Showing papers by "Shriners Hospitals for Children - Galveston published in 2018"

Production and transplantation of bioengineered lung into a large-animal model

Abstract: The inability to produce perfusable microvasculature networks capable of supporting tissue survival and of withstanding physiological pressures without leakage is a fundamental problem facing the field of tissue engineering. Microvasculature is critically important for production of bioengineered lung (BEL), which requires systemic circulation to support tissue survival and coordination of circulatory and respiratory systems to ensure proper gas exchange. To advance our understanding of vascularization after bioengineered organ transplantation, we produced and transplanted BEL without creation of a pulmonary artery anastomosis in a porcine model. A single pneumonectomy, performed 1 month before BEL implantation, provided the source of autologous cells used to bioengineer the organ on an acellular lung scaffold. During 30 days of bioreactor culture, we facilitated systemic vessel development using growth factor-loaded microparticles. We evaluated recipient survival, autograft (BEL) vascular and parenchymal tissue development, graft rejection, and microbiome reestablishment in autografted animals 10 hours, 2 weeks, 1 month, and 2 months after transplant. BEL became well vascularized as early as 2 weeks after transplant, and formation of alveolar tissue was observed in all animals (n = 4). There was no indication of transplant rejection. BEL continued to develop after transplant and did not require addition of exogenous growth factors to drive cell proliferation or lung and vascular tissue development. The sterile BEL was seeded and colonized by the bacterial community of the native lung.

Contemporary Burn Survival

Abstract: 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 x /(1 + e x ) where x = –6.44 – 0.12 age + 0.0042 age 2 – 0.0000283 age 3 + 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.

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

Abstract: 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.

The clinically used PARP inhibitor olaparib improves organ function, suppresses inflammatory responses and accelerates wound healing in a murine model of third-degree burn injury.

Abstract: Background and purpose The PARP inhibitor olaparib has recently been approved for human use for the therapy of cancer. Considering the role of PARP in critical illness, we tested the effect of olaparib in a murine model of burn injury, in order to begin exploring the feasibility of repurposing olaparib for the therapy of burn patients. Experimental approach Mice were subjected to scald burn injury and randomized into vehicle or olaparib (10 mg/kg/day i.p.) groups. Outcome variables included indices of organ injury, clinical chemistry parameters, plasma levels of inflammatory mediators (at 24 h, 7 days and 21 days) and burn wound size (at 21 days). Key results Olaparib reduced myeloperoxidase levels in heart and lung homogenates and reduced malon dialdehyde levels in all tissues 24 h post-burn. Olaparib also reduced circulating alkaline aminotransferase, amylase and blood urea nitrogen and creatinine levels, indicative of protection against hepatic, pancreatic and renal dysfunction. Pro-inflammatory mediator (TNF-α, IL-1β, IFN-γ, GCSF, GM-CSF, eotaxin, KC, MIP-1-α and interleukins 3,6 and 12) levels as well as the levels of several mediators that are generally considered anti-inflammatory (IL-4, 10 and 13) were reduced by olaparib. Plasma troponin-I levels (an indicator of skeletal muscle damage) was also attenuated by olaparib. Finally, olaparib stimulated wound healing. Conclusions and Implications The clinically approved PARP inhibitor olaparib improves organ function, suppresses inflammatory responses and accelerates wound healing in murine burn injury. The data raise the potential utility of olaparib for severe burn injury.

Early Inhibition of Fatty Acid Synthesis Reduces Generation of Memory Precursor Effector T Cells in Chronic Infection.

Abstract: Understanding the mechanisms of CD4 memory T cell (Tmem) differentiation in malaria is critical for vaccine development. However, the metabolic regulation of CD4 Tmem differentiation is not clear, particularly in persistent infections. In this study, we investigated the role of fatty acid synthesis (FAS) in Tmem development in Plasmodium chabaudi chronic mouse malaria infection. We show that T cell-specific deletion and early pharmaceutical inhibition of acetyl CoA carboxylase 1, the rate limiting step of FAS, inhibit generation of early memory precursor effector T cells (MPEC). To compare the role of FAS during early differentiation or survival of Tmem in chronic infection, a specific inhibitor of acetyl CoA carboxylase 1, 5-(tetradecyloxy)-2-furoic acid, was administered at different times postinfection. Strikingly, the number of Tmem was only reduced when FAS was inhibited during T cell priming and not during the Tmem survival phase. FAS inhibition during priming increased effector T cell (Teff) proliferation and strongly decreased peak parasitemia, which is consistent with improved Teff function. Conversely, MPEC were decreased, in a T cell-intrinsic manner, upon early FAS inhibition in chronic, but not acute, infection. Early cure of infection also increased mitochondrial volume in Tmem compared with Teff, supporting previous reports in acute infection. We demonstrate that the MPEC-specific effect was due to the higher fatty acid content and synthesis in MPEC compared with terminally differentiated Teff. In conclusion, FAS in CD4 T cells regulates the early divergence of Tmem from Teff in chronic infection.

Quantifying Contracture Severity at Hospital Discharge in Adults: A Burn Model System National Database Study.

Abstract: Contracture is a common complication of burn injury and can cause significant barriers to functional recovery and rehabilitation. There are limited studies of quantitative range of motion after burn injury. The purpose of this study is to examine quantitative contracture outcomes by anatomical location, burn size, and length of stay in adults. Data were obtained from the Burn Model System National Database from 1994 to 2003. All adult patients with a joint contracture at acute discharge were included and 16 joint motions were examined. Contractures were reported as both mean absolute loss of normal range of motion in degrees and percent loss of normal range of motion. Analysis of variance was used to assess for a linear trend for contracture severity by burn size and length of stay. Data from 659 patients yielded 6,228 instances of contracture. Mean absolute loss of normal range of motion ranged from 20° to 65° representing an 18 to 45% loss of normal movement across the studied joint motions. In the majority of joint motions, contracture severity significantly increased with larger burn size and longer length of stay; however, wrist and many lower extremity joint movements did not demonstrate this trend. The data illustrate the quantitative assessment of range of motion deficits in adults with burn injury at discharge and the relation to burn size and length of stay.

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

Abstract: 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.

Strength and Cardiorespiratory Exercise Rehabilitation for Severely Burned Patients During Intensive Care Units: A Survey of Practice.

Abstract: Minimizing the deconditioning of burn injury through early rehabilitation programs (RP) in the intensive care unit (ICU) is of importance for improving the recovery time. The aim of this study was to assess current standard of care (SOC) for early ICU exercise programs in major burn centers. We designed a survey investigating exercise RP on the ICU for burn patients with >30% total burned surface area. The survey was composed of 23 questions and submitted electronically via SurveyMonkey® to six major (pediatric and adult) burn centers in Texas and California. All centers responded and reported exercise as part of their RP on the ICU. The characteristics of exercises implemented were not uniform. All centers reported to perform resistive and aerobic exercises but only 83% reported isotonic and isometric exercises. Determination of intensity of exercise varied with 50% of centers using patient tolerance and 17% using vital signs. Frequency of isotonic, isometric, aerobic, and resistive exercise was reported as daily by 80%, 80%, 83%, and 50% of centers, respectively. Duration for all types of exercises was extremely variable. Mobilization was used as a form of exercise by 100% of burn centers. Our results demonstrate that although early RP seem to be integral during burn survivor's ICU stay, no SOC exists. Moreover, early RP are inconsistently administered and large variations exist in frequency, intensity, duration, and type of exercise. Thus, future prospective studies investigating the various components of exercise interventions are needed to establish a SOC and determine how and if early exercise benefits the burn survivor.

Natural Compound Oridonin Inhibits Endotoxin-Induced Inflammatory Response of Activated Hepatic Stellate Cells.

Abstract: Hepatic stellate cells (HSCs) play an important role in hepatic fibrogenesis and inflammatory modulation. Endotoxin is dramatically increased in portal venous blood after serious injury and can contribute to liver damage. However, the mechanism underlying endotoxin's effects on HSCs remains largely unknown. Oridonin is a bioactive diterpenoid isolated from Rabdosia rubescens that exhibits anti-inflammatory properties in different tissues. In the present study, we determined the effects of oridonin on endotoxin-induced inflammatory response and signaling pathways in vitro. The production of proinflammatory cytokines in activated human HSCs line LX-2 was measured by ELISA and Western blots. Immunofluorescence and nuclear fractionation assay were used to determine NF-κB activity. Oridonin treatment significantly inhibited LPS-induced proinflammatory cytokines IL-1β, IL-6, and MCP-1 production as well as cell adhesion molecules ICAM-1 and VCAM-1. Additionally, oridonin blocked LPS-induced NF-κB p65 nuclear translocation and DNA binding activity. Oridonin prevented LPS-stimulated NF-κB regulator IKKα/β and IκBα phosphorylation and IκBα degradation. Combined treatment of oridonin and an Hsp70 substrate binding inhibitor synergistically suppressed LPS-stimulated proinflammatory cytokines and NF-κB pathway activation. Therefore, oridonin inhibits LPS-stimulated proinflammatory mediators through IKK/IκBα/NF-κB pathway. Oridonin could be a promising agent for a hepatic anti-inflammatory.

The Long-Term Impact of Severe Burn Trauma on Musculoskeletal Health

Abstract: Severe burn injury causes a profound stress response that leads to muscle and bone cachexia. Evidence suggests that these deficits persist for several months or even years after injury and are associated with growth delay, increased incidence of fractures, and increased hospital admissions for musculoskeletal disorders. Thus, there is an overwhelming need to determine the optimal acute and rehabilitative strategies to mitigate these deficits and improve quality of life for burn survivors. To date, there is limited research on the long-term impact of cachexia on functional performance and overall health, as well as on the lasting impact of pharmacological, nutritional, and exercise interventions. The aim of this review is to emphasize the long-term consequences of musculoskeletal cachexia and determine the best evidence-based strategies to attenuate it. We also underline important knowledge gaps that need to be addressed in order to improve care of burn survivors.

The Effect of Burn Trauma on Lipid and Glucose Metabolism: Implications for Insulin Sensitivity

Abstract: Severe burns represent a unique form of trauma in terms of the magnitude and persistence of the stress response they incur. Given advances in acute burn care in the last quarter of a century and the resultant reduction in mortality rates, even for those with massive burns, greater emphasis is now placed on understanding the metabolic stress response to severe burn trauma in order to devise strategies that promote recovery and reduce morbidity. Derangements in metabolism including protein and lipid redistribution and altered glucose handling are hallmarks of the pathophysiological response to burn trauma. In this review article, we aim to distill and discuss the c urrent literature concerning the effect of burn trauma on lipid and glucose metabolism. Furthermore, we will discuss the implications of altered lipid metabolism with regards to insulin sensitivity and glucose control, while discussing the utility of agents and strategies aimed at restoring normal lipid and glucose metabolism in burned patients.

Short-term Metformin and Exercise Training Effects on Strength, Aerobic Capacity, Glycemic Control, and Mitochondrial Function in Children with Burn Injury

Abstract: Severely burned children experience a chronic state of sympathetic nervous system activation that is associated with hypermetabolic/cardiac stress and muscle wasting. Metformin, a diabetes medicati...

Burn Injury May Have Age-Dependent Effects on Strength and Aerobic Exercise Capacity in Males.

Abstract: Whether burn injury affects boys and men differently is currently unknown. To test the hypothesis that burned boys have lower exercise capacity and exercise training-induced responses compared with burned men, 40 young boys (12 ± 4 years, 149 ± 20 cm, 46 ± 18 kg) were matched to 35 adult men (33 ± 9 years, 174 ± 10 cm, 84 ± 16 kg) based on extent of burn injury (total body surface area burned, boys 46 ± 14% vs men 47 ± 30, P = .85) and length of hospital stay (boys 33 ± 23 vs men 41 ± 32 days, P = .23). Strength (peak torque) and cardiorespiratory fitness (peak VO2) were normalized to kg of lean body mass for group comparisons. Each group was also compared with normative age-sex matched values at discharge and after an aerobic and resistance exercise training (RET) program. A two-way factorial analysis of covariance assessed interaction and main effects of group and time. We found that boys and men showed similar pre-RET to post-RET increases in total lean (~4%) and fat (7%) mass (each P ≤ .008). Both groups had lower age-sex matched norm values at discharge for peak torque (boys 36%; men 51% of normative values) and peak VO2 (boys: 44; men: 59%; each P ≤ .0001). Boys strength were 13-15 per cent lower than men at discharge and after RET (main effect for group, P < .0001). Cardiorespiratory fitness improved to a greater extent in men (19%) compared with boys (10%) after the RET (group × time interaction, P = .011). These results show that at discharge and after RET, burn injury may have age-dependent effects and should be considered when evaluating efficacy and progress of the exercise program.

Rehabilitation Exercise Increases Physical Activity Levels in Severely Burned Children While Improving Aerobic Exercise Capacity and Strength.

Abstract: This study tested the hypothesis that participation in a rehabilitation exercise program following hospital discharge would increase the level of physical activity in burned children than that seen in free-living nonburned children. Thirty-one severely burned children (12 ± 3 years, 144 ± 18 cm, 42 ± 17 kg, 48 ± 12% TBSA burns) were matched to 31 nonburned children (12 ± 3 y, 147 ± 17 cm, 45 ± 15 kg) based on age and sex. Pedometers were used to track minutes and steps in burned children during their exercise rehabilitation and nonburned children under free-living conditions (healthy control). We found that the average minutes of activity per day was lower in burned children (56 ± 25minutes) than in nonburned children (74 ± 28 minutes, P < .05). However, no difference was detected for average steps per day or week or maximal minutes in 1 day or week. At discharge, burn children had peak torque and mean power values that were 61% of nonburned values, and exercise training improved these by 27 and 28%, respectively (88 and 89% of nonburned values; each P ≤ .0001). Likewise, cardiorespiratory fitness at discharge was 72% of nonburned values, and exercise training improved fitness by 10% (82% of nonburned values, P < .05). Percentage TBSA burned was inversely associated with steps (r = -0.54, P = .001) and minutes of activity (r = -0.53, P = .002), accounting for 28-29% of the variability in burned children. These results show that, at discharge, burned children are capable of matching steps of physical activity levels seen in nonburned healthy children. Physical activity monitoring may be a viable option for continued improvement of physical exercise capacity when burned children are under free-living conditions.