Showing papers by "Shriners Hospitals for Children - Galveston published in 2015"

Acute and perioperative care of the burn-injured patient.

Abstract: Care of burn-injured patients requires knowledge of the pathophysiologic changes affecting virtually all organs from the onset of injury until wounds are healed. Massive airway and/or lung edema can occur rapidly and unpredictably after burn and/or inhalation injury. Hemodynamics in the early phase of severe burn injury is characterized by a reduction in cardiac output and increased systemic and pulmonary vascular resistance. Approximately 2 to 5 days after major burn injury, a hyperdynamic and hypermetabolic state develops. Electrical burns result in morbidity much higher than expected based on burn size alone. Formulae for fluid resuscitation should serve only as guideline; fluids should be titrated to physiologic endpoints. Burn injury is associated basal and procedural pain requiring higher than normal opioid and sedative doses. Operating room concerns for the burn-injured patient include airway abnormalities, impaired lung function, vascular access, deceptively large and rapid blood loss, hypothermia, and altered pharmacology.

Predictive Value of IL-8 for Sepsis and Severe Infections After Burn Injury: A Clinical Study.

Abstract: The inflammatory response induced by burn injury contributes to increased incidence of infections, sepsis, organ failure, and mortality. Thus, monitoring postburn inflammation is of paramount importance but, so far, there are no reliable biomarkers available to monitor and/or predict infectious complications after burn. As interleukin 8 (IL-8) is a major mediator for inflammatory responses, the aim of our study was to determine whether IL-8 expression can be used to predict postburn sepsis, infections, and mortality. Plasma cytokines, acute-phase proteins, constitutive proteins, and hormones were analyzed during the first 60 days after injury from 468 pediatric burn patients. Demographics and clinical outcome variables (length of stay, infection, sepsis, multiorgan failure [MOF], and mortality) were recorded. A cutoff level for IL-8 was determined using receiver operating characteristic analysis. Statistical significance is set at P < 0.05. Receiver operating characteristic analysis identified a cutoff level of 234 pg/mL for IL-8 for survival. Patients were grouped according to their average IL-8 levels relative to this cutoff and stratified into high (H) (n = 133) and low (L) (n = 335) groups. In the L group, regression analysis revealed a significant predictive value of IL-8 to percent of total body surface area burned and incidence of MOF (P < 0.001). In the H group, IL-8 levels were able to predict sepsis (P < 0.002). In the H group, elevated IL-8 was associated with increased inflammatory and acute-phase responses compared with the L group (P < 0.05). High levels of IL-8 correlated with increased MOF, sepsis, and mortality. These data suggest that serum levels of IL-8 may be a valid biomarker for monitoring sepsis, infections, and mortality in burn patients.

Time-Dependent and Organ-Specific Changes in Mitochondrial Function, Mitochondrial DNA Integrity, Oxidative Stress and Mononuclear Cell Infiltration in a Mouse Model of Burn Injury.

Abstract: Severe thermal injury induces a pathophysiological response that affects most of the organs within the body; liver, heart, lung, skeletal muscle among others, with inflammation and hyper-metabolism as a hallmark of the post-burn damage. Oxidative stress has been implicated as a key component in development of inflammatory and metabolic responses induced by burn. The goal of the current study was to evaluate several critical mitochondrial functions in a mouse model of severe burn injury. Mitochondrial bioenergetics, measured by Extracellular Flux Analyzer, showed a time dependent, post-burn decrease in basal respiration and ATP-turnover but enhanced maximal respiratory capacity in mitochondria isolated from the liver and lung of animals subjected to burn injury. Moreover, we detected a tissue-specific degree of DNA damage, particularly of the mitochondrial DNA, with the most profound effect detected in lungs and hearts of mice subjected to burn injury. Increased mitochondrial biogenesis in lung tissue in response to burn injury was also observed. Burn injury also induced time dependent increases in oxidative stress (measured by amount of malondialdehyde) and neutrophil infiltration (measured by myeloperoxidase activity), particularly in lung and heart. Tissue mononuclear cell infiltration was also confirmed by immunohistochemistry. The amount of poly(ADP-ribose) polymers decreased in the liver, but increased in the heart in later time points after burn. All of these biochemical changes were also associated with histological alterations in all three organs studied. Finally, we detected a significant increase in mitochondrial DNA fragments circulating in the blood immediately post-burn. There was no evidence of systemic bacteremia, or the presence of bacterial DNA fragments at any time after burn injury. The majority of the measured parameters demonstrated a sustained elevation even at 20–40 days post injury suggesting a long-lasting effect of thermal injury on organ function. The current data show that there are marked time-dependent and tissue-specific alterations in mitochondrial function induced by thermal injury, and suggest that mitochondria-specific damage is one of the earliest responses to burn injury. Mitochondria may be potential therapeutic targets in the future experimental therapy of burns.

Propranolol attenuates hemorrhage and accelerates wound healing in severely burned adults

Abstract: Propranolol, a nonselective β-blocker, exerts an indirect effect on the vasculature by leaving α-adrenergic receptors unopposed, resulting in peripheral vasoconstriction. We have previously shown that propranolol diminishes peripheral blood following burn injury by increasing vascular resistance. The purpose of this study was to investigate whether wound healing and perioperative hemodynamics are affected by propranolol administration in severely burned adults. Sixty-nine adult patients with burns covering ≥30% of the total body surface area (TBSA) were enrolled in this IRB-approved study. Patients received standard burn care with (n = 35) or without (control, n = 34) propranolol. Propranolol was administered within 48 hours of burns and given throughout hospital discharge to decrease heart rate by approximately 20% from admission levels. Wound healing was determined by comparing the time between grafting procedures. Blood loss was determined by comparing pre- and postoperative hematocrit while factoring in operative graft area. Data were collected between first admission and first discharge. Demographics, burn size, and mortality were comparable in the control and propranolol groups. Patients in the propranolol group received an average propranolol dose of 3.3 ± 3.0 mg/kg/day. Daily average heart rate over the first 30 days was significantly lower in the propranolol group (P <0.05). The average number of days between skin grafting procedures was also lower in propranolol patients (10 ± 5 days) than in control patients (17 ± 12 days; P = 0.02), indicative of a faster donor site healing time in the propranolol group. Packed red blood cell infusion was similar between groups (control 5.3 ± 5.4 units vs. propranolol 4.4 ± 3.1 units, P = 0.89). Propranolol was associated with a 5 to 7% improvement in perioperative hematocrit during grafting procedures of 4,000 to 16,000 cm2 compared to control (P = 0.002). Administration of propranolol during the acute hospitalization period diminishes blood loss during skin grafting procedures and markedly improves wound healing in severely burned adults. As burn patients require serial surgical interventions for motor and cosmetic repair, restricting blood loss during operative intervention is optimal.

Acute and Perioperative Care of the Burn-Injured Patient

Abstract: Care of burn-injured patients requires knowledge of the pathophysiologic changes affecting virtually all organs from the onset of injury until wounds are healed. Massive airway and/or lung edema can occur rapidly and unpredictably after burn and/or inhalation injury. Hemodynamics in the early phase of severe burn injury is characterized by a reduction in cardiac output and increased systemic and pulmonary vascular resistance. Approximately 2 to 5 days after major burn injury, a hyperdynamic and hypermetabolic state develops. Electrical burns result in morbidity much higher than expected based on burn size alone. Formulae for fluid resuscitation should serve only as guideline; fluids should be titrated to physiologic endpoints. Burn injury is associated basal and procedural pain requiring higher than normal opioid and sedative doses. Operating room concerns for the burn-injured patient include airway abnormalities, impaired lung function, vascular access, deceptively large and rapid blood loss, hypothermia, and altered pharmacology.

Practice guidelines for the application of nonsilicone or silicone gels and gel sheets after burn injury.

Abstract: The objective of this review was to systematically evaluate available clinical evidence for the application of nonsilicone or silicone gels and gel sheets on hypertrophic scars and keloids after a burn injury so that practice guidelines could be proposed. This review provides evidence based recommendations, specifically for the rehabilitation interventions required for the treatment of aberrant wound healing after burn injury with gels or gel sheets. These guidelines are designed to assist all healthcare providers who are responsible for initiating and supporting scar management interventions prescribed for burn survivors. Summary recommendations were made after the literature, retrieved by systematic review, was critically appraised and the level of evidence determined according to Oxford Centre for Evidence-based Medicine criteria.

The Therapeutic Potential of Brown Adipocytes in Humans

Abstract: Obesity and its metabolic consequences represent a significant clinical problem. From a thermodynamic standpoint, obesity results from a discord in energy intake and expenditure. To date, lifestyle interventions based on reducing energy intake and/or increasing energy expenditure have proved ineffective in the prevention and/or treatment of obesity, owing to poor long-term adherence to such interventions. Thus, an effective strategy to prevent or correct obesity is currently lacking. As the combustion engines of our cells, mitochondria play a critical role in energy expenditure. At a whole-body level, approximately 80% of mitochondrial membrane potential generated by fuel oxidation is used to produce ATP, and the remaining 20% is lost through heat-producing uncoupling reactions. The coupling of mitochondrial respiration to ATP production represents an important component in whole-body energy expenditure. Brown adipose tissue (BAT) is densely populated with mitochondria containing the inner mitochondrial proton carrier uncoupling protein 1 (UCP1). UCP1 uncouples oxidative phosphorylation, meaning that mitochondrial membrane potential is dissipated as heat. The recent rediscovery of BAT depots in adult humans has rekindled scientific interest in the manipulation of mitochondrial uncoupling reactions as a means to increase metabolic rate, thereby counteracting obesity and its associated metabolic phenotype. In this article, we discuss the evidence for the role BAT plays in metabolic rate and glucose and lipid metabolism in humans and the potential for UCP1 recruitment in the white adipose tissue of humans. While the future holds much promise for a therapeutic role of UCP1 expressing adipocytes in human energy metabolism, particularly in the context of obesity, tissue-specific strategies that activate or recruit UCP1 in human adipocytes represent an obligatory translational step for this early promise to be realized.

Pruritus in pediatric burn survivors: defining the clinical course.

Abstract: Pruritus is a frequent and severe symptom and a significant cause of distress for adult burn patients. Its effects in children are largely unstudied. The aim of this study is to characterize postburn itch in the pediatric population. This is a retrospective review from 2006 to 2013 for pediatric burn survivors who were enrolled in a longitudinal multicenter outcomes study. Demographic data, injury characteristics, associated symptoms (skin-related problems, pain, and sleep), and incidence and intensity (Numerical Rating Scale) of itch were examined. Measures were completed at hospital discharge and at 6, 12, and 24 months after injury. Spearman's correlations were used to examine the correlation between itch intensity and associated symptoms. Multivariate regression analyses examined the impact of associated symptoms on itch intensity. There were 430 pediatric burn survivors with a mean age of 7.8 years and a mean TBSA of 40.8%. Pruritus is present in most children (93%) and is of moderate intensity (5.7 ± 3.1) at discharge. The frequency and intensity of pruritus decreases over time; a majority of children continue to report symptoms at 2 years (63%). Itch was significantly correlated with associated symptoms. Regression analyses showed a correlation between itch intensity and pain at each time point. There was no association between itch intensity and burn etiology, age, gender, or burn size. Pruritus is a frequent complication that lasts for at least 2 years after injury in a majority of pediatric burn survivors. This information will enable better tracking of outcomes and will serve as a baseline for assessing interventions.

Disruption of bone and skeletal muscle in severe burns.

Abstract: Severe burn injury triggers the body's nonspecific adaptive responses to acute insult, including the systemic inflammatory and stress responses, as well as the sympathetic response to immobilization. These responses trigger inflammatory bone resorption followed by glucocorticoid-induced apoptosis of osteoblasts and probably osteocytes. Because these patients are catabolic, they suffer concomitant muscle wasting and negative nitrogen balance. The use of anabolic agents such as recombinant human growth hormone and oxandrolone results in improved bone mineral content and muscle strength after approximately 1 year. Use of bisphosphonates within the first 10 days of a severe burn completely blocks the resorptive bone loss and has the added advantage of appearing to preserve muscle protein from excessive breakdown. The mechanism for the protective effect on muscle is not currently known. However, if the effect of bisphosphonates on muscle can be confirmed, it raises the possibility that bone communicates with muscle.

Upregulation and Mitochondrial Sequestration of Hemoglobin Occur in Circulating Leukocytes during Critical Illness, Conferring a Cytoprotective Phenotype

Abstract: The classical role of hemoglobin in the erythrocytes is to carry oxygen from the lungs to the tissues via the circulation However, hemoglobin also acts as a redox regulator and as a scavenger of the gaseous mediators nitric oxide (NO) and hydrogen sulfide (H2S) Here we show that upregulation of hemoglobin (α, β and δ variants of globin proteins) occurs in human peripheral blood mononuclear cells (PBMCs) in critical illness (patients with severe third-degree burn injury and patients with sepsis) The increase in intracellular hemoglobin concentration is a result of a combination of enhanced protein expression and uptake from the extracellular space via a CD163-dependent mechanism Intracellular hemoglobin preferentially localizes to the mitochondria, where it interacts with complex I and, on the one hand, increases mitochondrial respiratory rate and mitochondrial membrane potential, and on the other hand, protects from H2O2-induced cytotoxicity and mitochondrial DNA damage Both burn injury and sepsis were associated with increased plasma levels of H2S Incubation of mononuclear cells with H2S induced hemoglobin mRNA upregulation in PBMCs in vitro Intracellular hemoglobin upregulation conferred a protective effect against cell dysfunction elicited by H2S Hemoglobin uptake also was associated with a protection from, and induced the upregulation of, HIF-1α and Nrf2 mRNA In conclusion, PBMCs in critical illness upregulate their intracellular hemoglobin levels by a combination of active synthesis and uptake from the extracellular medium We propose that this process serves as a defense mechanism protecting the cell against cytotoxic concentrations of H2S and other gaseous transmitters, oxidants and free radicals produced in critically ill patients

Comparison of Gene Expression by Sheep and Human Blood Stimulated with the TLR4 Agonists Lipopolysaccharide and Monophosphoryl Lipid A.

Abstract: Background Animal models that mimic human biology are important for successful translation of basic science discoveries into the clinical practice. Recent studies in rodents have demonstrated the efficacy of TLR4 agonists as immunomodulators in models of infection. However, rodent models have been criticized for not mimicking important characteristics of the human immune response to microbial products. The goal of this study was to compare genomic responses of human and sheep blood to the TLR4 agonists lipopolysaccharide (LPS) and monophosphoryl lipid A (MPLA). Methods Venous blood, withdrawn from six healthy human adult volunteers (~ 28 years old) and six healthy adult female sheep (~3 years old), was mixed with 30 μL of PBS, LPS (1μg/mL) or MPLA (10μg/mL) and incubated at room temperature for 90 minutes on a rolling rocker. After incubation, 2.5 mL of blood was transferred to Paxgene Blood RNA tubes. Gene expression analysis was performed using an Agilent Bioanalyzer with the RNA6000 Nano Lab Chip. Agilent gene expression microarrays were scanned with a G2565 Microarray Scanner. Differentially expressed genes were identified. Results 11,431 human and 4,992 sheep probes were detected above background. Among them 1,029 human and 175 sheep genes were differentially expressed at a stringency of 1.5-fold change (p 1.5-fold changes in human samples. Genes of major inflammatory mediators, such as IL-1, IL-6 and IL-8, TNF alpha, NF-kappaB, ETS2, PTGS2, PTX3, CXCL16, KYNU, and CLEC4E were similarly (>2-fold) upregulated by LPS and MPLA in both species. Conclusion The genomic responses of peripheral blood to LPS and MPLA in sheep are quite similar to those observed in humans, supporting the use of the ovine model for translational studies that mimic human inflammatory diseases and the study of TLR-based immunomodulators.

Enhanced anti-fibrogenic effects of novel oridonin derivative CYD0692 in hepatic stellate cells

Abstract: Oridonin, isolated from Rabdosia rubescens, has been proven to possess various anti-neoplastic and anti-inflammatory properties. Previously, we reported the anti-fibrogenic effects of oridonin for liver in vitro. In the present study, we investigated the effects of a newly designed analog CYD0692 in vitro. Cell viability was measured by Alamar Blue assay. Cell apoptosis was assessed by Cell Death ELISA and Yo-Pro-1 staining. Western blots were performed for cellular proteins. Flow cytometry was used to measure cell cycle regulation. CYD0692 significantly inhibited LX-2 cells proliferation in a dose- and time-dependent manner with an IC50 value of ~0.7 μM for 48 h, ~tenfold greater potency than oridonin. Similar results were observed in HSC-T6 cells. In contrast, on the human hepatocyte cell line C3A, only 12 % of the cell growth was inhibited with 5 μM of CYD0692 treatment for 48 h, while 30 % inhibited at 10 μM. After CYD0692 treatment on LX-2 cells, apoptosis and S-phase cell cycle arrest were induced; cleaved-PARP, p21, and p53 were activated while cyclin-B1 levels declined. In addition, α-smooth muscle actin, type I Collagen, and fibronectin (FN) were markedly down regulated. Transforming growth factor β1 (TGF β1) has been identified as a dominant stimulator for ECM production in HSC. Our results indicated that pretreatment with CYD0692 blocked TGF β1-induced FN expression, thereby decreasing the downstream factors of TGF β1 signaling, such as Phospho-Smad2/3 and phospho-ERK. In comparison with oridonin, its novel derivative CYD0692 has demonstrated to be a more potent and potentially safer anti-fibrogenic agent for the treatment of hepatic fibrosis.

A percutaneous needle biopsy technique for sampling the supraclavicular brown adipose tissue depot of humans

Abstract: Brown adipose tissue (BAT) has been proposed as a potential target tissue against obesity and its related metabolic complications. Although the molecular and functional characteristics of BAT have been intensively studied in rodents, only a few studies have used human BAT specimens due to the difficulty of sampling human BAT deposits. We established a novel positron emission tomography and computed tomography-guided Bergstrom needle biopsy technique to acquire human BAT specimens from the supraclavicular area in human subjects. Forty-three biopsies were performed on 23 participants. The procedure was tolerated well by the majority of participants. No major complications were noted. Numbness (9.6%) and hematoma (2.3%) were the two minor complications noted, which fully resolved. Thus, the proposed biopsy technique can be considered safe with only minimal risk of adverse events. Adoption of the proposed method is expected to increase the sampling of the supraclavicular BAT depot for research purposes so as to augment the scientific knowledge of the biology of human BAT.

High-resolution episcopic microscopy (HREM): A useful technique for research in wound care

Abstract: Analysing the three-dimensional (3D) texture of skin substitute materials and evaluating their performance after covering skin defects is essential for improving their design and for optimising surgical procedures and post implantation wound treatment regimes. Here we explore the capacities of the recently developed High-resolution episcopic microscopy (HREM) method for generating digital volume data that permit structural 3D analysis of native and implanted collagen-elastin matrices. We employed HREM to visualise native collagen matrices and collagen matrices seeded with keratinocytes. In a second step, we visualised the appearance and the revascularisation of the matrices after their implantation beneath split skin grafts used for covering skin defects in the porcine model. For this, HREM data were generated from biopsies harvested 5, 10, and 15 days after surgery. In all instances, the high quality and resolution of the HREM data in combination with the relative large field of view proved to be sufficient for visualizing the exact fibre architecture by employing quick volume rendering algorithms. Precise analysis of the 3D distribution of keratinocytes in the matrices populated with keratinocytes and of the detailed topology of the sprouting blood vessels in the implanted matrices was feasible. Our results show that high-resolution episcopic microscopy can be adapted to serve as a tool for evaluating collagen-elastin materials ex- and in vivo.

Response to Comment on Chondronikola et al. Brown Adipose Tissue Improves Whole-Body Glucose Homeostasis and Insulin Sensitivity in Humans. Diabetes 2014;63:4089–4099

Abstract: We thank the Editor for inviting us to write a response to the letter by Drs. Dela and Helge (1) concerning our recent article in Diabetes (2). The authors draw our attention to an incorrect reference used to describe mitochondrial respiration measurements. The correct reference is an article that Dr. Dela’s group published in 2010 (3). We apologize for any confusion caused. We hope this alleviates the authors’ concerns on the methodology used for the mitochondrial respiration measurements; nevertheless, we provide further information here for clarity. Biopsies were immediately submerged in preservation buffer (BIOPS as described in ref. 3) and immediately (within 30 min) brought to the laboratory. …

Low exposure levels of respirable particles during the preparation of NexoBrid® bromelain powder

Abstract: Burns are common injuries that are usually covered with a layer of necrotic tissue called the eschar. Early removal of the eschar is the current standard of care, however, debridement using tangential excision is usually traumatic and may increase wound surface. In recent years a bromelain-based debriding agent called NexoBrid® that can remove the eschar selectively and thus causes less additional trauma was developed. Bromelain is a pineapple-stem derived mix of proteases. In its raw form bromelain is a yellowish powder. Cases are known where frequent inhalation of bromelain dust led to respiratory sensitization and subsequently to severe allergic reactions. In order to activate bromelain for debridement it has to be mixed with a hydrating gel. We aimed to assess the risk of sensitization by measuring the particle concentration in the air during the mixing process in order to determine the safety of the product for patients as well as practitioners. The mixing process was repeated five times in a row. Samples of the particle concentration in the workers breathing area were taken with an air particle counting device during continuous performance. The worker wore a lab coat and gloves but no face mask. Particle concentrations ranged from 0.010 mg/m3 to 0.012 mg/m3 (mean 0.010 mg/m3). The particles were chemically termed as “respirable dust”. We measured very low exposure levels of inhalable particles during the mixing process. Because the particle counter could not distinguish the components of the dust, it is possible that also background particles contributed to the results. A review of literature revealed that relatively high exposure levels are necessary for respiratory sensitization, whereas also low exposure levels may exacerbate an allergic reaction. We suggest that preparation of NexoBrid® is safe as long as standard safety precautions are met. Patients with known allergy to pineapple should be treated more carefully to prevent an allergic reaction.

Treatment of a recurrent digital hyperkeratosis in a skin graft with a CO2 laser.

Abstract: Tourniquet use is typically very safe (Odinsson and Finsen, 2006). Most tourniquet complications are associated with either the duration of ischaemia or the pressure generated beneath the cuff. Sometimes prolonged tourniquet use is needed to address a complication during surgery or to undertake multiple procedures. The absolute safe limit of tourniquet duration has not been established. Overall our findings reflect those of Flatt (1972), who showed that 60 patients with a tourniquet duration of between 2 hours 45 minutes had no post-operative complications. This is important as many authorities quote time limits for upper limb tourniquet use of 1 hour 30 minutes or more reasonably 2 hours. This study and Flatt’s work appear to show that tourniquet use can be safely extended to well beyond 2 hours. The majority of our patients had tourniquet times between 2 hours 45 minutes, and even in these patients there was a trend to more short-term symptoms. These may simply reflect responses to more surgery but may also be due to swelling and soft tissue injury from longer tourniquet times. There were only 11 patients with tourniquet times >2 hours 45 minutes and these patients had an even stronger trend towards more short-term symptoms, and the only patient with possible long term symptoms from tourniquet use was in this group. The data more strongly support the use of an arm tourniquet up to, than beyond 2 hours 45 minutes. The ability to use a tourniquet for >2 hours gives greater flexibility to surgeons planning complex operations or addressing complications during operations by allowing longer tourniquet use. It should also help resist spurious medico-legal claims based solely on prolonged tourniquet times. Nonetheless we would strongly advocate minimizing tourniquet use as we do not know whether there may be subtle physiological changes that should be minimized for patient benefit.