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Mechanical ventilation is necessary for patients with acute respiratory failure, but can cause or propagate lung injury. We previously identified cyclooxygenase-2 as a candidate gene in mechanical ventilation-induced lung injury. Our objective was to determine the role of cyclooxygenase-2 in mechanical ventilation-induced lung injury and the effects of cyclooxygenase-2 inhibition on lung inflammation and barrier disruption. Mice were mechanically ventilated at low and high tidal volumes, in the presence or absence of pharmacologic cyclooxygenase-2-specific inhibition with 3-(4-methylsulphonylphenyl)-4-phenyl-5-trifluoromethylisoxazole (CAY10404). Lung injury was assessed using markers of alveolar-capillary leakage and lung inflammation. Cyclooxygenase-2 expression and activity were measured by Western blotting, real-time PCR, and lung/plasma prostanoid analysis, and tissue sections were analyzed for cyclooxygenase-2 staining by immunohistochemistry. High tidal volume ventilation induced lung injury, significantly increasing both lung leakage and lung inflammation relative to control and low tidal volume ventilation. High tidal volume mechanical ventilation significantly induced cyclooxygenase-2 expression and activity, both in the lungs and systemically, compared with control mice and low tidal volume mice. The immunohistochemical analysis of lung sections localized cyclooxygenase-2 expression to monocytes and macrophages in the alveoli. The pharmacologic inhibition of cyclooxygenase-2 with CAY10404 significantly decreased cyclooxygenase activity and attenuated lung injury in mice ventilated at high tidal volume, attenuating barrier disruption, tissue inflammation, and inflammatory cell signaling. This study demonstrates the induction of cyclooxygenase-2 by mechanical ventilation, and suggests that the therapeutic inhibition of cyclooxygenase-2 may attenuate ventilator-induced acute lung injury.
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Ciclo-Oxigenase 2/metabolismo , Lesão Pulmonar/enzimologia , Respiração Artificial/efeitos adversos , Animais , Inibidores de Ciclo-Oxigenase 2/farmacologia , Imuno-Histoquímica , Lesão Pulmonar/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Background: Evidence shows poor adherence to strategies for reducing morbidity and mortality in intensive care unit (ICU) patients receiving mechanical ventilation globally. Best practice management relies on training all members of the interprofessional ICU team, each with complementary roles in patient management. Objectives: To develop and evaluate a novel two-phase, train-the-trainer, interprofessional and multicultural "Best Practice Management of the Ventilated ICU Patient" multimodality, simulation-enhanced curriculum for Thai education leaders in critical care. Methods: In phase 1 (Oregon Health and Science University cohort), two groups of nine ICU nurses and one critical care physician representing experts in critical care and education from a large hospital system in Thailand participated in a weeklong, immersive course consisting of didactic, simulation, and in situ immersive sessions focused on best practice management of mechanically ventilated ICU patients, as well as training in our educational techniques. Outcomes were assessed with pre- and postcourse knowledge assessments and overall course evaluation. In phase 2 (Thai cohort), participants from phase 1 returned to Thailand and implemented a lower fidelity curriculum in two hospitals, using the same pre- and posttest knowledge assessment in 41 participants, before the onset of the coronavirus disease (COVID-19) 6 pandemic. Results: In the Oregon Health and Science University cohort, the mean pretest knowledge score was 58.4 ± 13.2%, with a mean improvement to 82.5 ± 11.6% after completion of the course (P , 0.05). The greatest improvements were seen in respiratory physiology and advanced/disease-specific concepts, which demonstrated absolute improvements of 30.4% and 30.6%, respectively (P < 0.05). Participants had a high degree of satisfaction, with 90% rating the course as "excellent" and .90% reporting that the course "greatly improved" their understanding of best practices and comfort in managing mechanical ventilation. The Thai cohort had a mean baseline score of 45.4 ± 15.0% and a mean improvement to 70.3 ± 19.1% after training (P < 0.05). This cohort also saw the greatest improvement in respiratory physiology and advanced/disease-specific concepts, with 26.2% and 26.3% absolute improvements, respectively (P < 0.05). Conclusion: A novel, two-phase, interprofessional, multicultural, simulation-enhanced train-the-trainer curriculum was feasible and effective in improving education in best practice management of mechanically ventilated patients and may be a useful model for improving the care of ICU patients across the world.
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BACKGROUND: Management of mechanical ventilation (MV) is an important and complex aspect of caring for critically ill patients. Management strategies and technical operation of the ventilator are key skills for physicians in training, as lack of expertise can lead to substantial patient harm. OBJECTIVE: We performed a narrative review of the literature describing MV education in graduate medical education (GME) and identified best practices for training and assessment methods. METHODS: We searched MEDLINE, PubMed, and Google Scholar for English-language, peer-reviewed articles describing MV education and assessment. We included articles from 2000 through July 2018 pertaining to MV education or training in GME. RESULTS: Fifteen articles met inclusion criteria. Studies related to MV training in anesthesiology, emergency medicine, general surgery, and internal medicine residency programs, as well as subspecialty training in critical care medicine, pediatric critical care medicine, and pulmonary and critical care medicine. Nearly half of trainees assessed were dissatisfied with their MV education. Six studies evaluated educational interventions, all employing simulation as an educational strategy, although there was considerable heterogeneity in content. Most outcomes were assessed with multiple-choice knowledge testing; only 2 studies evaluated the care of actual patients after an educational intervention. CONCLUSIONS: There is a paucity of information describing MV education in GME. The available literature demonstrates that trainees are generally dissatisfied with MV training. Best practices include establishing MV-specific learning objectives and incorporating simulation. Next research steps include developing competency standards and validity evidence for assessment tools that can be utilized across MV educational curricula.
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Competência Clínica/normas , Internato e Residência , Aprendizagem , Respiração Artificial/normas , Treinamento por Simulação/normas , Educação de Pós-Graduação em Medicina , Medicina de Emergência/educação , Humanos , Medicina Interna/educação , MédicosRESUMO
BACKGROUND: Earlier studies reported that many patients were frequently hospitalized for asthma exacerbation. However, there have been no recent multicenter studies to characterize this patient population with high morbidity and health care utilization. OBJECTIVE: To examine the proportion and characteristics of children and adults with frequent hospitalizations for asthma exacerbation. METHODS: A multicenter chart review study of patients aged 2 to 54 years who were hospitalized for asthma exacerbation at 1 of 25 hospitals across 18 US states during the period 2012 to 2013 was carried out. The primary outcome was frequency of hospitalizations for asthma exacerbation in the past year (including the index hospitalization). RESULTS: The cohort included 369 children (aged 2-17 years) and 555 adults (aged 18-54 years) hospitalized for asthma exacerbation. Over the 12-month period, 36% of the children and 42% of the adults had 2 or more (frequent) hospitalizations for asthma exacerbation. Among patients with frequent hospitalizations, guideline-recommended outpatient management was suboptimal. For example, among adults, 32% were not on inhaled corticosteroids at the time of index hospitalization and 75% had no evidence of a previous evaluation by an asthma specialist. At hospital discharge, among adults with frequent hospitalizations who had used no controller medications previously, 37% were not prescribed inhaled corticosteroids. Likewise, during a 3-month postdischarge period, 64% of the adults with frequent hospitalizations were not referred to an asthma specialist. Although the proportion of patients who did not receive these guideline-recommended outpatient care appeared higher in adults, these preventive measures were still underutilized in children; for example, 38% of the children with frequent hospitalizations were not referred to asthma specialist after the index hospitalization. CONCLUSIONS: This multicenter study of US patients hospitalized with asthma exacerbation demonstrated a disturbingly high proportion of patients with frequent hospitalizations and ongoing evidence of suboptimal longitudinal asthma care.
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Asma/epidemiologia , Hospitalização/estatística & dados numéricos , Adolescente , Adulto , Asma/imunologia , Criança , Pré-Escolar , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: A multicenter study in the late 1990s demonstrated suboptimal emergency asthma care for pregnant women in US EDs. After a decade, follow-up data are lacking. We aimed to examine changes in emergency asthma care of pregnant women since the 1990s. METHODS: We combined data from four multicenter observational studies of ED patients with acute asthma performed in 1996 to 2001 (three studies) and 2011 to 2012 (one study). We restricted the data so that comparisons were based on the same 48 EDs in both time periods. We identified all pregnant patients aged 18 to 44 years with acute asthma. Primary outcomes were treatment with systemic corticosteroids in the ED and, among those sent home, at ED discharge. RESULTS: Of 4,895 ED patients with acute asthma, the analytic cohort comprised 125 pregnant women. Between the two time periods, there were no significant changes in patient demographics, chronic asthma severity, or initial peak expiratory flow. In contrast, ED systemic corticosteroid treatment increased significantly from 51% to 78% across the time periods (OR, 3.11; 95% CI, 1.27-7.60; P = .01); systemic corticosteroids at discharge increased from 42% to 63% (OR, 2.49; 95% CI, 0.97-6.37; P = .054). In the adjusted analyses, pregnant women in recent years were more likely to receive systemic corticosteroids, both in the ED (OR, 4.76; 95% CI, 1.63-13.9; P = .004) and at discharge (OR, 3.18; 95% CI, 1.05-9.61; P = .04). CONCLUSIONS: Between the two time periods, emergency asthma care in pregnant women significantly improved. However, with one in three pregnant women being discharged home without systemic corticosteroids, further improvement is warranted.
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Corticosteroides/uso terapêutico , Asma/tratamento farmacológico , Complicações na Gravidez/terapia , Adolescente , Adulto , Serviços Médicos de Emergência , Serviço Hospitalar de Emergência , Feminino , Humanos , Masculino , Estudos Observacionais como Assunto , Padrões de Prática Médica , Gravidez , Pontuação de Propensão , Adulto JovemRESUMO
Despite improvements in resuscitation and treatment of sepsis, the morbidity and mortality remain unacceptably high. Microvascular dysfunction has been shown to play a significant role in the pathogenesis of sepsis and is a potential new target in the management of sepsis. Clinical studies, aided by new techniques that allow for real-time assessment of the microcirculation, have shown that disturbances in microcirculatory flow are common in sepsis and correlate with worse outcomes. Bedside measurement of microcirculatory perfusion has become simpler and more accessible, and may provide key insights into prognosis in sepsis and guide future therapeutics, much like mean arterial pressure (MAP), lactate, and mixed central oxygen saturation (SvO(2)) do now. The authors review here the role of microcirculatory dysfunction in sepsis and its potential role as a therapeutic target in sepsis.
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Sepse/diagnóstico , Sepse/terapia , Doenças Vasculares/diagnóstico , Doenças Vasculares/terapia , Humanos , Microcirculação/fisiologia , Sepse/fisiopatologiaRESUMO
Increasing evidence supports the contribution of genetic influences on susceptibility/severity in acute lung injury (ALI), a devastating syndrome requiring mechanical ventilation with subsequent risk for ventilator-associated lung injury (VALI). To identify VALI candidate genes, we determined that Brown Norway (BN) and Dahl salt-sensitive (SS) rat strains were differentially sensitive to VALI (tidal volume of 20 ml/kg, 85 breaths/min, 2 h) defined by bronchoalveolar lavage (BAL) protein and leukocytes. We next exploited differential sensitivities and phenotyped both the VALI-sensitive BN and the VALI-resistant SS rat strains by expression profiling coupled to a bioinformatic-intense candidate gene approach (Significance Analysis of Microarrays, i.e., SAM). We identified 106 differentially expressed VALI genes representing gene ontologies such as "transcription" and "chemotaxis/cell motility." We mapped the chromosomal location of the differentially expressed probe sets and selected consomic SS rats with single BN introgressions of chromosomes 2, 13, and 16 (based on the highest density of probe sets) while also choosing chromosome 20 (low probe sets density). VALI exposure of consomic rats with introgressions of BN chromosomes 13 and 16 resulted in significant increases in both BAL cells and protein (compared to parental SS strain), whereas introgression of BN chromosome 2 displayed a large increase only in BAL protein. Introgression of BN chromosome 20 had a minimal effect. These results suggest that genes residing on BN chromosomes 2, 13, and 16 confer increased sensitivity to high tidal volume ventilation. We speculate that the consomic-microarray-SAM approach is a time- and resource-efficient tool for the genetic dissection of complex diseases including VALI.
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Modelos Animais de Doenças , Genômica/métodos , Respiração Artificial/efeitos adversos , Síndrome do Desconforto Respiratório/genética , Síndrome do Desconforto Respiratório/fisiopatologia , Animais , Biologia Computacional , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos Dahl , Ratos Sprague-Dawley , Síndrome do Desconforto Respiratório/etiologia , Especificidade da EspécieRESUMO
Acute lung injury (ALI) is a complex and devastating illness, often occurring in the setting of sepsis and trauma. Despite recent advances in the understanding and treatment of ALI, pathogenic mechanisms and genetic modifiers in ALI remain incompletely understood. Furthermore, there has been increasing interest in the identification of genetic variations that contribute to ALI susceptibility and severity in order to gain unique insights into ALI pathogenesis and to design novel treatment strategies. However, the sporadic nature of ALI and the lack of family-based cohort studies preclude conventional genomic approaches such as linkage mapping (or "positional cloning"). We have used a "candidate gene approach" with extensive gene expression profiling studies in animal (rat, murine, canine) and human models of ALI to identify potential ALI candidate genes associated with sepsis and ventilator-associated lung injury. These studies, when combined with innovative in silico bioinformatics approaches, revealed both novel (pre--B-cell colony enhancing factor, myosin light chain kinase) and previously identified (interleukin 6, macrophage migration inhibitory factor) gene candidates. Subsequent single nucleotide polymorphism discovery and genotyping studies revealed polymorphisms that demonstrate an influence on ALI susceptibility in patients. These studies indicate that the candidate gene approach is a robust strategy to provide novel insights into the genetic basis of ALI, and the identification of potentially novel therapeutic targets.