscle satellite cell response is key in the aetiology of burn-induced cachexia. Muscle biopsies from the m. vastus lateralis were obtained from 12 male pediatric burn patients (>30% total body surface area burn) and 12 young, healthy male subjects. Satellite cell content, activation and apoptosis were determined via immunohistochemistry, as were muscle fibre regeneration and myonuclear apoptosis. Embryonic myosin heavy chain expression and central nucleation, indices of skeletal muscle regeneration, were elevated in burn patients (P < 0.05). Myonuclear apoptosis, quantified by TUNEL positive myonuclei and cleaved caspase-3 positive myonuclei, was also elevated in burn patients (P < 0.05). Satellite cell content was reduced in burn patients, with approximately 20% of satellite cells positive for TUNEL staining, indicating DNA damage associated with apoptosis (P < 0.05). Additionally, a significant percentage of satellite cells in burn patients expressed Ki67, a marker for cellular proliferation (P < 0.05). Satellite cell activation was also observed in burn patients with increased expression of MyoD compared to healthy controls (P < 0.05). Robust skeletal muscle atrophy occurs after burn injury, even in muscles located distally to the site of injury. The activation and apoptosis of satellite cells probably impacts the recovery of lean tissue following a severe burn, contributing to prolonged frailty in burn survivors.

Hold the Pendulum: Rates of Acute Kidney Injury are Increased in Patients Who Receive Resuscitation Volumes Less than Predicted by the Parkland Equation.

OBJECTIVE: To determine whether restrictive fluid resuscitation results in increased rates of acute kidney injury (AKI) or infectious complications. BACKGROUND: Studies demonstrate that patients often receive volumes in excess of those predicted by the Parkland equation, with potentially detrimental sequelae. However, the consequences of under-resuscitation are not well-studied. METHODS: Data were collected from a multicenter prospective cohort study. Adults with greater than 20% total burned surface area injury were divided into 3 groups on the basis of the pattern of resuscitation in the first 24 hours: volumes less than (restrictive), equal to, or greater than (excessive) standard resuscitation (4 to 6 cc/kg/% total burned surface area). Multivariable regression analysis was employed to determine the effect of fluid group on AKI, burn wound infections (BWIs), and pneumonia. RESULTS: Among 330 patients, 33% received restrictive volumes, 39% received standard resuscitation volumes, and 28% received excessive volumes. The standard and excessive groups had higher mean baseline APACHE scores (24.2 vs 16, P < 0.05 and 22.3 vs 16, P < 0.05) than the restrictive group, but were similar in other characteristics. After adjustment for confounders, restrictive resuscitation was associated with greater probability of AKI [odds ratio (OR) 3.25, 95% confidence interval (95% CI) 1.18-8.94]. No difference in the probability of BWI or pneumonia among groups was found (BWI: restrictive vs standard OR 0.74, 95% CI 0.39-1.40, excessive vs standard OR 1.40, 95% CI 0.75-2.60, pneumonia: restrictive vs standard, OR 0.52, 95% CI 0.26-1.05; excessive vs standard, OR 1.12, 95% CI 0.58-2.14). CONCLUSIONS: Restrictive resuscitation is associated with increased AKI, without changes in infectious complications.

Reversal of Growth Arrest With the Combined Administration of Oxandrolone and Propranolol in Severely Burned Children.

BACKGROUND: The hypercatabolic response in severely burned pediatric patients is associated with increased production of catecholamines and corticosteroids, decreased formation of testosterone, and reduced strength alongside growth arrest for up to 2 years after injury. We have previously shown that, in the pediatric burned population, the administration of the testosterone analog oxandrolone improves lean body mass accretion and bone mineral content and that the administration of the ß1-, ß2-adrenoceptor antagonist propranolol decreases cardiac work and resting energy expenditure while increasing peripheral lean mass. Here, we determined whether the combined administration of oxandrolone and propranolol has added benefit. METHODS: In this prospective, randomized study of 612 burned children [52% ±â€Š1% of total body surface area burned, ages 0.5-14 years (boys); ages 0.5-12 years (girls)], we compared controls to the individual administration of these drugs, and the combined administration of oxandrolone and propranolol at the same doses, for 1 year after burn. Data were recorded at discharge, 6 months, and 1 and 2 years after injury. RESULTS: Combined use of oxandrolone and propranolol shortened the period of growth arrest by 84 days (P = 0.0125 vs control) and increased growth rate by 1.7 cm/yr (P = 0.0024 vs control). CONCLUSIONS: Combined administration of oxandrolone and propranolol attenuates burn-induced growth arrest in pediatric burn patients. The present study is registered at clinicaltrials.gov: NCT00675714 and NCT00239668.

The use of skin substitutes and burn care-a survey.

OBJECTIVE: The aim of our Internet survey was to assess the preferences of burn specialists who use skin substitutes in patients with burns covering 20% or more of their total body surface area (TBSA). METHODS: An open, voluntary Internet-based cross-sectional survey was performed. Responses to 19 noncompulsory questions, and participant career and location information were collected. RESULTS: One hundred eleven specialists from 36 countries responded to our questionnaire. Sixty participants were located in Europe (54%), followed by 31 (28%) in North America, 15 (14%) in Asia, three (3%) in South America, one (1%) in Africa, and one (1%) in Australia. The importance of skin substitutes in medium-sized burns (covering 20%-60% TBSA) was rated as "essential" by 28% and "desirable" by 56% of the respondents. In severe burns >60% of TBSA, 81% of responders rated the use of skin substitutes as "essential" and 14% as "desirable". Skin substitutes were used in daily clinical practice by 96% of all participants. Biological and synthetic dressings were used by 53%. A majority (86%) think that biological dressings do not pose a risk to patients. Allografts represent the most frequently used wound coverage (51%), followed by xenografts (28%). All participants of the survey indicated that as of yet, there is no ideal skin substitute available. CONCLUSIONS: Split-thickness autografts still represent the most used wound cover for definitive treatment of severe burns. However, creation and implementation of an ideal skin substitute have yet to be achieved and therefore should be the focus of future work.

Anabolic and anticatabolic agents in critical care.

PURPOSE OF REVIEW: A complex network of hormones and other effectors characterize the hypermetabolic response in critical illness; these mediators work together to induce numerous pathophysiologic alterations. Increased incidence of infection, multiorgan failure, long-term debilitation, delays in rehabilitation, and death result from an inability to meet the prohibitively elevated protein and energy requirements, which occur during illness and can persist for several years. Pharmacologic interventions have been successfully utilized to attenuate particular aspects of the hypermetabolic response; these modalities are a component of managing critically ill patients - including those patients with severe burns. Here, we review recent advances in pharmacologically attenuating the hypermetabolic and catabolic responses. RECENT FINDINGS: Propranolol, a nonspecific ß-adrenergic receptor antagonist, is one of the most widely used anticatabolic therapies. Oxandrolone, testosterone, and intensive insulin therapy represent anabolic pharmacological strategies. Promising therapies, such as metformin, glucagon-like peptide 1, peroxisome proliferator-activated receptor agonists, are currently being investigated. SUMMARY: Profound metabolic derangements occur in critically ill patients; this hypermetabolic response is a major contributor to adverse outcomes. Despite the pharmacological therapies currently available to counteract this devastating cascade, future studies are warranted to explore new multimodality agents that will counteract these effects while maintaining glycemic control and preventing unfavorable complications.

Genomic responses in mouse models poorly mimic human inflammatory diseases.

A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R(2) between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.

Cardiovascular Dysfunction Following Burn Injury: What We Have Learned from Rat and Mouse Models.

Severe burn profoundly affects organs both proximal and distal to the actual burn site. Cardiovascular dysfunction is a well-documented phenomenon that increases morbidity and mortality following a massive thermal trauma. Beginning immediately post-burn, during the ebb phase, cardiac function is severely depressed. By 48 h post-injury, cardiac function rebounds and the post-burn myocardium becomes tachycardic and hyperinflammatory. While current clinical trials are investigating a variety of drugs targeted at reducing aspects of the post-burn hypermetabolic response such as heart rate and cardiac work, there is still a paucity of knowledge regarding the underlying mechanisms that induce cardiac dysfunction in the severely burned. There are many animal models of burn injury, from rodents, to sheep or swine, but the majority of burn related cardiovascular investigations have occurred in rat and mouse models. This literature review consolidates the data supporting the prevalent role that ß-adrenergic receptors play in mediating post-burn cardiac dysfunction and the idea that pharmacological modulation of this receptor family is a viable therapeutic target for resolving burn-induced cardiac deficits.