Peripheral and respiratory muscle impairment during murine acute lung injury.

Acute respiratory distress syndrome is associated with skeletal muscle compromise, which decreases survival and impairs functional capacity. A comparative analysis of peripheral and respiratory muscles' atrophy and dysfunction in acute lung injury (ALI) has not been performed. We aimed to evaluate diaphragmatic and peripheral muscle mass and contractility in an ALI animal model. ALI was induced in C57BL/6 mice by intratracheal lipopolysaccharides instillation. Muscle mass and in vitro contractility were evaluated at different time points in hindlimb soleus (slow-twitch) and extensor digitorum longus (EDL, fast-twitch), as well as in the main respiratory muscle diaphragm. Myogenic precursor satellite cell-specific transcription factor Pax7 expression was determined by Western blot. Lung injury was associated with atrophy of the three studied muscles, although it was more pronounced and persistent in the diaphragm. Specific contractility was reduced during lung injury in EDL muscle but restored by the time lung injury has resolved. Specific force was not affected in soleus and diaphragm. A persistent increase in Pax7 expression was detected in diaphragm and EDL muscles after induction of ALI, but not in soleus muscle. Different peripheral and respiratory skeletal muscles are distinctly affected during the course of ALI. Each of the studied muscles presented a unique pattern in terms of atrophy development, contractile dysfunction and Pax7 expression.

Esophageal stricture as an initial manifestation of Crohn's disease.

Crohn's disease located in the esophagus is rare, being exceptional as the initial manifestation of the disease. Erosive ulcerative esophagitis, stricture and fistula are forms of presentation, as in other esophageal pathologies, so the differential diagnosis is broad. The histologic features of esophageal Crohn's disease can be nonspecific and increase the diagnostic challenge. Esophageal Crohn's disease should be included in the differential diagnosis of esophageal strictures and may require esophagectomy if medical-endoscopic treatment is not effective.

Uso de máscaras de buceo modificadas para aplicación segura de ventilación no invasiva. Estudio piloto / Modified snorkeling facemasks for safe application of non-invasive ventilation. A pilot study / Uso de máscaras de mergulho modificadas para aplicação segura de ventilação não invasiva. Estudo piloto

Resumen: Introducción: en el contexto de la pandemia de SARS-CoV-2, diferentes autores propusieron adaptaciones a máscaras de buceo comerciales (máscaras modificadas, MM) para proporcionar oxigenoterapia a pacientes con o sin presión positiva. Hasta la fecha, ninguno ha evaluado su desempeño como interfaz para la ventilación no invasiva (VNI) en el modo de soporte de presión inspiratoria (PSI). Objetivos: desarrollar una interfaz de VNI utilizando MM y evaluar su rendimiento en comparación con una máscara oronasal (MC) convencional. Métodos: las MM se adaptaron como interfaces VNI utilizando dos piezas creadas mediante impresión 3D. Se comparó su desempeño contra una MC en 10 voluntarios sanos en modo PSI (3 cmH2O) con dos niveles de presión positiva al final de la espiración (PEEP 4 y 8 cmH2O). Se compararon: fugas del sistema, frecuencia respiratoria, volumen corriente, oximetría de pulso, CO2 transcutáneo y comodidad. Resultados: con 4 cmH2O de PEEP no hubo diferencias significativas entre las máscaras en ninguna de las variables estudiadas. Con 8 cmH2O de PEEP, el uso de MM se asoció con un menor nivel de CO2tc (41,0±5,7 vs 43,5±8,1 mmHg; p=0,03) y un mayor confort (8,3±1,1 vs 6,5±1,4; p<0,01) que las MC. Conclusiones: el uso de MM para realizar VNI presenta, en voluntarios sanos, un rendimiento similar a las mascarillas oronasales estándar, con la ventaja de mayor comodidad y menor costo. Si bien restan estudios para avalar su utilización, en la emergencia sanitaria provocada por la pandemia SARS-CoV-2, la adaptación de máscaras de buceo podría representar una opción válida frente a la escasez de interfaces comerciales.

Abstract: Introduction: within the context of the SARS-CoV-2 pandemic, different authors proposed adaptations to snorkeling masks available in the market (modified masks: MM) to provide oxygen therapy with positive pressure ventilation or not. Until today, none of them has assessed its performance as an interface for non-invasive ventilation (NIV) in the inspiratory pressure support mode. Objective: to develop an interface of NIV using MM and assess its performance with a conventional full mask. Method: the MM were adapted as NIV interfaces using two pieces created by 3D printing. Their performance was compared to a that of a conventional mask in 10 healthy volunteers in inspiratory pressure support (3 cmH2O) mode with two levels of positive pressure towards the end of expiration (PEEP 4 and 8 cmH2O). The following were compared: system leaks, respiratory rate, normal volume, pulse oximetry, transcutaneous car bon dioxide and comfort. Results: with 4 cmH2O of PEEP, no significant differences were found between masks in none of the variables studied. With 8 cmH2O de PEEP, the use of MM were associated to a lower level of CO2tc (41.0±5.7 vs 43.5±8.1 mmHg; p=0.03) and greater comfort (8.3±1.1 vs 6.5±1.4; p<0.01) than conventional masks (CM). Conclusions: in healthy volunteers, MM for NIV evidence a similar performance than that of standard oronasal masks, and have a further advantage, as they are more comfortable and cheaper. Even if further studies are needed to support its use, modified snorkeling masks could represent a valid option during the health emergency caused by the SARS-CoV-2 pandemic in consideration of the scarce interfaces available in the market.

Resumo: Introdução: no contexto da pandemia de SARS-CoV2, diferentes autores propuseram adaptações às máscaras de mergulho comerciais (máscaras modificadas, MM) para fornecer oxigenoterapia a pacientes com ou sem pressão positiva. Até o momento, nenhum avaliou seu desempenho como interface para ventilação não invasiva (VNI) no modo de suporte de pressão inspiratória (PSI). Objetivos: desenvolver uma interface de VNI usando MM e avaliar seu desempenho em comparação com uma máscara oronasal convencional (MC). Métodos: as MMs foram adaptadas como interfaces VNI usando duas peças criadas por impressão 3D. Seu desempenho contra uma MC foi comparado em 10 voluntários saudáveis no modo PSI (3 cmH2O) com dois níveis de pressão positiva no final da expiração (PEEP 4 e 8 cmH2O). Vazamentos do sistema, frequência respiratória, volume corrente, oximetria de pulso, CO2 transcutâneo e conforto foram comparados. Resultados: com 4 cmH2O de PEEP, não se observaram diferenças significativas entre as máscaras em nenhuma das variáveis estudadas. Com PEEP de 8 cmH2O, o uso de MM foi associado a um menor nível de CO2tc (41,0 ± 5,7 vs 43,5 ± 8,1 mmHg; p = 0,03) e maior conforto (8,3 ± 1,1 vs 6,5 ± 1,4; p <0,01) do que a MC. Conclusões: o uso do MM para a realização da VNI apresenta, em voluntários saudáveis, desempenho semelhante às máscaras oronasais padrão, com a vantagem de maior conforto e menor custo. Embora ainda sejam necessários mais estudos que embasem seu uso, na emergência sanitária ocasionada pela pandemia do SARS-CoV-2, a adaptação de máscaras de mergulho pode representar uma opção válida diante da escassez de interfaces comerciais.

Complete Blood Count and Derived Indices: Evolution Pattern and Prognostic Value in Adult Burned Patients.

Certain parameters of complete blood count (CBC) such as red cell distribution width (RDW) and mean platelet volume, as well as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and RDW-to-platelet ratio (RPR) have been associated with inflammatory status and outcome in diverse medical conditions. The aim of this study was to describe the evolution pattern of these parameters in adult burned patients. Adult burned patients admitted to the National Burn Center in Uruguay between May 2017 and February 2018 (discovery cohort) and between March 2018 and August 2019 (validation cohort) were included. Patients' characteristics and outcomes were recorded, as well as CBC parameters on days 1, 3, 5, and 7 after thermal injury. Eighty-eight patients were included in the discovery cohort. Total body surface area burned was 14 [7-23]% and mortality was 15%. Nonsurvivors presented higher RDW and mean platelet volume (P < .01). NLR decreased after admission in all patients (P < .01), but was higher in nonsurvivors (P < .01). Deceased patients also presented higher RPR on days 3, 5, and 7 (P < .001). On the contrary, PLR was reduced in nonsurvivors (P < .05). There was a significant correlation between NLR on admission and burn extension and severity. Kaplan-Meier analysis revealed that NLR, PLR, and RPR could identify patients with increased mortality. These findings were confirmed in the validation cohort (n = 95). Basic CBC parameters and derived indices could be useful as biomarkers to determine prognosis in adults with thermal injuries.

Mortality analysis of adult burn patients in Uruguay. / Análise da mortalidade em pacientes queimados adultos no Uruguai.

OBJECTIVE: To determine the independent risk factors associated with mortality in adult burn patients. METHODS: This was a retrospective, observational study performed at the Centro Nacional de Queimados do Uruguai. All patients with skin burns admitted to the unit since its opening on July 1, 1995 through December 31, 2018 were included. The demographic data, burn profiles, length of stay, mechanical ventilation duration and hospital mortality were studied. A multivariate logistic regression was used to identify the risk factors for mortality. The standardized mortality ratio was calculated by dividing the number of observed deaths by the number of expected deaths (according to the Abbreviated Burn Severity Index). RESULTS: During the study period, 3,132 patients were included. The median total body surface area burned was 10% (3%-22%). The Abbreviated Burn Severity Index was 6 (4 - 7). Invasive mechanical ventilation was required in 60% of the patients for a median duration of 6 (3 - 16) days. The median length of stay in the unit was 17 (7 - 32) days. The global mortality was 19.9%. Crude mortality and standardized mortality ratio decreased from 1995 through 2018. The global standardized mortality ratio was 0.99. A need for mechanical ventilation (OR 8.80; 95%CI 5.68 - 13.62), older age (OR 1.07 per year; 95%CI 1.06 - 1.09), total body surface area burned (OR 1.05 per 1%; 95%CI 1.03 - 1.08) and extension of third-degree burns (OR 1.05 per 1%; 95%CI 1.03 - 1.07) were independent risk factors for mortality. CONCLUSION: The need for mechanical ventilation, older age and burn extension were independent risk factors for mortality in the burned adult Uruguayan population.

High CO2 Levels Impair Lung Wound Healing.

Delayed lung repair leads to alveolopleural fistulae, which are a major cause of morbidity after lung resections. We have reported that intrapleural hypercapnia is associated with delayed lung repair after lung resection. Here, we provide new evidence that hypercapnia delays wound closure of both large airway and alveolar epithelial cell monolayers because of inhibition of epithelial cell migration. Cell migration and airway epithelial wound closure were dependent on Rac1-GTPase activation, which was suppressed by hypercapnia directly through the upregulation of AMP kinase and indirectly through inhibition of injury-induced NF-κB-mediated CXCL12 (pleural CXC motif chemokine 12) release, respectively. Both these pathways were independently suppressed, because dominant negative AMP kinase rescued the effects of hypercapnia on Rac1-GTPase in uninjured resting cells, whereas proteasomal inhibition reversed the NF-κB-mediated CXCL12 release during injury. Constitutive overexpression of Rac1-GTPase rescued the effects of hypercapnia on both pathways as well as on wound healing. Similarly, exogenous recombinant CXCL12 reversed the effects of hypercapnia through Rac1-GTPase activation by its receptor, CXCR4. Moreover, CXCL12 transgenic murine recipients of orthotopic tracheal transplantation were protected from hypercapnia-induced inhibition of tracheal epithelial cell migration and wound repair. In patients undergoing lobectomy, we found inverse correlation between intrapleural carbon dioxide and pleural CXCL12 levels as well as between CXCL12 levels and alveolopleural leak. Accordingly, we provide first evidence that high carbon dioxide levels impair lung repair by inhibiting epithelial cell migration through two distinct pathways, which can be restored by recombinant CXCL12.

Elevated CO2 regulates the Wnt signaling pathway in mammals, Drosophila melanogaster and Caenorhabditis elegans.

Carbon dioxide (CO2) is sensed by cells and can trigger signals to modify gene expression in different tissues leading to changes in organismal functions. Despite accumulating evidence that several pathways in various organisms are responsive to CO2 elevation (hypercapnia), it has yet to be elucidated how hypercapnia activates genes and signaling pathways, or whether they interact, are integrated, or are conserved across species. Here, we performed a large-scale transcriptomic study to explore the interaction/integration/conservation of hypercapnia-induced genomic responses in mammals (mice and humans) as well as invertebrates (Caenorhabditis elegans and Drosophila melanogaster). We found that hypercapnia activated genes that regulate Wnt signaling in mouse lungs and skeletal muscles in vivo and in several cell lines of different tissue origin. Hypercapnia-responsive Wnt pathway homologues were similarly observed in secondary analysis of available transcriptomic datasets of hypercapnia in a human bronchial cell line, flies and nematodes. Our data suggest the evolutionarily conserved role of high CO2 in regulating Wnt pathway genes.

Evolución histórica de la mortalidad de los pacientes internados en el Centro Nacional de Quemados entre 1995 y 2017 / Historical evolution of the mortality in burned patient at the Centro Nacional de Quemados (National Burns Center) between 1995 and 2017 / Evolução histórica da mortalidade dos pacientes queimados atendidos no Centro Nacional de Quemados entre 1995 e 2017

Introducción: la mortalidad de los pacientes con injuria térmica ha descendido a nivel mundial. Este hecho se ha relacionado en parte con la creación de centros especializados en el tratamiento de esta patología. En nuestro medio no existen estudios recientes que evalúen la evolución de la mortalidad en este tipo de centros. Objetivo: describir las características de la población asistida y la evolución de la mortalidad en el Centro Nacional de Quemados. Material y método: estudio transversal, observacional, descriptivo. Se incluyeron todos los pacientes ingresados con diagnóstico de quemadura cutánea o de injuria inhalatoria desde la inauguración del centro en 1995 hasta el 31 de diciembre de 2017. Resultados: ingresaron en el período de estudio 3.050 pacientes quemados, 25% presentaron una superficie corporal quemada superior o igual a 20%. Existió un predominio de pacientes jóvenes (más de 60% menores de 50 años) y de sexo masculino (62%). El agente causal más frecuente fue el fuego directo (71%), seguido por líquidos calientes (9%) y electricidad (5%). El 43% de los pacientes requirió asistencia ventilatoria mecánica, y la estadía media en el centro fue de 17 días. La mortalidad global fue de 19,7%, similar a la esperada de acuerdo a scores de severidad específicos. La mortalidad de los pacientes más graves ha descendido desde la apertura del centro. Conclusiones: nuestro centro asiste predominantemente a pacientes jóvenes, con siniestros que involucran al fuego como el principal agente causal. La mortalidad es acorde a la esperada de acuerdo a los scores de severidad, destacándose un descenso continuo de la misma a lo largo de los años. (AU)

Introduction: burned patients mortality has decreased because of a better understanding of initial shock pathophysiology, early surgical interventions, antibiotic therapy optimization and appropriate nutritional support. Mortality reduction has also been related to the creation of specialized burn centers. There are no recent reports of burn injury patients in our country. Objective: to describe characteristics and evolution of patients assisted at the national burned center (Centro Nacional de Quemados, Uruguay). Methods: transversal, observational, descriptive study. All patients admitted in the center with diagnosis of skin burns or inhalation injury, from the center's opening in 1995 through December 31, 2017. Results: during the study period 3,050-burned patients were admitted, 25% of which had a total body surface area burnt of at least 20%. There was a predominance of male sex (62%) and young patients (more than 60% had less than 50 years old). The most frequent responsible agent was direct fire (71%), followed by hot liquids (9%) and electricity (5%). Mechanical ventilation was needed in 43% of the patients, and mean length of stay in the center was 17 days. Overall mortality rate was 19.7%, accordingly to that predicted by specific severity scores. In the sub-group of more severe patients, mortality has progressively decreased since the center opening. Conclusions: our center assists young patients with burn injuries mostly caused by direct fire. Overall mortality is in line with the expected according to severity scores, having decreased progressively since the center inauguration.

Introduction: burned patients mortality has decreased because of a better understanding of initial shock pathophysiology, early surgical interventions, antibiotic therapy optimization and appropriate nutritional support. Mortality reduction has also been related to the creation of specialized burn centers. There are no recent reports of burn injury patients in our country. Objective: to describe characteristics and evolution of patients assisted at the national burned center (Centro Nacional de Quemados, Uruguay). Methods: transversal, observational, descriptive study. All patients admitted in the center with diagnosis of skin burns or inhalation injury, from the center's opening in 1995 through December 31, 2017. Results: during the study period 3,050-burned patients were admitted, 25% of which had a total body surface area burnt of at least 20%. There was a predominance of male sex (62%) and young patients (more than 60% had less than 50 years old). The most frequent responsible agent was direct fire (71%), followed by hot liquids (9%) and electricity (5%). Mechanical ventilation was needed in 43% of the patients, and mean length of stay in the center was 17 days. Overall mortality rate was 19.7%, accordingly to that predicted by specific severity scores. In the sub-group of more severe patients, mortality has progressively decreased since the center opening. Conclusions: our center assists young patients with burn injuries mostly caused by direct fire. Overall mortality is in line with the expected according to severity scores, having decreased progressively since the center inauguration.

Respiratory and Peripheral Muscle Assessment in the Intensive Care Unit. / Evaluación muscular respiratoria y periférica en la Unidad de Cuidados Intensivos.

Atrophy and weakness of the respiratory and peripheral muscles is a common problem in the intensive care unit (ICU). It is difficult to diagnose, particularly in the early stages of critical disease. Consequently, many cases are detected only in advanced stages, for example, when difficulties in mechanical ventilation weaning are encountered. The aim of this review is to describe the main tools that are currently available for evaluation of peripheral and respiratory muscles in the ICU. Techniques of varying complexity and specificity are discussed, and particular emphasis is placed on those with greater relevance in daily clinical practice, such as ultrasound.

Influenza A Virus Infection Induces Muscle Wasting via IL-6 Regulation of the E3 Ubiquitin Ligase Atrogin-1.

Muscle dysfunction is common in patients with adult respiratory distress syndrome and is associated with morbidity that can persist for years after discharge. In a mouse model of severe influenza A pneumonia, we found the proinflammatory cytokine IL-6 was necessary for the development of muscle dysfunction. Treatment with a Food and Drug Administration-approved Ab antagonist to the IL-6R (tocilizumab) attenuated the severity of influenza A-induced muscle dysfunction. In cultured myotubes, IL-6 promoted muscle degradation via JAK/STAT, FOXO3a, and atrogin-1 upregulation. Consistent with these findings, atrogin-1+/- and atrogin-1-/- mice had attenuated muscle dysfunction following influenza infection. Our data suggest that inflammatory endocrine signals originating from the injured lung activate signaling pathways in the muscle that induce dysfunction. Inhibiting these pathways may limit morbidity in patients with influenza A pneumonia and adult respiratory distress syndrome.

Hypercapnia increases airway smooth muscle contractility via caspase-7-mediated miR-133a-RhoA signaling.

The elevation of carbon dioxide (CO2) in tissues and the bloodstream (hypercapnia) occurs in patients with severe lung diseases, including chronic obstructive pulmonary disease (COPD). Whereas hypercapnia has been recognized as a marker of COPD severity, a role for hypercapnia in disease pathogenesis remains unclear. We provide evidence that CO2 acts as a signaling molecule in mouse and human airway smooth muscle cells. High CO2 activated calcium-calpain signaling and consequent smooth muscle cell contraction in mouse airway smooth muscle cells. The signaling was mediated by caspase-7-induced down-regulation of the microRNA-133a (miR-133a) and consequent up-regulation of Ras homolog family member A and myosin light-chain phosphorylation. Exposure of wild-type, but not caspase-7-null, mice to hypercapnia increased airway contraction and resistance. Deletion of the Caspase-7 gene prevented hypercapnia-induced airway contractility, which was restored by lentiviral transfection of a miR-133a antagonist. In a cohort of patients with severe COPD, hypercapnic patients had higher airway resistance, which improved after correction of hypercapnia. Our data suggest a specific molecular mechanism by which the development of hypercapnia may drive COPD pathogenesis and progression.

Capturing the multifactorial nature of ARDS - "Two-hit" approach to model murine acute lung injury.

Severe acute respiratory distress syndrome (ARDS) presents typically with an initializing event, followed by the need for mechanical ventilation. Most animal models of ALI are limited by the fact that they focus on a singular cause of acute lung injury (ALI) and therefore fail to mimic the complex, multifactorial pathobiology of ARDS. To better capture this scenario, we provide a comprehensive characterization of models of ALI combining two injuries: intra tracheal (i.t.) instillation of LPS or hypochloric acid (HCl) followed by ventilator-induced lung injury (VILI). We hypothesized, that mice pretreated with LPS or HCl prior to VILI and thus receiving a ("two-hit injury") will sustain a superadditive lung injury when compared to VILI. Mice were allocated to following treatment groups: control with i.t. NaCl, ventilation with low peak inspiratory pressure (PIP), i.t. HCl, i.t. LPS, VILI (high PIP), HCl i.t. followed by VILI and LPS i.t. followed by VILI. Severity of injury was determined by protein content and MPO activity in bronchoalveolar lavage (BAL), the expression of inflammatory cytokines and histopathology. Mice subjected to VILI after HCl or LPS instillation displayed augmented lung injury, compared to singular lung injury. However, mice that received i.t. LPS prior to VILI showed significantly increased inflammatory lung injury compared to animals that underwent i.t. HCl followed by VILI. The two-hit lung injury models described, resulting in additive but differential acute lung injury recaptures the clinical relevant multifactorial etiology of ALI and could be a valuable tool in translational research.

Effects of hypercapnia in acute respiratory distress syndrome.

In patients with acute respiratory distress syndrome (ARDS) hypercapnia is a marker of poor prognosis, however there is controversial information regarding the effect of hypercapnia on outcomes. Recently two studies in a large population of mechanical ventilation patients showed higher mortality associated independently to hypercapnia. Key roles responsible for the poor clinical outcomes observed in critically ill patients exposed to hypercapnia are not well known, two possible mechanisms involved are the effect of CO2 on the muscle and the alveolar epithelium. Hypercapnia frequently coexists with muscle atrophy and dysfunction, moreover patients surviving ARDS present reduced muscle strength and decreased physical quality of life. One of the possible mechanisms responsible for these abnormalities could be the effects of hypercapnia during the course of ARDS. More over controversy persists about the hypercapnia role in the alveolar space, in the last years there is abundant experimental information on its deleterious effects on essential functions of the alveolar epithelium.

Síndrome por infusión de propofol: reporte de un caso / Propofol infusion syndrome: a case report

El propofol es un anestésico ampliamente utilizado en las unidades de cuidados intensivos. Su empleo puede provocar un efecto adverso poco frecuente pero extremadamente grave, conocido como síndrome por infusión de propofol (SIP), caracterizado por inestabilidad hemodinámica, rabdomiólisis, acidosis láctica y disfunción multiorgánica. Presentamos un caso de SIP con desenlace fatal, discutiendo su fisiopatología, clínica y consideraciones a tener en cuenta al emplear propofol.

Propofol is a widely used anesthetic in the Intensive Care Unit. At times it may cause rather an unusual adverse reaction known as propofol infusion syndrome (PRIS), characterized by hemodynamic instability, rhabdomyolysis, lactic acidosis, and multiple-organ dysfunction. The study presents a case of PRIS with fatal outcome, including a discussion of its physiopathology, clinical aspects and considerations to be borne in mind when using propofol.

O propofol é um anestésico amplamente utilizado nas Unidades de Cuidados Intensivos. Sua utilização pode provocar um efeito adverso pouco frequente mas extremamente grave conhecido como síndrome por infusão de propofol (SIP), caracterizado por instabilidade hemodinâmica, rabdomiólise, acidose lática e disfunção múltipla de órgãos. Apresentamos um caso fatal de SIP e discutimos a fisiopatologia, clínica e os aspectos que devem ser considerados quando se utiliza esta droga.