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1.
Crit Care Explor ; 6(3): e1058, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38415021

RESUMO

BACKGROUND: Streptococcal toxic shock syndrome (STSS) is a fulminant complication of predominantly invasive group A streptococcal infections. STSS is often characterized by influenza-like symptoms, including fever, chills, and myalgia that can quickly progress to sepsis with hypotension, tachycardia, tachypnea, and multiple organ failure (kidney, liver, lung, or blood). Mortality can exceed 50% depending on the severity of symptoms. CASE SUMMARY: Here, we describe a novel, multi-extracorporeal intervention strategy in a case of severe septic shock secondary to STSS. A 28-year-old woman 5 days after cesarean section developed STSS with respiratory distress, hypotension, and multiple organ failure. Despite conventional therapy with intubation, antibiotics, vasopressors, and fluid resuscitation, her condition worsened. She was placed on venoarterial extracorporeal membrane oxygenation (VA-ECMO) with subsequent initiation of pathogen hemoperfusion using the Seraph 100 blood filter, followed by immunomodulation with the selective cytopheretic device (SCD). No device-related adverse events were observed. The patient's condition gradually stabilized with discontinuation of vasopressors after 4 days, ECMO decannulation after 6 days, evidence of renal recovery after 7 days, and extubation from mechanical ventilation after 14 days. She was transferred to conventional hemodialysis after 13 days and discontinued all kidney replacement therapy 11 days later. CONCLUSIONS: This is the first reported use of VA-ECMO, Seraph 100 hemoperfusion, and cell-directed immunomodulation with SCD. This multimodal approach to extracorporeal support represents a promising therapeutic strategy for the most refractory critical care cases. Further studies are needed to assess the safety and efficacy of this sequential approach.

2.
J Burn Care Res ; 43(6): 1260-1270, 2022 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-35863690

RESUMO

Thermal burn injuries are still a serious public health concern in the United States, due to the initial insult and resulting comorbidities. Burned patients are increasingly susceptible to colonization by endogenous and exogenous microorganisms after having lost skin, which acts as the primary protective barrier to environmental contaminants. Furthermore, the onset of additional pathophysiologies, specifically sepsis, becomes more likely in burned patients compared to other injuries. Despite improvements in the early care of burn patients, infections, and sepsis, these pathophysiologies remain major causes of morbidity and mortality and warrant further investigation of potential therapies. Vitamin E may be one such therapy. We aimed to identify publications of studies that evaluated the effectiveness of vitamin E as it pertains to thermal burn injuries, infection, and sepsis. Several investigations ranging from in vitro bench work to clinical studies have examined the impact on, or influence of, vitamin E in vitro, in vivo, and in the clinical setting. To the benefit of subjects it has been shown that enteral or parenteral vitamin E supplementation can prevent, mitigate, and even reverse the effects of thermal burn injuries, infection, and sepsis. Therefore, a large-scale prospective observational study to assess the potential benefits of vitamin E supplementation in patients is warranted and could result in clinical care practice paradigm changes.


Assuntos
Queimaduras , Sepse , Humanos , Queimaduras/terapia , Vitamina E , Estudos Prospectivos , Pele , Estudos Observacionais como Assunto
3.
Stem Cell Res Ther ; 12(1): 270, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33957963

RESUMO

BACKGROUND: Patients with severe burn injury (over 20% of the total body surface area) experience profound hypermetabolism which significantly prolongs wound healing. Adipose-derived stem cells (ASCs) have been proposed as an attractive solution for treating burn wounds, including the potential for autologous ASC expansion. While subcutaneous adipocytes display an altered metabolic profile post-burn, it is not known if this is the case with the stem cells associated with the adipose tissue. METHODS: ASCs were isolated from discarded burn skin of severely injured human subjects (BH, n = 6) and unburned subcutaneous adipose tissue of patients undergoing elective abdominoplasty (UH, n = 6) and were analyzed at passages 2, 4, and 6. Flow cytometry was used to quantify ASC cell surface markers CD90, CD105, and CD73. Mitochondrial abundance and reactive oxygen species (ROS) production were determined with MitoTracker Green and MitoSOX Red, respectively, while JC-10 Mitochondrial Membrane Potential Assays were also performed. Mitochondrial respiration and glycolysis were analyzed with a high-resolution respirometer (Seahorse XFe24 Analyzer). RESULTS: There was no difference in age between BH and UH (34 ± 6 and 41 ± 4 years, respectively, P = 0.49). While passage 2 ASCs had lower ASC marker expression than subsequent passages, there were no significant differences in the expression between BH and UH ASCs. Similarly, no differences in mitochondrial abundance or membrane potential were found amongst passages or groups. Two-way ANOVA showed a significant effect (P < 0.01) of passaging on mitochondrial ROS production, with increased ROS in BH ASCs at later passages. Oxidative phosphorylation capacities (leak and maximal respiration) increased significantly in BH ASCs (P = 0.035) but not UH ASCs. On the contrary, basal glycolysis significantly decreased in BH ASCs (P = 0.011) with subsequent passaging, but not UH ASCs. CONCLUSIONS: In conclusion, ASCs from burned individuals become increasingly oxidative and less glycolytic upon passaging when compared to ASCs from unburned patients. This increase in oxidative capacities was associated with ROS production in later passages. While the autologous expansion of ASCs holds great promise for treating burned patients with limited donor sites, the potential negative consequences of using them require further investigation.


Assuntos
Adipócitos , Tecido Adiposo , Diferenciação Celular , Humanos , Estresse Oxidativo , Espécies Reativas de Oxigênio , Células-Tronco
4.
Shock ; 55(2): 143-146, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33433166
5.
Toxicol Appl Pharmacol ; 362: 9-19, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30248415

RESUMO

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.


Assuntos
Cicatriz Hipertrófica/tratamento farmacológico , Etanolaminas/farmacologia , Fibroblastos/efeitos dos fármacos , Linhagem Celular , Cicatriz Hipertrófica/metabolismo , Colágeno/metabolismo , Matriz Extracelular/efeitos dos fármacos , Fibroblastos/metabolismo , Fibrose , Humanos , Relação Estrutura-Atividade , Fator de Crescimento Transformador beta1/metabolismo
6.
Burns ; 44(8): 1863-1869, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30077487

RESUMO

Severe burns in children can lead to growth delays, bone loss, and wasting of lean body mass and muscle with subsequent long-term effects such as osteoporosis. The following review examines 11 randomized, placebo-controlled, prospective clinical trials in pediatric burns between 1995 and 2017. These studies included approximately 250 burned children, and they were conducted to evaluate the impact of severe burn on markers of bone formation and bone metabolism. Some trials also analyzed current therapy regimens such as pamidronate and vitamin D. The clinical utility of these outlined biomarkers is uncertain with regard to acute burn care, as the current literature remains unclear. This review thus serves to address the impact of severe burn on markers of bone formation and bone metabolism in pediatric patients but will not focus on the clinical utility of the markers. The aim of this review is to summarize the findings of the trials to guide the future care of burned patients to maximize bone recovery.


Assuntos
Remodelação Óssea , Osso e Ossos/metabolismo , Queimaduras/metabolismo , Osteogênese , Proteínas Adaptadoras de Transdução de Sinal , Alumínio/metabolismo , Composição Corporal , Densidade Óssea , Conservadores da Densidade Óssea/uso terapêutico , Proteína Morfogenética Óssea 2/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Cálcio/metabolismo , Criança , Colágeno Tipo I/metabolismo , Cobre/metabolismo , Marcadores Genéticos , Glucocorticoides/metabolismo , Humanos , Magnésio/metabolismo , Osteoblastos , Osteocalcina/metabolismo , Osteoclastos , Osteoporose/prevenção & controle , Pamidronato/uso terapêutico , Hormônio Paratireóideo/metabolismo , Vitamina D/análogos & derivados , Vitamina D/metabolismo , Vitamina D/uso terapêutico , Zinco/metabolismo
7.
Ann Surg ; 268(3): 431-441, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30048322

RESUMO

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.


Assuntos
Anabolizantes/uso terapêutico , Queimaduras/complicações , Cicatriz Hipertrófica/etiologia , Cicatriz Hipertrófica/prevenção & controle , Oxandrolona/uso terapêutico , Propranolol/uso terapêutico , Vasodilatadores/uso terapêutico , Adolescente , Anabolizantes/administração & dosagem , Biomarcadores/metabolismo , Biópsia , Criança , Cicatriz Hipertrófica/metabolismo , Método Duplo-Cego , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Oxandrolona/administração & dosagem , Propranolol/administração & dosagem , Estudos Prospectivos , Qualidade de Vida , Recuperação de Função Fisiológica , Resultado do Tratamento , Vasodilatadores/administração & dosagem
8.
J Am Coll Surg ; 226(4): 453-463, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29530306

RESUMO

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.


Assuntos
Queimaduras/mortalidade , Queimaduras/terapia , Adolescente , Adulto , Fatores Etários , Superfície Corporal , Queimaduras/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
9.
J Trauma Acute Care Surg ; 83(3): 532-542, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28697015

RESUMO

Since the inception of the P50 Research Center in Injury and Peri-operative Sciences (RCIPS) funding mechanism, the National Institute of General Medical Sciences has supported a team approach to science. Many advances in critical care, particularly burns, have been driven by RCIPS teams. In fact, burns that were fatal in the early 1970s, prior to the inception of the P50 RCIPS program, are now routinely survived as a result of the P50-funded research. The advances in clinical care that led to the reduction in postburn death were made by optimizing resuscitation, incorporating early excision and grafting, bolstering acute care including support for inhalation injury, modulating the hypermetabolic response, augmenting the immune response, incorporating aerobic exercise, and developing antiscarring strategies. The work of the Burn RCIPS programs advanced our understanding of the pathophysiologic response to burn injury. As a result, the effects of a large burn on all organ systems have been studied, leading to the discovery of persistent dysfunction, elucidation of the underlying molecular mechanisms, and identification of potential therapeutic targets. Survival and subsequent patient satisfaction with quality of life have increased. In this review article, we describe the contributions of the Galveston P50 RCIPS that have changed postburn care and have considerably reduced postburn mortality.


Assuntos
Pesquisa Biomédica/história , Queimaduras/mortalidade , Queimaduras/terapia , Insuficiência de Múltiplos Órgãos/história , National Institute of General Medical Sciences (U.S.)/história , Apoio à Pesquisa como Assunto/história , Centros de Traumatologia/história , História do Século XX , História do Século XXI , Humanos , Estados Unidos
10.
Pediatr Crit Care Med ; 18(10): e472-e476, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28723881

RESUMO

OBJECTIVES: Determine whether the peripheral capillary oxygenation/FIO2 ratio correlates with the PaO2/FIO2 ratio in burned children with smoke inhalation injury, with the goal of understanding if the peripheral capillary oxygenation/FIO2 ratio can serve as a surrogate for the PaO2/FIO2 ratio for the diagnosis of acute respiratory distress syndrome. DESIGN: Retrospective chart review. SETTING: Shriners Hospitals for Children-Galveston. PATIENTS: All burned children with smoke inhalation injury who were admitted from 1996 to 2014 and had simultaneously obtained peripheral capillary oxygenation, FIO2 and PaO2 measurements. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two hundred seventy-three patients (63% male, 8 ± 5 yr, 53% ± 24% total body surface area burns) were analyzed. Peripheral capillary oxygenation/FIO2 ratios were divided into four subgroups based on peripheral capillary oxygenation values (≤ 100%, ≤ 98%, ≤ 95%, and ≤ 92%). Significance was accepted at r greater than 0.81. The r (number of matches) was 0.66 (23,072) for less than or equal to 100%, 0.87 (18,932) for less than or equal to 98%, 0.89 (7,056) for less than or equal to 95%, and 0.93 (4,229) for less than or equal to 92%. In the subgroup of patients who developed acute respiratory distress syndrome, r was 0.65 (8,357) for less than or equal to 100%, 0.89 (7,578) for less than or equal to 98%, 0.89 (4,115) for less than or equal to 95%, and 0.91 (2,288) less than or equal to 92%. CONCLUSIONS: PaO2/FIO2 and peripheral capillary oxygenation/FIO2 strongly correlate in burned children with smoke inhalation injury, with a peripheral capillary oxygenation of less than 92% providing the strongest correlation. Thus, peripheral capillary oxygenation/FIO2 ratio may be able to serve as surrogate for PaO2/FIO2, especially when titrating FIO2 to achieve a peripheral capillary oxygenation of 90-95% (i.e., in the acute respiratory distress syndrome range).


Assuntos
Queimaduras/complicações , Oxigênio/sangue , Síndrome do Desconforto Respiratório/diagnóstico , Lesão por Inalação de Fumaça/complicações , Adolescente , Biomarcadores/sangue , Gasometria , Capilares , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Síndrome do Desconforto Respiratório/sangue , Síndrome do Desconforto Respiratório/etiologia , Estudos Retrospectivos
11.
JBMR Plus ; 1(2): 59-65, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30283881

RESUMO

Approximately 85% of the body's phosphate pool resides within the skeleton. The remaining 15% is stored as high-energy phosphates or in its free form, where it acts as a substrate for adenosine triphosphate (ATP) production. Accordingly, phosphate plays a crucial role in energy metabolism. Trauma and critical illness result in a hypermetabolic state in which energy expenditure increases. The impact of trauma and critical illness on the body's phosphate stores and phosphate-dependent metabolic reactions is poorly understood. We had previously observed that after severe burn trauma, increased energy expenditure is temporally related to a marked reduction in serum concentrations of both parathyroid hormone and fibroblast growth factor 23, both of which have phosphaturic effects. The aim of this article is to describe as far as is known the similarities and differences in phosphate metabolism in different types of injury and to infer what these differences tell us about possible signaling pathways that may link increased phosphate utilization and phosphate retention. © 2017 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

12.
Ann Surg ; 264(3): 421-8, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27433905

RESUMO

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.


Assuntos
Queimaduras/complicações , Transtornos do Crescimento/tratamento farmacológico , Oxandrolona/administração & dosagem , Propranolol/administração & dosagem , Adolescente , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Crescimento/efeitos dos fármacos , Transtornos do Crescimento/etiologia , Humanos , Lactente , Masculino , Estudos Prospectivos , Testosterona/análogos & derivados
13.
J Burn Care Res ; 37(5): 273-7, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27171844

RESUMO

Pulmonary dysfunction is a significant contributor to morbidity and mortality in the pediatric burned population. We have previously reported that the administration of a synthetic testosterone derivative, oxandrolone, significantly reduced hypermetabolism, and significantly increased height percentile, bone mineral content, lean body mass, and strength in pediatric burned patients. We hypothesize that the administration of oxandrolone will improve pulmonary function in burned pediatric subjects. A subset of severely burned pediatric subjects from a prospective clinical trial (n = 222) were included in our study (n = 54, 7-18 years, ≥30% TBSA burn). The subjects were previously randomized to either the control arm (n = 35) or the oxandrolone arm (0.1 mg/kg twice/day for 12 months, n = 19). Maximum voluntary ventilation, the ratio between forced expiratory volume and forced vital capacity, and diffusion capacity were measured 6 months following burn injury, and results were compared between burned subjects with and without oxandrolone administration. Maximum expired ventilation (VEmax) was also measured in a subset of burned subjects. Subjects treated with oxandrolone had a significantly higher maximum voluntary ventilation (98 ± 53 L/min vs 115 ± 56 with treatment, P = .03). During maximal exercise, subjects treated with oxandrolone had a significantly higher VEmax compared with untreated subjects (32.0 ± 8.7 L/min vs 43.7 ± 13.6 with treatment, P = .02). The administration of oxandrolone was associated with improved lung function in pediatric burned patients.


Assuntos
Queimaduras/terapia , Proteínas de Neoplasias/efeitos dos fármacos , Proteínas Nucleares/efeitos dos fármacos , Oxandrolona/administração & dosagem , Ubiquitina-Proteína Ligases/efeitos dos fármacos , Adolescente , Criança , Feminino , Humanos , Masculino , Ventilação Voluntária Máxima , Oxandrolona/uso terapêutico , Estudos Prospectivos
14.
Burns ; 41(8): 1775-1787, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26392023

RESUMO

UNLABELLED: Oxidative stress may be involved in the cellular damage and tissue destruction as burn wounds continues to progress after abatement of the initial insult. Since iron and calcium ions play key roles in oxidative stress, this study tested whether topical application of Livionex formulation (LF) lotion, that contains disodium EDTA as a metal chelator and methyl sulfonyl methane (MSM) as a permeability enhancer, would prevent or reduce burns. METHODS: We used an established brass comb burn model with some modifications. Topical application of LF lotion was started 5 min post-burn, and repeated every 8 h for 3 consecutive days. Rats were euthanized and skin harvested for histochemistry and immunohistochemistry. Formation of protein adducts of 4-hydroxynonenal (HNE), malonadialdehyde (MDA) and acrolein (ACR) and expression of aldehyde dehydrogenase (ALDH) isozymes, ALDH1 and ALDH2 were assessed. RESULTS: LF lotion-treated burn sites and interspaces showed mild morphological improvement compared to untreated burn sites. Furthermore, the lotion significantly decreased the immunostaining of lipid aldehyde-protein adducts including protein -HNE, -MDA and -ACR adducts, and restored the expression of aldehyde dehydrogenase isozymes in the unburned interspaces. CONCLUSION: This data, for the first time, demonstrates that a topically applied EDTA-containing lotion protects burns progression with a concomitant decrease in the accumulation of reactive lipid aldehydes and protection of aldehyde dehydrogenase isozymes. Present studies are suggestive of therapeutic intervention of burns by this novel lotion.


Assuntos
Queimaduras , Quelantes/farmacologia , Dimetil Sulfóxido/farmacologia , Ácido Edético/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Pele/efeitos dos fármacos , Sulfonas/farmacologia , Acroleína/metabolismo , Administração Cutânea , Aldeído Desidrogenase/efeitos dos fármacos , Aldeído Desidrogenase/metabolismo , Família Aldeído Desidrogenase 1 , Aldeído-Desidrogenase Mitocondrial , Aldeídos/metabolismo , Animais , Cobre , Modelos Animais de Doenças , Imuno-Histoquímica , Malondialdeído/metabolismo , Proteínas Mitocondriais/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Permeabilidade/efeitos dos fármacos , Ratos , Retinal Desidrogenase/efeitos dos fármacos , Retinal Desidrogenase/metabolismo , Pele/metabolismo , Pele/patologia , Índices de Gravidade do Trauma , Zinco
15.
Burns ; 41(7): 1435-41, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26093952

RESUMO

UNLABELLED: This study examines the structural integrity of the airway epithelium in autopsy tissues from pediatric burn subjects. METHODS: A semi-quantitative score for the degree of airway epithelial integrity was made for seventy- two pediatric burn autopsies. Multivariate ordinal logistic regression was performed to identify relationships between epithelial integrity and conditions related to tissue fixation, time of death after injury, age, total body surface area burn (TBSA), extent of 3rd degree burn, presence of inhalation injury, ventilator days and pneumonia. RESULTS: No significant difference in epithelial integrity scores was identified between burn only cases and those with inhalation injury. Significant correlations with bronchiolar epithelial integrity scores were identified for age, p=0.02, and percent 3rd degree burn, p=0.02. There was no significant relationship between epithelial integrity and time between death and autopsy, p>0.44. CONCLUSIONS: Airway epithelial loss seen in autopsy tissue is not simply an artifact of tissue fixation. The degree of compromise correlates most strongly with age and degree of burn. Further studies are needed to identify physiological or critical care factors following burn injury that contribute to compromise in the structural and functional properties of the airway epithelium.


Assuntos
Queimaduras/patologia , Mucosa Respiratória/patologia , Adolescente , Adulto , Fatores Etários , Autopsia , Brônquios/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Modelos Logísticos , Masculino , Lesão por Inalação de Fumaça/patologia , Adulto Jovem
16.
J Am Coll Surg ; 220(4): 570-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25724604

RESUMO

BACKGROUND: Inhalation injury, which is among the causes of acute lung injury and acute respiratory distress syndrome (ARDS), continues to represent a significant source of mortality in burned patients. Inhalation injury often requires mechanical ventilation, but the ideal tidal volume strategy is not clearly defined in burned pediatric patients. The aim of this study was to determine the effects of low and high tidal volume on the number of ventilator days, ventilation pressures, and incidence of atelectasis, pneumonia, and ARDS in pediatric burned patients with inhalation injury within 1 year post burn injury. METHODS: From 1986 to 2014, inhalation injury was diagnosed by bronchoscopy in pediatric burned patients (n = 932). Patients were divided into 3 groups: unventilated (n = 241), high tidal volume (HTV, 15 ± 3 mL/kg, n = 190), and low tidal volume (LTV, 9 ± 3 mL/kg, n = 501). RESULTS: High tidal volume was associated with significantly decreased ventilator days (p < 0.005) and maximum positive end expiratory pressure (p < 0.0001) and significantly increased maximum peak inspiratory pressure (p < 0.02) and plateau pressure (p < 0.02) compared with those in patients with LTV. The incidence of atelectasis (p < 0.0001) and ARDS (p < 0.02) was significantly decreased with HTV compared with LTV. However, the incidence of pneumothorax was significantly increased in the HTV group compared with the LTV group (p < 0.03). CONCLUSIONS: High tidal volume significantly decreases ventilator days and the incidence of both atelectasis and ARDS compared with low tidal volume in pediatric burned patients with inhalation injury. Therefore, the use of HTV may interrupt sequences leading to lung injury in our patient population.


Assuntos
Queimaduras por Inalação/complicações , Respiração com Pressão Positiva/métodos , Atelectasia Pulmonar/terapia , Síndrome do Desconforto Respiratório/terapia , Volume de Ventilação Pulmonar/fisiologia , Adolescente , Queimaduras por Inalação/diagnóstico , Queimaduras por Inalação/terapia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Atelectasia Pulmonar/epidemiologia , Atelectasia Pulmonar/etiologia , Síndrome do Desconforto Respiratório/epidemiologia , Síndrome do Desconforto Respiratório/etiologia , Estudos Retrospectivos , Texas/epidemiologia , Resultado do Tratamento
17.
Burns ; 41(3): 519-27, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25445004

RESUMO

UNLABELLED: Pulmonary abnormalities occur in 30-80% of fatalities after burn. The objective of our study is to investigate lung pathology in autopsy tissues of pediatric burn patients. METHODS: Three scientists with pathology training in pediatric burn care reviewed masked autopsy slides of burned children who died after admission to a burn center from 2002 to 2012 (n=43). Autopsy lung tissue was assigned scores for histologic abnormalities in 9 categories, including alveolar and interstitial fibrosis, hyaline membranes, and type II epithelial cell proliferation. Scores were then tested for correlation with age, TBSA burn, number of days between burn and death, time between burn and admission, and the presence of inhalation injury using analyses with linear models. RESULTS: Type II epithelial cell proliferation was significantly more common in cases with a longer time between burn and admission (p<0.02). Interstitial fibrosis was significantly more severe in cases with longer survival after burn (p<0.01). The scores for protein were significantly higher in cases with longer survival after burn (p<0.03). Enlarged air spaces were significantly more prominent in cases with longer survival after burn (p<0.01), and in cases with the presence of inhalation injury (p<0.01). CONCLUSIONS: Histological findings associated with diffuse alveolar damage (DAD), which is the pathological correlate of the acute respiratory distress syndrome (ARDS), were seen in approximately 42% of autopsies studied. Protein-rich alveolar edema, which is the abnormality that leads to ARDS, may occur from multiple causes, including inhalation injury.


Assuntos
Lesão Pulmonar Aguda/patologia , Queimaduras/complicações , Pulmão/patologia , Síndrome do Desconforto Respiratório/patologia , Lesão por Inalação de Fumaça/patologia , Lesão Pulmonar Aguda/complicações , Adolescente , Autopsia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Fibrose/complicações , Fibrose/patologia , Hemorragia/complicações , Hemorragia/patologia , Humanos , Hialina , Lactente , Recém-Nascido , Masculino , Edema Pulmonar/complicações , Edema Pulmonar/patologia , Síndrome do Desconforto Respiratório/complicações , Estudos Retrospectivos , Lesão por Inalação de Fumaça/complicações , Fatores de Tempo
18.
J Trauma Acute Care Surg ; 76(1): 126-33, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24368367

RESUMO

BACKGROUND: Pulmonary coagulopathy has become an important therapeutic target in adult respiratory distress syndrome (ARDS). We hypothesized that combining intravenous recombinant human antithrombin (rhAT), nebulized heparin, and nebulized tissue plasminogen activator (TPA) more effectively improves pulmonary gas exchange compared with a single rhAT infusion, while maintaining the anti-inflammatory properties of rhAT in ARDS. Therefore, the present prospective, randomized experiment was conducted using an established ovine model. METHODS: Following burn and smoke inhalation injury (40% of total body surface area, third-degree flame burn, and 4 × 12 breaths of cold cotton smoke), 18 chronically instrumented sheep were randomly assigned to receive intravenous saline plus saline nebulization (control), intravenous rhAT (6 IU/kg/h) started 1 hour after injury plus saline nebulization (AT i.v.) or intravenous rhAT combined with nebulized heparin (10,000 IU every 4 hours, started 2 hours after injury), and nebulized TPA (2 mg every 4 hours, started 4 hours after injury) (triple therapy, n = 6 each). All animals were mechanically ventilated and fluid resuscitated according to standard protocols during the 48-hour study period. RESULTS: Both treatment approaches attenuated ARDS compared with control animals. Notably, triple therapy was associated with an improved PaO2/FiO2 ratio (p = 0.007), attenuated pulmonary obstruction (p = 0.02) and shunting (p = 0.025), as well as reduced ventilatory pressures (p < 0.05 each) versus AT i.v. at 48 hours. However, the anti-inflammatory effects of sole AT i.v., namely, the inhibition of neutrophil activation (neutrophil count in the lymph and pulmonary polymorphonuclear cells, p < 0.05 vs. control each), pulmonary transvascular fluid flux (lymph flow, p = 0.004 vs. control), and systemic vascular leakage (cumulative net fluid balance, p < 0.001 vs. control), were abolished in the triple therapy group. CONCLUSION: Combining intravenous rhAT with nebulized heparin and nebulized TPA more effectively restores pulmonary gas exchange, but the anti-inflammatory effects of sole rhAT are abolished with the triple therapy. Interferences between the different anticoagulants may represent a potential explanation for these findings.


Assuntos
Antitrombinas/uso terapêutico , Heparina/uso terapêutico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Ativador de Plasminogênio Tecidual/uso terapêutico , Administração por Inalação , Administração Intravenosa , Animais , Antitrombinas/administração & dosagem , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Heparina/administração & dosagem , Nebulizadores e Vaporizadores , Troca Gasosa Pulmonar/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Respiração Artificial , Ovinos , Ativador de Plasminogênio Tecidual/administração & dosagem
19.
Crit Care Med ; 41(12): e439-46, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24107637

RESUMO

OBJECTIVE: To test the hypothesis that restoration of antithrombin plasma concentrations attenuates vascular leakage by inhibiting neutrophil activation through syndecan-4 receptor inhibition in an established ovine model of acute lung injury. DESIGN: Randomized controlled laboratory experiment. SETTING: University animal research facility. SUBJECTS: Eighteen chronically instrumented sheep. INTERVENTIONS: Following combined burn and smoke inhalation injury (40% of total body surface area, third-degree flame burn; 4 × 12 breaths of cold cotton smoke), chronically instrumented sheep were randomly assigned to receive an IV infusion of 6 IU/kg/hr recombinant human antithrombin III or normal saline (n = 6 each) during the 48-hour study period. In addition, six sham animals (not injured, continuous infusion of vehicle) were used to obtain reference values for histological and immunohistochemical analyses. MEASUREMENTS AND MAIN RESULTS: Compared to control animals, recombinant human antithrombin III reduced the number of neutrophils per hour in the pulmonary lymph (p < 0.01 at 24 and 48 hr), alveolar neutrophil infiltration (p = 0.04), and pulmonary myeloperoxidase activity (p = 0.026). Flow cytometric analysis revealed a significant reduction of syndecan-4-positive neutrophils (p = 0.002 vs control at 24 hr). Treatment with recombinant human antithrombin III resulted in a reduction of pulmonary nitrosative stress (p = 0.002), airway obstruction (bronchi: p = 0.001, bronchioli: p = 0.013), parenchymal edema (p = 0.044), and lung bloodless wet-to-dry-weight ratio (p = 0.015). Clinically, recombinant human antithrombin III attenuated the increased pulmonary transvascular fluid flux (12-48 hr: p ≤ 0.001 vs control each) and the deteriorated pulmonary gas exchange (12-48 hr: p < 0.05 vs control each) without increasing the risk of bleeding. CONCLUSIONS: The present study provides evidence for the interaction between antithrombin and neutrophils in vivo, its pathophysiological role in vascular leakage, and the therapeutic potential of recombinant human antithrombin III in a large animal model of acute lung injury.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/fisiopatologia , Antitrombina III/uso terapêutico , Antitrombinas/uso terapêutico , Permeabilidade Capilar/efeitos dos fármacos , Ativação de Neutrófilo/efeitos dos fármacos , Neutrófilos/fisiologia , Receptores Acoplados a Proteínas G/metabolismo , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/patologia , Obstrução das Vias Respiratórias/tratamento farmacológico , Animais , Queimaduras/complicações , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Edema/tratamento farmacológico , Feminino , Pulmão/enzimologia , Pulmão/patologia , Neutrófilos/metabolismo , Peroxidase/metabolismo , Troca Gasosa Pulmonar/efeitos dos fármacos , Distribuição Aleatória , Proteínas Recombinantes/uso terapêutico , Ovinos , Lesão por Inalação de Fumaça/complicações , Sindecana-4/metabolismo
20.
Crit Care ; 17(3): R86, 2013 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-23663695

RESUMO

INTRODUCTION: We hypothesized that maintaining physiological plasma levels of antithrombin attenuates myocardial dysfunction and inflammation as well as vascular leakage associated with burn and smoke inhalation injury. Therefore, the present prospective, randomized experiment was conducted using an established ovine model. METHODS: Following 40% of total body surface area, third degree flame burn and 4 × 12 breaths of cold cotton smoke, chronically instrumented sheep were randomly assigned to receive an intravenous infusion of 6 IU/kg/h recombinant human antithrombin (rhAT) or normal saline (control group; n = 6 each). In addition, six sheep were designated as sham animals (not injured, continuous infusion of vehicle). During the 48 h study period the animals were awake, mechanically ventilated and fluid resuscitated according to standard formulas. RESULTS: Compared to the sham group, myocardial contractility was severely impaired in control animals, as suggested by lower stroke volume and left ventricular stroke work indexes. As a compensatory mechanism, heart rate increased, thereby increasing myocardial oxygen consumption. In parallel, myocardial inflammation was induced via nitric oxide production, neutrophil accumulation (myeloperoxidase activity) and activation of the p38-mitogen-activated protein kinase pathway resulting in cytokine release (tumor necrosis factor-alpha, interleukin-6) in control vs. sham animals. rhAT-treatment significantly attenuated these inflammatory changes leading to a myocardial contractility and myocardial oxygen consumption comparable to sham animals. In control animals, systemic fluid accumulation progressively increased over time resulting in a cumulative positive fluid balance of about 4,000 ml at the end of the study period. Contrarily, in rhAT-treated animals there was only an initial fluid accumulation until 24 h that was reversed back to the level of sham animals during the second day. CONCLUSIONS: Based on these findings, the supplementation of rhAT may represent a valuable therapeutic approach for cardiovascular dysfunction and inflammation after burn and smoke inhalation injury.


Assuntos
Antitrombinas/uso terapêutico , Queimaduras/tratamento farmacológico , Queimaduras/fisiopatologia , Coração/fisiopatologia , Inflamação/fisiopatologia , Lesão por Inalação de Fumaça/tratamento farmacológico , Lesão por Inalação de Fumaça/fisiopatologia , Animais , Antitrombinas/sangue , Capilares/fisiopatologia , Citocinas/metabolismo , Modelos Animais de Doenças , Ativação Enzimática , Hemodinâmica , Neutrófilos/metabolismo , Óxido Nítrico/metabolismo , Consumo de Oxigênio , Estudos Prospectivos , Troca Gasosa Pulmonar , Proteínas Recombinantes/sangue , Proteínas Recombinantes/uso terapêutico , Ovinos , Equilíbrio Hidroeletrolítico/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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