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PURPOSE: This survey of bile replacement (BR) was conducted on patients with external biliary drainage to assess the current status of indication and implementation protocol of BR with special reference to infection control. METHODS: A 12-item questionnaire regarding the performance of perioperative BR was sent to 124 institutions in Japan. RESULTS: BR was performed in 29 institutions, and the indication protocol was introduced in 19. BR was performed preoperatively in 11 institutions, pre- and postoperatively in 12, and postoperatively in 6. The methods used for BR administration included oral intake (n = 10), nasogastric tube (n = 1), enteral nutrition tube (n = 3), oral intake and enteral nutrition tube (n = 6), oral intake or nasogastric tube (n = 2), nasogastric tube and enteral nutrition tube (n = 2), and oral intake or nasogastric tube and enteral nutrition tube (n = 5). In 10 of 29 institutions, isolation of multidrug-resistant organisms and a high bacterial load were considered contraindications for the use of BR. Seven institutions experienced environmental contamination. CONCLUSIONS: Given the different implementation of BR among institutions, the appropriate indication and protocols for BR should be established for infection control.
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Bilis , Intubación Gastrointestinal , Drenaje/métodos , Humanos , Control de Infecciones , Encuestas y CuestionariosRESUMEN
OBJECTIVES: The optimal target temperature during targeted temperature management for patients after cardiac arrest remains under debate. The aim of this study was to evaluate the association between targeted temperature management at lower target temperatures and the neurologic outcomes among patients classified by the severity of postcardiac arrest syndrome. DESIGN: A multicenter observational study from the out-of-hospital cardiac arrest registry of the Japanese Association for Acute Medicine, which is a nationwide prospective registry of out-of-hospital cardiac arrest patients. SETTING: A total of 125 critical care medical centers or hospitals with an emergency care department across Japan. PATIENTS: A total of 1,111 out-of-hospital cardiac arrest patients who had received targeted temperature management. MEASUREMENTS AND MAIN RESULTS: We divided all 1,111 postcardiac arrest syndrome patients treated with targeted temperature management into two groups: those who received targeted temperature management at a lower target temperature (33-34°C) and those who received targeted temperature management at a higher target temperature (35-36°C). In regard to classification of the patients, we divided the patients into three categories of severity (low, moderate, and high severities) using the risk classification tool, post-Cardiac Arrest Syndrome for Therapeutic hypothermia, which was previously validated. The primary outcome was the percentage of patients with a good neurologic outcome at 30 days, and the secondary outcome was the survival rate at 30 days. Multivariate analysis showed that targeted temperature management at 33-34°C was significantly associated with a good neurologic outcome and survival at 30 days in the moderate severity (odds ratio, 1.70 [95% CI, 1.03-2.83] and 1.90 [95% CI, 1.15-3.16], respectively), but not in the patients of low or high severity (pinteraction = 0.033). Propensity score analysis also showed that targeted temperature management at 33-34°C was associated with a good neurologic outcome in the moderate-severity group (p = 0.022). CONCLUSIONS: Targeted temperature management at 33-34°C was associated with a significantly higher rate of a good neurologic outcome in the moderate-severity postcardiac arrest syndrome group, but not in the low- or high-severity group.
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Temperatura Corporal , Hipotermia Inducida/métodos , Paro Cardíaco Extrahospitalario/terapia , Síndrome de Paro Post-Cardíaco/terapia , Anciano , Servicios Médicos de Urgencia/métodos , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Síndrome de Paro Post-Cardíaco/fisiopatología , Estudios Prospectivos , Sistema de Registros , Factores de TiempoRESUMEN
Development of a novel agent against life-threatening sepsis requires the in-depth understanding of the relevant pathophysiology and therapeutic targets. Given the function of microRNAs (miRNAs) as potent oligonucleotide therapeutics, here we investigated the pathophysiological role of exogenously applied miRNA in sepsis-induced multiple organ injury. In vitro, miR-16, miR-126, miR-146a, and miR-200b suppressed the production of pro-inflammatory cytokines in RAW264.7 macrophage cells after lipopolysaccharide (LPS) stimulation. Of these, miR-146a displayed the most highly suppressive effect, wherein the transcriptional activity of nuclear factor kappa B (NF-κB) was decreased via targeting of interleukin 1 receptor-associated kinase 1 and tumor necrosis receptor-associated factor 6. Sepsis was induced in mice via cecal ligation and puncture (CLP) and an intravenous injection of a complex of miR-146a-expressing plasmid and polyethyleneimine. Treatment with this complex significantly decreased the level of serum inflammatory cytokines, attenuated organ injury including kidney injury, and led to increased survival from polymicrobial sepsis induced by CLP. miR-146a-expressing plasmid was abundantly distributed in splenic macrophages, but not in renal parenchymal cells. CLP mice treated with miR-146a displayed significantly decreased NF-κB activation and splenocyte apoptosis. Splenectomy diminished the anti-inflammatory effects of miR-146a. The collective results support the conclusion that the induction of miR-146a expression in splenic macrophages prevents excessive inflammation and sepsis-induced multiple organ injury. This study establishes a novel and critical pathophysiological role for splenic macrophage interference in sepsis-related organ injury.
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Macrófagos , MicroARNs/farmacología , Insuficiencia Multiorgánica/prevención & control , Sepsis/prevención & control , Animales , Modelos Animales de Enfermedad , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética , Plásmidos/genética , Células RAW 264.7 , Bazo/citologíaRESUMEN
Hypothermia is a significant sign of sepsis, which is associated with poor prognosis, but few mechanisms underlying the regulation of hypothermia are known. Inducible nitric oxide synthase (iNOS) is a key inflammatory mediator of sepsis. However, the therapeutic benefit of iNOS inhibition in sepsis is still controversial, and requires elucidation in an accurate model system. In this study, wild-type (WT) mice showed temperature drops in a biphasic manner at the early and late phase of sepsis, and all mice died within 48 h of sepsis. In contrast, iNOS-knockout (KO) mice never showed the second temperature drop and exhibited improved mortality. Plasma nitric oxide (NO) levels of WT mice increased in the late phase of sepsis and correlated to hypothermia. The results indicate that iNOS-derived NO during the late phase of sepsis caused vasodilation-induced hypothermia and a lethal hypodynamic state. The expression of the iNOS mRNA was high in the lung of WT mice with sepsis, which reflects the pathology of acute respiratory distress syndrome (ARDS). We obtained the results in a modified keyhole-type cecal ligation and puncture model of septic shock induced by minimally invasive surgery. In this accurate and reproducible model system, we transplanted the bone marrow cells of GFP transgenic mice into WT and iNOS-KO mice, and evaluated the role of increased pulmonary iNOS expression in cell migration during the late phase of sepsis. We also investigated the quantity and type of bone marrow-derived cells (BMDCs) in the lung. The number of BMDCs in the lung of iNOS-KO mice was less than that in the lung of WT mice. The major BMDCs populations were CD11b-positive, iNOS-negative cells in WT mice, and Gr-1-positive cells in iNOS-KO mice that expressed iNOS. These results suggest that sustained hypothermia may be a beneficial guide for future iNOS-targeted therapy of sepsis, and that iNOS modulated the migratory efficiency and cell type of BMDCs in septic ARDS.
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Movimiento Celular , Hipotermia/etiología , Óxido Nítrico Sintasa de Tipo II/fisiología , Sepsis/complicaciones , Animales , Células de la Médula Ósea/fisiología , Modelos Animales de Enfermedad , Pulmón/enzimología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Síndrome de Dificultad Respiratoria/inmunología , Sepsis/inmunologíaRESUMEN
Sepsis-associated encephalopathy (SAE), characterized as diffuse brain dysfunction and neurological manifestations secondary to sepsis, is a common complication in critically ill patients and can give rise to poor outcome, but understanding the molecular basis of this disorder remains a major challenge. Given the emerging role of G protein-coupled receptor 2 (GRK2), first identified as a G protein-coupled receptor (GPCR) regulator, in the regulation of non-G protein-coupled receptor-related molecules contributing to diverse cellular functions and pathology, including inflammation, we tested the hypothesis that GRK2 may be linked to the neuropathogenesis of SAE. When mouse MG6 microglial cells were challenged with lipopolysaccharide (LPS), GRK2 cytosolic expression was highly up-regulated. The ablation of GRK2 by small interfering RNAs (siRNAs) prevented an increase in intracellular reactive oxygen species generation in LPS-stimulated MG6 cells. Furthermore, the LPS-induced up-regulation of inducible nitric-oxide synthase expression and increase in nitric oxide production were negated by GRK2 inhibitor or siRNAs. However, GRK2 inhibition was without effect on overproduction of tumor necrosis factor-α, interleukin (IL)-6, and IL-1ß in LPS-stimulated MG cells. In mice with cecal ligation and puncture-induced sepsis, treatment with GRK2 inhibitor reduced high levels of oxidative and nitrosative stress in the mice brains, where GRK2 expression was up-regulated, alleviated neurohistological damage observed in cerebral cortex sections, and conferred a significant survival advantage to CLP mice. Altogether, these results uncover the novel role for GRK2 in regulating cellular oxidative and nitrosative stress during inflammation and suggest that GRK2 may have a potential as an intriguing therapeutic target to prevent or treat SAE.
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Quinasa 2 del Receptor Acoplado a Proteína-G/fisiología , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Encefalopatía Asociada a la Sepsis/patología , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , Citocinas/biosíntesis , Inhibidores Enzimáticos/uso terapéutico , Quinasa 2 del Receptor Acoplado a Proteína-G/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/enzimología , Óxido Nítrico Sintasa de Tipo II/metabolismo , ARN Interferente Pequeño/farmacología , Encefalopatía Asociada a la Sepsis/complicaciones , Encefalopatía Asociada a la Sepsis/tratamiento farmacológico , Regulación hacia Arriba/efectos de los fármacosRESUMEN
OBJECTIVES: Inflammation and apoptosis are decisive mechanisms for the development of end-organ injury in sepsis. Activator protein-1 may play a key role in regulating expression of harmful genes responsible for the pathophysiology of septic end-organ injury along with the major transcription factor nuclear factor-κB. We investigated whether in vivo introduction of circular dumbbell activator protein-1 decoy oligodeoxynucleotides can provide benefits for reducing septic end-organ injury. DESIGN: Laboratory and animal/cell research. SETTINGS: University research laboratory. SUBJECTS: Male BALB/c mice (8-10 wk old). INTERVENTIONS: Activator protein-1 decoy oligodeoxynucleotides were effectively delivered into tissues of septic mice in vivo by preparing into a complex with atelocollagen given 1 hour after surgery. MATERIALS AND MAIN RESULTS: Polymicrobial sepsis was induced by cecal ligation and puncture in mice. Activator protein-1 decoy oligodeoxynucleotide transfection inhibited abnormal production of proinflammatory and chemotactic cytokines after cecal ligation and puncture. Histopathologic changes in lung, liver, and kidney tissues after cecal ligation and puncture were improved by activator protein-1 decoy oligodeoxynucleotide administration. When activator protein-1 decoy oligodeoxynucleotides were given, apoptosis induction was strikingly suppressed in lungs, livers, kidneys, and spleens of cecal ligation and puncture mice. These beneficial effects of activator protein-1 decoy oligodeoxynucleotides led to a significant survival advantage in mice after cecal ligation and puncture. Apoptotic gene profiling indicated that activator protein-1 activation was involved in the up-regulation of many of proapoptotic and antiapoptotic genes in cecal ligation and puncture-induced sepsis. CONCLUSIONS: Our results indicate a detrimental role of activator protein-1 in the sepsis pathophysiology and the potential usefulness of activator protein-1 decoy oligodeoxynucleotides for the prevention and treatment of septic end-organ failure.
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Oligodesoxirribonucleótidos/uso terapéutico , Sepsis/terapia , Factor de Transcripción AP-1/uso terapéutico , Transfección/métodos , Animales , Apoptosis , Citocinas/sangre , Modelos Animales de Enfermedad , Ensayo de Cambio de Movilidad Electroforética , Masculino , Ratones , Ratones Endogámicos BALB C , Oligodesoxirribonucleótidos/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Sepsis/genética , Sepsis/mortalidad , Sepsis/patología , Factor de Transcripción AP-1/genéticaRESUMEN
OBJECTIVES: Occurrence of delirium in the ICU is associated with a longer stay in the ICU. To examine whether the use of ramelteon, a melatonin agonist, can prevent delirium and shorten the duration of ICU stay of critically ill patients. DESIGN: A single-center, triple-blinded, randomized placebo-controlled trial. SETTING: ICU of an academic hospital. PATIENTS: Eligible patients were ICU patients who could take medicines orally or through a nasogastric tube during the first 48 hours of admission. INTERVENTIONS: The intervention group received ramelteon (8 mg/d), and the control group received placebo (1 g/d of lactose powder) at 20:00 hours every day until discharge from the ICU. MEASUREMENTS AND MAIN RESULTS: A total of 88 subjects were randomized to the ramelteon group (45 subjects) or the placebo group (43 subjects). As the primary endpoint, there was a trend toward decrease in the duration of ICU stay (4.56 d) in the ramelteon group compared with the placebo group (5.86 d) (p = 0.082 and p = 0.028 before and after adjustments). As the secondary endpoints, statistically significant decreases in the occurrence rate (24.4% vs 46.5%; p = 0.044) and duration (0.78 vs 1.40 d; p = 0.048) of delirium were observed in the ramelteon group. The nonintubated patients of the ramelteon group showed statistically significantly fewer awakenings per night and a higher proportion of nights without awakenings. CONCLUSIONS: Ramelteon tended to decrease the duration of ICU stay as well as decreased the occurrence rate and duration of delirium statistically significantly.
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Indenos/uso terapéutico , Unidades de Cuidados Intensivos/estadística & datos numéricos , Tiempo de Internación/estadística & datos numéricos , Receptores de Melatonina/agonistas , Anciano , Delirio/epidemiología , Delirio/prevención & control , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Dobutamine has been used in septic shock for many years as an only inotrope, but its benefit has been questioned. We weighed the effects of dobutamine and milrinone as inotropes in mice with cecal ligation and puncture (CLP)-induced polymicrobial sepsis. CLP-induced septic mice exhibited significant cardiac inflammation, as indicated by greatly increased mRNAs of proinflammatory cytokines and robust infiltration of inflammatory cells in the ventricular myocardium. Elevations of plasma cardiac troponin-I showed cardiac injury in CLP mice. Noninvasive echocardiographic assessment of cardiac function revealed that despite preserved left ventricular function in the presence of fluid replacement, the dobutamine inotropic response was significantly impaired in CLP mice compared with sham-operated controls. By contrast, milrinone exerted inotropic effects in sham-operated and CLP mice in an equally effective manner. Surface expression levels of ß1-adrenoceptors and α-subunits of three main G protein families in the myocardium were unaffected by CLP-induced sepsis. Plasma cAMP levels were significantly elevated in both sham-operated and CLP mice in response to milrinone but only in sham-operated controls in response to dobutamine. Of phosphodiesterase (PDE) isoforms, PDE4D, but not PDE3A, both of which are responsible for cardiac cAMP hydrolysis, was significantly upregulated in CLP mouse myocardium. We define a novel mechanism for the impaired responsiveness to dobutamine as an inotrope in sepsis, and understanding the role of PDE4D in modulating cardiac functional responsiveness in sepsis may open the potential of a PDE4D-targeted therapeutic option in septic patients with low cardiac output who have a need for inotropic support.NEW & NOTEWORTHY Advisability of the usefulness of dobutamine in septic shock management is limited. Here, we reveal that the effect of dobutamine as a positive inotrope is impaired in mice with cecal ligation and puncture-induced sepsis without changes in cardiac ß1-adrenoceptor signaling as a result of cAMP breakdown achieved by upregulated phosphodiesterase 4D.
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Cardiotónicos/farmacología , Ciego/cirugía , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Dobutamina/farmacología , Milrinona/farmacología , Contracción Miocárdica/efectos de los fármacos , Miocardio/enzimología , Inhibidores de Fosfodiesterasa 3/farmacología , Sepsis/tratamiento farmacológico , Sepsis/enzimología , Adenilil Ciclasas/metabolismo , Animales , Ciego/microbiología , AMP Cíclico/sangre , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Hidrólisis , Mediadores de Inflamación/metabolismo , Ligadura , Masculino , Ratones Endogámicos BALB C , Punciones , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo , Sepsis/microbiología , Sepsis/fisiopatología , Transducción de Señal , Regulación hacia ArribaRESUMEN
Histamine mediates a wide range of cellular responses, including allergic and inflammatory reactions, gastric acid secretion, and neurotransmission in the central nervous system. Histamine also exerts a series of actions upon the cardiovascular system but may not normally play a significant role in regulating cardiovascular function. During tissue injury, inflammation, and allergic responses, mast cells (or non-mast cells) within the tissues can release large amounts of histamine that leads to noticeable cardiovascular effects. Owing to intensive research during several decades, the distribution, function, and pathophysiological role of cardiovascular H1- and H2-receptors has become recognized adequately. Besides the recognized H1- and H2-receptor-mediated cardiovascular responses, novel roles of H3- and H4-receptors in cardiovascular physiology and pathophysiology have been identified over the last decade. In this review, we describe recent advances in our understanding of cardiovascular function and dysfunction mediated by histamine receptors, including H3- and H4-receptors, their potential mechanisms of action, and their pathological significance.
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Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/patología , Sistema Cardiovascular/fisiopatología , Histamina/metabolismo , Receptores Histamínicos/metabolismo , Animales , Humanos , Mastocitos/metabolismo , Mastocitos/fisiologíaRESUMEN
In the emergency and critical care medicine, infection is easy to merge to various basic conditions and diseases. In the social structure aging in critical care, the immune weakness was revealed as the result of severe infection and septic shock in the reduced function of neutrophils and lymphocytes. In the life-saving emergency care, cardiovascular diseases, diabetes, chronic renal failure and lever dysfunction are often observed, and the underlying diseases have the foundation of biological invasion after a first inflammatory attack of surgery, trauma, burn, and systemic injury. It will be placed into a susceptible situation such as artificial respiratory management. In this review, we discussed severe infection in emergency and critical care. It is necessary to pay attention to the drug resistance bacterias in own critical care setting by trends.
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Cuidados Críticos , Servicios Médicos de Urgencia , Infecciones/terapia , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Bacterias/efectos de los fármacos , Bacterias/aislamiento & purificación , Farmacorresistencia Bacteriana , Humanos , Control de Infecciones , Infecciones/inmunología , Infecciones/microbiología , Índice de Severidad de la Enfermedad , Choque SépticoRESUMEN
OBJECTIVES: The calcium sensitizer levosimendan is used in treatment of decompensated heart failure and may also exhibit anti-inflammatory properties. We examined whether treatment with levosimendan is substantially beneficial in mice with cecal ligation and puncture-induced polymicrobial sepsis, and its arbitration mechanism was explored in the mouse macrophage cell line RAW264.7. DESIGN: Laboratory and animal/cell research. SETTING: University research laboratory. SUBJECTS: BALB/c mice (8-10 wk old) and mouse macrophage cell line RAW264.7 cells. INTERVENTIONS: Levosimendan (0.5 µg/kg/min) was administered to mice through an osmotic pump that was implanted into the peritoneal cavity immediately following surgery. In RAW264.7 cells, levosimendan was added to the culture medium 30 minutes before lipopolysaccharide. MEASUREMENTS AND MAIN RESULTS: When levosimendan was continuously administered to cecal ligation and puncture-induced septic mice, a significant improvement of left ventricular function was found without any change in heart rate, and hypotension was significantly mitigated. Furthermore, levosimendan conferred substantial protection against sepsis-associated inflammation in mice, as indicated by reduced lung injury and decreased blood proinflammatory and chemotactic cytokine levels. These beneficial effects of levosimendan led to a significant improvement of survival in mice after cecal ligation and puncture. In endotoxin-stimulated RAW264.7 macrophages, treatment with levosimendan and pimobendan suppressed overproduction of proinflammatory and chemotactic cytokines. Levosimendan and pimobendan were without effect on activation of the nuclear factor-κB, mitogen-activated protein kinase, and Akt pathways. Instead, levosimendan and pimobendan prevented high mobility group box 1 release from the nucleus to the extracellular space in macrophages. This was associated with inhibition of the Rho kinase signaling pathway. The elevated serum high mobility group box 1 levels in cecal ligation and puncture-induced septic mice were also inhibited by continued administration of levosimendan and pimobendan. CONCLUSIONS: We define a novel mechanism for the anti-inflammatory action of levosimendan and suggest that the pharmacological profiles of levosimendan as both an inotrope and an anti-inflammatory agent could contribute to its clinical benefit in patients with sepsis with heart problems.
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Antiinflamatorios/farmacología , Citocinas/metabolismo , Hidrazonas/farmacología , Macrófagos/efectos de los fármacos , Piridazinas/farmacología , Sepsis/tratamiento farmacológico , Sepsis/patología , Animales , Biopsia con Aguja , Western Blotting , Ciego/cirugía , Células Cultivadas , Citocinas/efectos de los fármacos , Modelos Animales de Enfermedad , Ecocardiografía/métodos , Ensayo de Inmunoadsorción Enzimática , Inmunohistoquímica , Inyecciones Intravenosas , Ligadura/métodos , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Distribución Aleatoria , Reacción en Cadena en Tiempo Real de la Polimerasa , Valores de Referencia , Sepsis/mortalidad , Simendán , Estadísticas no Paramétricas , Tasa de SupervivenciaRESUMEN
Radial arterial cannulation is a popular technique for continuous hemodynamic monitoring in an area of anesthesia and intensive care. Although the risk for invasive monitoring is considerable, there is scarce information about the change in blood flow of cannulated vessel after the catheterization. In the current investigation, we evaluated the change in the cannulated arterial blood flow. Six volunteers (study 1) and eight post-surgical patients (study 2) were enrolled into the studies. In the study 1, the both side of diameter of radial artery (RA), ulnar artery (UA) and dorsal branch of radial artery (DBRA) of participants were measured using power Doppler ultrasound (PDU) with or without proximal oppression. In the study 2, the diameter of RA, UA and DBRA of the both intact and cannulated side were compared. Study 1: The diameter of RA was 3.4 (0.52) [mean (SD)] mm and the proximal oppression significantly decreased the diameter to 1.8 (0.59) mm. The diameter of DBRA measured by PDU also decreased 2.0 (0.60)-1.3 (0.59) mm. Study 2: There was no difference between the diameters of right and left RA, however, the UA was larger [3.4 (0.60) vs. 2.8 (0.83) mm] and the DBRA was narrower [1.4 (0.43) vs. 2.0 (0.47) mm] in the cannulated side. The diameters of DBRA were different between the intact and cannulated side in the patients. Although there is no information of relationships between cause of severe complication and decreased flow, significant reduction of blood flow should be concerned.
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Artefactos , Velocidad del Flujo Sanguíneo/fisiología , Interpretación de Imagen Asistida por Computador/métodos , Arteria Radial/diagnóstico por imagen , Arteria Radial/fisiología , Ultrasonografía Doppler/métodos , Adulto , Anciano , Anciano de 80 o más Años , Cateterismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Sepsis is defined as the body's overwhelming and life-threatening response to infection that can lead to tissue damage, organ failure, and death. Since bacterial infection is one of the main causes of sepsis, appropriate antimicrobial therapy remains the cornerstone of sepsis and septic shock management. However, since sepsis is a multifaceted chaos involving inflammation and anti-inflammation disbalance leading to the unregulated widespread release of inflammatory mediators, cytokines, and pathogen-related molecules leading to system-wide organ dysfunction, the whole body control to prevent the progression of organ dysfunction is needed. In sepsis and septic shock, pathogen-associated molecular patterns (PAMPs), such as bacterial exotoxins, cause direct cellular damage and/or trigger an immune response in the host. PAMPs are recognized by pattern recognizing receptors (PRRs) expressed on immune-reactive cells. PRRs are also activated by host nuclear, mitochondrial, and cytosolic proteins, known as damage-associated molecular patterns (DAMPs) that are released from cells during sepsis. Thus, most PRRs respond to PAMPs or DAMPs by triggering activation of transcriptional factors, NF-κB, AP1, and STAT-3. On the other hand, sepsis leads to immune (lymphocytes and macrophages) and nonimmune (endothelial and epithelial cells) cell death. Apoptosis has been the major focus of research on cell death in sepsis, but autophagy, necrosis, necroptosis, pyroptosis, NETosis, and ferroptosis may also play an important role in this critical situation. The recent development in our understanding regarding the cellular pathogenesis of sepsis will help in developing new treatment of sepsis.
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Sepsis , Choque Séptico , Humanos , Insuficiencia Multiorgánica/etiología , Moléculas de Patrón Molecular Asociado a Patógenos , Apoptosis , AlarminasRESUMEN
Administration in a lipid emulsion can modify the pharmacodynamics of drugs via a process known as lipid resuscitation. However, the detailed mechanism remains unclear. We studied the volume and another pharmacodynamic effect, the lipid sink, using propofol and thiamylal. Male adult mice (ddY) were intravenously administered 10 ml/kg propofol or thiamylal diluted with physiological saline, 10% soybean oil, or 20% soybean oil. The 50% effective dose (ED50) for achieving hypnosis was calculated using probit analysis. To investigate the volume effect, 0, 10, or 20 ml/kg of saline or soybean oil was administered, either simultaneously or beforehand. Next, a two- or three-fold dose of the anesthetics was administered and the durations of anesthesia were measured. Finally, at 30 s after the first injection, supplemental soybean oil was administered. The mean (± SE) ED50 values of propofol and thiamylal were 5.79 mg/kg (0.61) and 8.83 mg/kg (0.84), respectively. Lipid dilution increased the ED50 values of both anesthetics. After injection of a dose two-fold the ED50 value, the respective mean (± SD) durations of anesthesia were 125 ± 35 s and 102 ± 38 s. Supplemental administration of soybean oil significantly shortened the duration of anesthesia of propofol, but not that of thiamylal. The results indicate that administration of a lipid emulsion vitiated the anesthetic effect of propofol by reducing the non-emulsified free fraction in the aqueous phase, which may elucidate the lipid resuscitation likely caused by the lipid sink mechanism.
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Propofol , Masculino , Ratones , Animales , Propofol/farmacología , Tiamilal/farmacología , Hipnóticos y Sedantes/farmacología , Anestésicos Intravenosos/farmacología , Aceite de Soja/farmacología , EmulsionesRESUMEN
BACKGROUND: Adenosine triphosphate (ATP)-sensitive K(+) channels contribute to significant regulatory mechanisms related to organ blood flow in both physiological and pathological conditions. High glucose impairs arterial ATP-sensitive K(+) channel activity via superoxide production. However, the effects of anesthetics on this pathological process have not been evaluated in humans. In the present study, we investigated whether pretreatment with the volatile anesthetic isoflurane preserves ATP-sensitive K(+) channel activity in the human artery exposed to oxidative stress caused by high glucose. METHODS: All experiments were performed using human omental arteries without endothelium in the presence of d-glucose (5.5 mmol/L). Some arteries were treated with isoflurane (1.15% or 2.3%) in combination with d- or l-glucose (20 mmol/L) for 60 minutes, and then only isoflurane was discontinued. Relaxation and hyperpolarization of arterial segments in response to an ATP-sensitive K(+) channel opener levcromakalim were evaluated using the isometric force recording or electrophysiological study, respectively. Superoxide production was determined by dihydroethidium fluorescence. Immunohistochemical analysis for a subunit of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase p47phox was performed. Data were evaluated using repeated-measures analysis of variance or a factorial analysis of variance as appropriate, followed by Scheffé test. RESULTS: The ATP-sensitive K(+) channel antagonist glibenclamide (10(-6) mol/L) abolished relaxation induced by cumulative addition of levcromakalim (10(-8) to 10(-5) mol/L) in arteries treated with l-glucose (20 mmol/L). Incubation with d-glucose (20 mmol/L) impaired the vasorelaxation induced by levcromakalim. The selective NADPH oxidase NOX2 inhibitor gp91ds-tat (10(-6) mol/L) and pretreatment with isoflurane (1.15% and 2.3%) restored relaxation in response to levcromakalim in arteries treated with d-glucose (20 mmol/L). Isoflurane (2.3%), gp91ds-tat (10(-6) mol/L), and their combination similarly restored hyperpolarization in response to levcromakalim (3 × 10(-6) mol/L) in arteries treated with d-glucose (20 mmol/L). Along with these results, isoflurane (2.3%) reduced superoxide production and the intracellular mobilization of the cytosolic NOX2 subunit p47phox toward smooth muscle cell membrane in arteries treated with d-glucose (20 mmol/L). CONCLUSIONS: We have demonstrated for the first time a beneficial effect from the pretreatment with isoflurane on the isolated human artery. Pretreatment with isoflurane preserves ATP-sensitive K(+) channel activity in the human omental artery exposed to oxidative stress induced by high glucose, whereas the effect seems to be mediated by NADPH oxidase inhibition. Volatile anesthetics may protect human visceral arteries from malfunction caused by oxidative stress.
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Anestésicos por Inhalación/farmacología , Arterias/efectos de los fármacos , Glucosa/metabolismo , Isoflurano/farmacología , Canales KATP/efectos de los fármacos , Epiplón/irrigación sanguínea , Estrés Oxidativo/efectos de los fármacos , Anciano , Arterias/metabolismo , Cromakalim/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Inmunohistoquímica , Canales KATP/metabolismo , Masculino , Potenciales de la Membrana , Persona de Mediana Edad , Miografía , NADPH Oxidasas/antagonistas & inhibidores , NADPH Oxidasas/metabolismo , Bloqueadores de los Canales de Potasio/farmacología , Superóxidos/metabolismo , Factores de Tiempo , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
BACKGROUND: Emergency departments deal with large patient loads on a day-to-day basis. The importance of patient self-assessment in the triage process has not been fully considered when determining the need for hospital admission. OBJECTIVE: To determine the validity of a series of self-administered triage questions in determining the need for hospitalisation in the emergency setting. DESIGN: Prospective cohort study. SETTING: Emergency department in a tertiary-care, municipal hospital in Japan. PARTICIPANTS: 5380 consecutive walk-in patients visiting the emergency department of Okazaki City Hospital were asked to self-evaluate the urgency and severity of their condition and their perceived need for hospital admission. These patients were then assessed by emergency physicians blinded to the results from each patient's self-assessment. MAIN OUTCOME MEASURES: Sensitivity, specificity and likelihood ratios were calculated for each self-assessment by comparing these with findings from assessments made by emergency physicians. RESULTS: Patient-perceived need for hospitalisation had a sensitivity of 0.79 (95% CI 0.76 to 0.82) and a specificity of 0.93 (95% CI 0.92 to 0.93) in determining hospital admission. The positive and negative likelihood ratios for self-assessments were 10.68 (95% CI 9.59 to 11.90) and 0.22 (95% CI 0.19 to 0.26), respectively, in the diagnosis of hospital admission (p<0.01). CONCLUSIONS: The patient self-triage questions concerning condition with five categories (medication only to life threatening) seem to supplement the triage process for hospital admission in emergency departments.
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Autoevaluación Diagnóstica , Servicio de Urgencia en Hospital , Estado de Salud , Admisión del Paciente , Triaje/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sensibilidad y Especificidad , Adulto JovenRESUMEN
PURPOSE: Investigation into the characteristics of anesthetic interactions may provide clues to anesthesia mechanisms. Dexmedetomidine, an α(2)-adrenergic receptor agonist, has become a popular sedative in intensive care, and hydroxyzine, a histamine receptor antagonist, is well known as a tranquilizing premedication for anesthesia. However, no experimental or pharmacological evaluation has been reported concerning their combination with propofol. Thus, we studied their combined effect with a hypnotic dose of propofol in ddY mice. METHODS: Male adult mice were intravenously administered either dexmedetomidine (30 µg/kg) or hydroxyzine (5 mg/kg) with propofol (3.75-10 mg/kg) to induce hypnosis, defined as a loss of the righting reflex (LRR). Other mice were intravenously administered propofol, dexmedetomidine (300 µg/kg), or hydroxyzine (50 mg/kg) alone, and subsequent behavioral changes were observed. The 50% effective dose (ED(50)) for LRR was calculated, and the duration of LRR was determined. RESULTS: The hypnotic dose of propofol was 9.95 ± 1.04 mg/kg (ED(50) ± SEM) without combination. Dexmedetomidine and hydroxyzine reduced the ED(50) of propofol to 5.32 ± 0.57 and 5.63 ± 0.57 mg/kg, respectively. Coadministration of dexmedetomidine significantly extended LRR duration compared with propofol alone, whereas hydroxyzine significantly shortened LRR duration. A maximal dose of dexmedetomidine or hydroxyzine alone did not induce hypnosis. CONCLUSIONS: Dexmedetomidine and hydroxyzine demonstrated no hypnotic action alone; however, their coadministration potentiated the hypnotic activity of propofol. Although reduction in the dose of propofol was similar, only dexmedetomidine prolonged the duration of hypnosis.
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Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Dexmedetomidina/farmacología , Antagonistas de los Receptores Histamínicos H1/farmacología , Hidroxizina/farmacología , Hipnóticos y Sedantes/farmacología , Propofol/farmacología , Animales , Sinergismo Farmacológico , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Receptores de GABA-A/fisiologíaRESUMEN
We encountered three patients who showed ECG changes, suggesting cardiac conduction abnormality, immediately after the induction of general anesthesia with remifentanil and thiamylal. The first patient was a 42-year-old man (172cm and 75kg). The second patient was a 75-year-old woman (153 cm and 62 kg) and the last patient was 16-year-old woman (166 cm and 46 kg). Remarkable past history was not noted and pre-anesthetic evaluations including 12 lead electrocardiogram demonstrated no abnormality in all patients. Immediately after the induction of anesthesia, atrioventricular dissociation, sinus arrest and atrioventricular junctional rhythm were diagnosed by monitoring electrocardiogram, respectively. The conduction abnormalities were not followed by severe bradycardia and hypotension, and observed without drug administration. In the first and second patient, sinus rhythm returned within 15 to 20 min after the induction. The junctional rhythm in the third patient continued during the operation; however, the recovery to sinus rhythm was observed at the end of operation lasting about 1 hr. No severe adverse clinical complication was found; however, careful monitoring might be required to pre vent circulatory depression with combination of remifentanil and thiamylal.