Effects of sevoflurane on ventilator induced lung injury in a healthy lung experimental model | Revista Española de Anestesiología y Reanimación (English Edition)

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Romero, A. Moreno, J. García, C. Sánchez, M. Santos" "autores" => array:6 [ 0 => array:4 [ "nombre" => "A." "apellidos" => "Romero" "email" => array:1 [ 0 => "antonromero@hotmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "A." "apellidos" => "Moreno" ] 2 => array:2 [ "nombre" => "J." "apellidos" => "García" ] 3 => array:2 [ "nombre" => "C." "apellidos" => "Sánchez" ] 4 => array:2 [ "nombre" => "M." "apellidos" => "Santos" ] 5 => array:2 [ "nombre" => "J." "apellidos" => "García" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Departamento de Anestesiología, Reanimación y Cuidados Críticos, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda, Madrid, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Efectos de sevoflurano en la lesión pulmonar inducida por la ventilación mecánica en un modelo experimental de pulmón sano" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 713 "Ancho" => 950 "Tamanyo" => 238095 ] ] "descripcion" => array:1 [ "en" => "Peribronchial inflammatory injury in the sevoflurane group." ] ] ] "textoCompleto" => "IntroductionMost patients undergoing general anesthesia and a large percentage of patients admitted to intensive care units receive mechanical ventilation in order to alleviate the work of breathing while lung function is restored. Incorrect use of mechanical ventilation can damage the lungs or aggravate an existing lung injury, and give rise to ventilator-induced lung injury (VILI)<a class="elsevierStyleCrossRefs" href="#bib0135">1,2</a> caused by an amplification and generalization of the systemic inflammatory response (biotrauma). During this inflammatory response, blood and tissue levels of proinflammatory cytokines such as the tumor necrosis factor (TNF-α), Interleukin (IL) 1β, IL-6 and la IL-8 are increased.<a class="elsevierStyleCrossRef" href="#bib0145">3</a>VILI is mainly associated with phenomena such as the use of insufficient positive end-expiratory pressure (PEEP) to prevent cyclic alveolar collapse-reopening (atelectrauma), which increases perialveolar leukocyte infiltration<a class="elsevierStyleCrossRef" href="#bib0150">4</a>; the delivery of high alveolar pressure (barotrauma), which causes alveolar and perivascular edema<a class="elsevierStyleCrossRef" href="#bib0155">5</a>; and the use of high respiratory frequency, due to stress cycles.<a class="elsevierStyleCrossRef" href="#bib0160">6</a> The damaging effect of high tidal volumes (volutrauma), which can induce overdistension of alveoli, has also been suggested as a cause of VILI.<a class="elsevierStyleCrossRefs" href="#bib0165">7,8</a>A classic experimental VILI induction model involves the delivery of cyclic inflation pressures (>30cmH2O) at different time intervals.<a class="elsevierStyleCrossRef" href="#bib0165">7</a>Volatile anesthetics have been shown to have an anti-inflammatory action.<a class="elsevierStyleCrossRef" href="#bib0175">9</a> Therefore, volatile anesthetics attenuate ischemia–reperfusion injury in the heart,<a class="elsevierStyleCrossRef" href="#bib0180">10</a> the kidney,<a class="elsevierStyleCrossRef" href="#bib0185">11</a> the liver<a class="elsevierStyleCrossRef" href="#bib0190">12</a> and the lungs,<a class="elsevierStyleCrossRefs" href="#bib0195">13,14</a> and decrease the inflammatory response in in vivo<a class="elsevierStyleCrossRefs" href="#bib0175">9,15–17</a> and in vitro<a class="elsevierStyleCrossRef" href="#bib0215">17</a> sepsis-induced pulmonary injury models. Furthermore, recent studies have shown that sevoflurane could act as a pre- and postconditioning agent in endotoxin-induced lung injury models.<a class="elsevierStyleCrossRef" href="#bib0220">18</a> Nevertheless, no studies have explored the possible protective effect of sevoflurane against VILI in previously healthy lungs.The aim of this study is to evaluate the effect of sevoflurane on VILI, analyzing histopathological damage, the degree of pulmonary edema, and level of inflammatory cytokines in rats.Materials and methodsWe studied 20 Wistar rats with a mean weight of 215±35g. The animals were kept in groups of 6 in U-TEMP polyetherimide cages. They were given free access to food and water, with 12h of light and 12h of darkness, a temperature of 20±2°C and a relative humidity of 50–70%. The animals were kept in these conditions for at least 1 week to allow them to acclimatize before starting the experiments. The animals were handled in accordance with European and Spanish laws governing the protection of experimental animals (2010/63/EU and RD 53/2013), and the study was approved by the institutional Animal Experimentation Ethics Committee.The animals were anesthetized with an intraperitoneal injection of ketamine (75mg/kg) and diazepam (5mg/kg). When the target level of hypnosis had been reached, the animal was intubated using a 16G polyethylene catheter (Abbott Ireland, Sligo, Republic of Ireland), using the otoscope method<a class="elsevierStyleCrossRef" href="#bib0225">19</a> to connect the catheter to the semi-closed anesthesia breathing system (Julian, Dräger, Lübeck, Germany).Following this, pressure-controlled mechanical ventilation was started, with a peak inspiratory pressure (PIP) of 12cmH2O, PEEP of 3cmH2O, an FiO2 of 0.5, and a breathing rate of 30rpm.The trachea was dissected by means of a medial incision in the neck. The airway was tied off using suture thread, a line was placed in the left carotid artery (24G polyethylene catheter, Abbott Ireland) to monitor heart rate (HR) and mean arterial pressure with a calibrated pressure transducer, and arterial blood samples were taken to determine pH, PaO2 and PaCO2.A 24G polyethylene catheter (Abbott Ireland) was placed in the tail vein to administer 10mL/kg/h 0.9% physiological saline solution, and a temperature probe was placed in the rectum. An air heater set to 45°C was used to maintain room temperature within physiological limits (37–38°C).Following this, the animals were randomized to one of two study groups: CONTROL (n=10), which did not receive sevoflurane, and SEV (n=10), which were ventilated with 3% sevoflurane vaporized in 1l/min of oxygen.After 30min (BASELINE time), VILI was induced by increasing PIP to 35cmH2O with a driving pressure of 35cmH2O for 20min (INJURY time). Following this, ventilation continued for 30min at the initial setting of 12cmH2O peak pressure and 3cmH2O PEEP (POSTINJURY time) in order to allow time for proinflammatory cytokine levels in lung tissue to increase. During this process, the SEV group continued to receive 3% sevoflurane. At the end of each experiment, the animals were sacrificed with 50meq/kg of intravenous potassium chloride and the lungs were removed to study cytokine levels, the wet/dry weight ratio, and to perform histopathological studies.Hemodynamic and blood gas parametersHR, mean arterial pressure and arterial blood gases (pH, PaO2 and PaCO2) were measured immediately prior to lung injury induction (baseline), 20min after start of VILI, and at the end of the study (30min POSTINJURY).Determination of the wet/dry lung weight ratioThe wet/dry weight ratio was calculated in the whole left lungs of all study animals. Lungs were dehydrated in a thermostat-controlled chamber at 80°C for 72h and the dry weight was measured. The wet/dry weight ratio was calculated to evaluate the percentage of pulmonary edema.Determination of TNF-α, IL-1β and IL-6 in lung tissueThe same lung segment (lower right lobe) was excised from all rats and stored at −80°C until needed for study. TNF-α, IL-1β and IL-6 in lung tissue was measured. The segment was place in saline solution and centrifuged for 10min at 10,000rpm, at 4°C. Cytokine levels were measured in the supernatant by means of an ELISA test.Histopathological analysisThe upper right lobes of all rats was excised and fixed in 10% formaldehyde. They were then stained with hematoxylin and eosin and embedded in paraffin for study by a histopathologist blinded to the study.A 4-point qualitative ordinal variable injury scale (negative=0, minor=1, moderate=2, severe=3) was used to evaluate each of the following characteristics. The 4 main characteristics based on 15 individual items are: atelectasis, edema (septal edema, interstitial edema, lymphangiectasia, intra-alveolar exudate), inflammation (alveolar neutrophil infiltration, interstitial neutrophil infiltration, interstitial lymphocyte infiltration, granulocyte adhesion), and other (alveolar hemorrhage, hyperemia, thrombocyte aggregation, fibrin deposits, hyaline membrane formation, peeling of the bronchial and bronchiolar epithelium). A summary of the results obtained for each parameter in all animals is given below. The sum of all 15 parameters was then divided by the number of animals in each group to obtain the total injury score.Statistical analysisStatistical analysis of study data was performed on SPSS® v. 15.0 (SPSS Inc., Chicago, IL, USA). Based on the findings of earlier studies conducted by our group, we determined that each group should comprise 7 animals in order to detect a difference in HR of 50bpm or over, with a p value of 0.05, a statistical power of 95% in a bilateral comparison, and a loss to follow-up or 0%.All data were grouped and summarized as mean±standard deviation. Hemodynamic and blood gas parameters were analyzed using Shapiro–Wilk normality testing, followed by repeated measures analysis of variance (ANOVA) testing and a Bonferroni multiple comparison test. For inter-group comparison of wet/dry weight ratio, TNF-α, IL-1β and IL-6, the unpaired t-test was used. Statistical significance was set at p<0.05.ResultsHemodynamic and blood gas parametersArterial blood gas analysis showed respiratory alkalosis in both groups at VILI time vs baseline time (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Difference between CONTROLs and the SEV group were not statistically significant.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Mean arterial pressure in the CONTROL group was significantly higher at the 3 study time points vs the SEV group (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). No statistically significant differences in HR were observed.Determination of the wet/dry lung weight ratioWet/dry lung weight ratio as an indicator of the percentage of pulmonary edema was significantly lower in the SEV group vs CONTROLs (79.49%±1.78% vs 84.97%±1.69%; p<0.0001) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Determination of TNF-α, IL-1β and IL-6 in lung tissueTNF-α and IL-6 levels in lung tissue were significantly lower in the SEV group vs CONTROLs (144±25 vs 243±51pg/mL for IL-6 [p<0.0001] and 14±4 vs 23±4pg/mL for TNF-α [p<0.0001]) (<a class="elsevierStyleCrossRefs" href="#fig0010">Figs. 2 and 3</a>); however, no statistically significant differences in changes in IL-1β levels in lung tissue were found between groups (128±92 in CONTROL vs 115±69pg/mL in SEV) (p=0.715) (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia>Histopathological analysisHistopathological findings were similar in the sevoflurane group (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>) and the CONTROL group (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>), and showed peribronchial inflammatory injury, edema, and centrilobular emphysema. The extent of injury was based on the score obtained from the 4-point qualitative ordinal variable scale: the CONTROL group had a mean score of 1.2±0.33, with the SEV group scoring 0.8±0.36, which describes a minor injury with no statistically significant difference between groups.<elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia>DiscussionFollowing induction of VILI with an inflation pressure of 35cmH2O for 20min, neither study group showed any clinically significant severe histopathological injuries or oxygen deficit on examination. This indicates that neither the pressure nor the duration of delivery was sufficient to induce severe histopathological lung injury, or that postinjury time was not sufficient for these changes to show up on histopathological analysis. Nevertheless, the wet/dry lung weight ratio, which quantifies mechanical stress markers (pulmonary edema and IL-6 and TNF-α levels), shows significantly less pulmonary edema and inflammatory response in the SEV group vs CONTROLs.Other experimental studies have shown that mechanical ventilation with a driving pressure of 14cmH2O does not induce histological changes in the lung, while subjects receiving driving pressures of between 30 and 45cmH2O present significant perivascular and alveolar edema after 30min of delivery.<a class="elsevierStyleCrossRefs" href="#bib0135">1,2,20</a> In our study, we observed similar histopathological injuries using a driving pressure of 35cmH2O for 20min, although in this case the injuries were not as severe as those reported in the foregoing studies. This shows that the time of exposure to high pressure (increased from 20 to 30min) and the inflation pressure within this high pressure range (30, 35 or 40cmH2O) are both key factors in determining the severity of lung injury.In our study, the quantification of pulmonary edema by means of the wet/dry lung weight ratio, and the quantification and measurement of proinflammatory cytokine levels were shown to be more sensitive early markers of inflation pressure-induced lung injury than histopathological injury, as this latter requires a more prolonged exposure to high pressures.Reduction in the extent of pulmonary edema in the sevoflurane group coincides with the findings obtained from pulmonary ischemia-reperfusion injury<a class="elsevierStyleCrossRef" href="#bib0200">14</a> and in sepsis-induced pulmonary injury models.<a class="elsevierStyleCrossRef" href="#bib0215">17</a>In vitro, sevoflurane stimulates the Na+/K+-ATPase activity in injury-induced type ii alveolar epithelial cells, one of the functions of which is to regulate transport of ClNa and H2O into the alveolar space.<a class="elsevierStyleCrossRef" href="#bib0235">21</a> In in vivo experiments, however, there is evidence that sevoflurane does not affect water reabsorption and edema resolution, but could contribute to edema formation.<a class="elsevierStyleCrossRef" href="#bib0215">17</a>The antiinflammatory effect of volatile anesthetics has been explained by their involvement in preconditioning.<a class="elsevierStyleCrossRef" href="#bib0175">9</a> Pharmacological preconditioning is a protection mechanism that makes cells relatively resistant to the myocellular death resulting from ischemia-reperfusion injury.<a class="elsevierStyleCrossRef" href="#bib0205">15</a> In the lung, volatile anesthetic-induced preconditioning protects against injury caused by both ischemia-reperfusion<a class="elsevierStyleCrossRefs" href="#bib0195">13,14</a> and sepsis.<a class="elsevierStyleCrossRefs" href="#bib0175">9,15–17</a> Both types of injury are characterized by activation of proinflammatory cytokines, such as TNF-α, IL-1β and IL-6.No significant differences in proinflammatory cytokines concentrations in bronchoalveolar lavage were found during mechanical ventilation with sevoflurane or pentobarbital<a class="elsevierStyleCrossRef" href="#bib0240">22</a>; however, VILI-induced inflammatory response is characterized by activation of these proinflammatory cytokines.<a class="elsevierStyleCrossRef" href="#bib0145">3</a> The pulmonary homogenate obtained in our study shows less proinflammatory cytokine secretion in all cytokine secreting alveolar cells (TNF-α and IL-6, but not IL-1β) in animals ventilated with sevoflurane. This confirms that the same anti-inflammatory and cell protective action of sevoflurane reported in other lung injury models is also found in healthy lungs, where it protects alveoli against damage induce by mechanical ventilation with high driving pressure.Many alveolar cells involved in cytokine secretion, such as alveolar macrophages<a class="elsevierStyleCrossRef" href="#bib0240">22</a> and polymorphonuclear leukocytes,<a class="elsevierStyleCrossRef" href="#bib0210">16</a> can be affected by volatile anesthetics. Type ii alveolar epithelial cells, together with inflammatory alveolar cells, form part of the intra-alveolar cytokine network, secreting IL-6,<a class="elsevierStyleCrossRef" href="#bib0245">23</a> TNF-α,<a class="elsevierStyleCrossRef" href="#bib0250">24</a> and other interleukins. Giraud et al.<a class="elsevierStyleCrossRef" href="#bib0255">25</a> showed in vitro that volatile anesthetics in general, and halotane in particular, reduce secretion of TNF-α and IL-6 in type ii epithelial cells. Subsequent in vitro experiments have shown the pre- and postconditioning with sevoflurane reduces expression of inflammatory mediators in alveolar epithelial cells.<a class="elsevierStyleCrossRef" href="#bib0220">18</a>In contrast to our results, isoflurane and sevoflurane were found to reduce plasma concentrations of IL-1β in a sepsis-induced lung injury model.<a class="elsevierStyleCrossRef" href="#bib0205">15</a> We believe that no significant intra-group differences in IL-1β levels were found in our study because samples were taken too soon to enable measurement of IL peaks in lung tissue (30min POSTINJURY). This time frame was chosen to prevent loss of the IL-6 and TNF-α peaks, which occur earlier, because alveolar macrophages secrete IL-1β 8h following lipopolysaccharide stimulation.<a class="elsevierStyleCrossRef" href="#bib0260">26</a>This study is subject to the limitation typical of any experimental study in rats. This means that the results cannot be directly extrapolated to clinical practice in humans, and more experimental studies are needed to confirm these preliminary findings. Ultimately, clinical trials should be conducted in human subjects to confirm our results. Furthermore, the VILI model used in our study was subject to a short injury exposure time (20min). This means that although lung injury occurred, it had no significant clinical impact on gas exchange. Studies using higher pressure settings should be conducted, above all with longer exposure times, to show whether sevoflurane continues to exert an anti-inflammatory and cell protection effect even when lung damage is more severe and the clinical impact greater.In conclusion, our study shows that sevoflurane attenuates VILI in health lungs in a subclinical rat model of VILI. Our findings suggest that further experimental and clinical studies are needed before the real clinical benefit of the cytoprotective effects of this anesthetic can be confirmed.FundingThis study has been fully funded by departmental research funds managed by the Instituto de Investigación del Hospital Puerta de Hierro.Conflict of interestThe authors declare they have no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres594485" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec609425" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres594484" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción y objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec609426" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Hemodynamic and blood gas parameters" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Determination of the wet/dry lung weight ratio" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Determination of TNF-α, IL-1β and IL-6 in lung tissue" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Histopathological analysis" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Statistical analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0040" "titulo" => "Results" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Hemodynamic and blood gas parameters" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Determination of the wet/dry lung weight ratio" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Determination of TNF-α, IL-1β and IL-6 in lung tissue" ] 3 => array:2 [ "identificador" => "sec0060" "titulo" => "Histopathological analysis" ] ] ] 7 => array:2 [ "identificador" => "sec0065" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0070" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "sec0075" "titulo" => "Conflict of interest" ] 10 => array:2 [ "identificador" => "xack199988" "titulo" => "Acknowledgments" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-01-10" "fechaAceptado" => "2015-04-13" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec609425" "palabras" => array:5 [ 0 => "Anesthesia" 1 => "Lung injury" 2 => "Mechanical ventilation" 3 => "Inflammation" 4 => "Sevoflurane" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec609426" "palabras" => array:5 [ 0 => "Anestesia" 1 => "Daño pulmonar" 2 => "Ventilación mecánica" 3 => "Inflamación" 4 => "Sevoflurano" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Introduction and objectiveVentilator-induced lung injury (VILI) causes a systemic inflammatory response in tissues, with an increase in IL-1, IL-6 and TNF-α in blood and tissues. Cytoprotective effects of sevoflurane in different experimental models are well known, and this protective effect can also be observed in VILI. The objective of this study was to assess the effects of sevoflurane in VILI. Material and methodsA prospective, randomized, controlled study was designed. Twenty female rats were studied. The animals were mechanically ventilated, without sevoflurane in the control group and sevoflurane 3% in the treated group (SEV group). VILI was induced applying a maximal inspiratory pressure of 35cmH2O for 20min without any positive end-expiratory pressure for 20min (INJURY time). The animals were then ventilated 30min with a maximal inspiratory pressure of 12cmH2O and 3cmH2O positive end-expiratory pressure (time 30min POST-INJURY), at which time the animals were euthanized and pathological and biomarkers studies were performed. Heart rate, invasive blood pressure, pH, PaO2, and PaCO2 were recorded. The lung wet-to-dry weight ratio was used as an index of lung edema. ResultsNo differences were found in the blood gas analysis parameters or heart rate between the 2 groups. Blood pressure was statistically higher in the control group, but still within the normal clinical range. The percentage of pulmonary edema and concentrations of TNF-α and IL-6 in lung tissue in the SEV group were lower than in the control group. ConclusionsSevoflurane attenuates VILI in a previous healthy lung in an experimental subclinical model in rats." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "Introducción y objetivoEl daño pulmonar inducido por la ventilación mecánica (VILI) provoca una respuesta inflamatoria sistémica, con elevación en sangre y tejidos de IL-1, IL-6 y TNF-α. Conocidos los efectos citoprotectores de sevoflurano en diferentes modelos experimentales, este podría tener un comportamiento similar ante el VILI. El objetivo de este estudio es valorar el efecto de sevoflurano en el VILI. Material y métodosEstudio experimental, prospectivo, controlado y aleatorizado. Se utilizaron 20 ratas hembra. Los animales fueron ventilados mecánicamente sin sevoflurano en el grupo control y con sevoflurano al 3% en el grupo tratado (grupo SEV). Se provocó el VILI mediante una presión inspiratoria máxima de 35cmH2O sin presión positiva al final de la expiración durante 20min (tiempo LESIÓN). Después, los animales fueron ventilados 30min con una presión inspiratoria máxima de 12cmH2O y 3cmH2O de presión positiva al final de la expiración (tiempo 30min POSLESIÓN). Se registraron la frecuencia cardiaca, las presiones arteriales sistólica, diastólica y media, el pH, la PaO2 y la PaCO2. Se analizó la ratio peso húmedo/seco del tejido pulmonar. ResultadosNo existieron diferencias estadísticamente significativas en los parámetros gasométricos ni en la frecuencia cardiaca entre los 2 grupos en estudio. La PAM fue significativamente mayor en el grupo control, pero dentro de límites clínicos normales. El porcentaje de edema pulmonar y las concentraciones de TNF-α e IL-6 en tejido pulmonar en el grupo de animales ventilados con sevoflurano fueron menores que en el grupo control. ConclusionesSevoflurano atenúa el VILI en pulmón previamente sano, en un modelo experimental de VILI subclínico en ratas." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción y objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Romero A, Moreno A, García J, Sánchez C, Santos M, García J. Efectos de sevoflurano en la lesión pulmonar inducida por la ventilación mecánica en un modelo experimental de pulmón sano. Rev Esp Anestesiol Reanim. 2016;63:22–28." ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 955 "Ancho" => 1495 "Tamanyo" => 33772 ] ] "descripcion" => array:1 [ "en" => "Wet/dry lung weight ratio as a marker of the percentage of pulmonary edema following establishment of a mechanical ventilation-induced lung injury in rat models anesthetized with (SEV) or without (CONTROL) sevoflurane. *Statistically significant (p<0.05) with respect to the CONTROL group." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1065 "Ancho" => 1192 "Tamanyo" => 32315 ] ] "descripcion" => array:1 [ "en" => "TNF-α levels in lung tissue following establishment of mechanical ventilation-induced lung injury in rat models anesthetized with (SEV) or without (CONTROL) sevoflurane. *Statistically significant (p<0.05) with respect to the CONTROL group." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1131 "Ancho" => 1504 "Tamanyo" => 39312 ] ] "descripcion" => array:1 [ "en" => "L-6 and IL-1β levels in lung tissue following establishment of a mechanical ventilation-induced lung injury in rat models anesthetized with (SEV) or without (CONTROL) sevoflurane. *Statistically significant (p<0.05) with respect to the CONTROL group." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 713 "Ancho" => 950 "Tamanyo" => 238095 ] ] "descripcion" => array:1 [ "en" => "Peribronchial inflammatory injury in the sevoflurane group." ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 713 "Ancho" => 950 "Tamanyo" => 203748 ] ] "descripcion" => array:1 [ "en" => "Peribronchial inflammatory injury in the CONTROL group." ] ] 5 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "Data expressed as mean±standard deviation." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">CONTROL \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">SEV \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">pH</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Baseline \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.337±0.047 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.287±0.021 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">INJURY \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.482±0.026<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.442±0.123<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">30min POSTINJURY \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.306±0.041 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.268±0.145 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">PaO2(mmHg)</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Baseline \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">230±16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">232±20 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">INJURY \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">258±14<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">256±22<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">30min POSTINJURY \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">218±28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">206±25 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">PaCO2(mmHg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Baseline \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">30.9±3.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">26.4±7.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">INJURY \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">17.3±2.0<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">17.1±1.3<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">30min POSTINJURY \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">31.4±4.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">26.8±1.0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Heart rate (bpm)</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Baseline \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">368±45 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">342±37 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">INJURY \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">357±28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">333±35 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">30min POSTINJURY \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">385±27 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">362±27 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Mean arterial pressure (mmHg)</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Baseline \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">93±15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">80±10<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">INJURY \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">86±11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">74±13<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">30min POSTINJURY \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">101±13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">81±19<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab972109.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Statistically significant (p<0.05) with respect to baseline (p<0.05)." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "Statistically significant (p<0.05) with respect to CONTROL group (p<0.05)." ] ] ] "descripcion" => array:1 [ "en" => "Physiological parameters at baseline, VILI, and the end of the experiment in rats treated with (SEV) and without (CONTROL) sevoflurane." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" 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Effects of sevoflurane on ventilator induced lung injury in a healthy lung experimental model

Efectos de sevoflurano en la lesión pulmonar inducida por la ventilación mecánica en un modelo experimental de pulmón sano

A. Romero

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antonromero@hotmail.com

Corresponding author.

, A. Moreno, J. García, C. Sánchez, M. Santos, J. García

Departamento de Anestesiología, Reanimación y Cuidados Críticos, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda, Madrid, Spain

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    "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>"
    "titulo" => "Effects of sevoflurane on ventilator induced lung injury in a healthy lung experimental model"
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            "entidad" => "Departamento de Anestesiolog&#237;a&#44; Reanimaci&#243;n y Cuidados Cr&#237;ticos&#44; Hospital Universitario Puerta de Hierro-Majadahonda&#44; Majadahonda&#44; Madrid&#44; Spain"
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        "titulo" => "Efectos de sevoflurano en la lesi&#243;n pulmonar inducida por la ventilaci&#243;n mec&#225;nica en un modelo experimental de pulm&#243;n sano"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Peribronchial inflammatory injury in the sevoflurane group&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Most patients undergoing general anesthesia and a large percentage of patients admitted to intensive care units receive mechanical ventilation in order to alleviate the work of breathing while lung function is restored&#46; Incorrect use of mechanical ventilation can damage the lungs or aggravate an existing lung injury&#44; and give rise to ventilator-induced lung injury &#40;VILI&#41;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">1&#44;2</span></a> caused by an amplification and generalization of the systemic inflammatory response &#40;biotrauma&#41;&#46; During this inflammatory response&#44; blood and tissue levels of proinflammatory cytokines such as the tumor necrosis factor &#40;TNF-&#945;&#41;&#44; Interleukin &#40;IL&#41; 1&#946;&#44; IL-6 and la IL-8 are increased&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">VILI is mainly associated with phenomena such as the use of insufficient positive end-expiratory pressure &#40;PEEP&#41; to prevent cyclic alveolar collapse-reopening &#40;atelectrauma&#41;&#44; which increases perialveolar leukocyte infiltration<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">4</span></a>&#59; the delivery of high alveolar pressure &#40;barotrauma&#41;&#44; which causes alveolar and perivascular edema<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">5</span></a>&#59; and the use of high respiratory frequency&#44; due to stress cycles&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">6</span></a> The damaging effect of high tidal volumes &#40;volutrauma&#41;&#44; which can induce overdistension of alveoli&#44; has also been suggested as a cause of VILI&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">7&#44;8</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">A classic experimental VILI induction model involves the delivery of cyclic inflation pressures &#40;&#62;30<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O&#41; at different time intervals&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">7</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Volatile anesthetics have been shown to have an anti-inflammatory action&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">9</span></a> Therefore&#44; volatile anesthetics attenuate ischemia&#8211;reperfusion injury in the heart&#44;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">10</span></a> the kidney&#44;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">11</span></a> the liver<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">12</span></a> and the lungs&#44;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">13&#44;14</span></a> and decrease the inflammatory response in <span class="elsevierStyleItalic">in vivo</span><a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">9&#44;15&#8211;17</span></a> and <span class="elsevierStyleItalic">in vitro</span><a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">17</span></a> sepsis-induced pulmonary injury models&#46; Furthermore&#44; recent studies have shown that sevoflurane could act as a pre- and postconditioning agent in endotoxin-induced lung injury models&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">18</span></a> Nevertheless&#44; no studies have explored the possible protective effect of sevoflurane against VILI in previously healthy lungs&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The aim of this study is to evaluate the effect of sevoflurane on VILI&#44; analyzing histopathological damage&#44; the degree of pulmonary edema&#44; and level of inflammatory cytokines in rats&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and methods</span><p id="par0030" class="elsevierStylePara elsevierViewall">We studied 20 Wistar rats with a mean weight of 215<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>35<span class="elsevierStyleHsp" style=""></span>g&#46; The animals were kept in groups of 6 in U-TEMP polyetherimide cages&#46; They were given free access to food and water&#44; with 12<span class="elsevierStyleHsp" style=""></span>h of light and 12<span class="elsevierStyleHsp" style=""></span>h of darkness&#44; a temperature of 20<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>&#176;C and a relative humidity of 50&#8211;70&#37;&#46; The animals were kept in these conditions for at least 1 week to allow them to acclimatize before starting the experiments&#46; The animals were handled in accordance with European and Spanish laws governing the protection of experimental animals &#40;2010&#47;63&#47;EU and RD 53&#47;2013&#41;&#44; and the study was approved by the institutional Animal Experimentation Ethics Committee&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The animals were anesthetized with an intraperitoneal injection of ketamine &#40;75<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; and diazepam &#40;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41;&#46; When the target level of hypnosis had been reached&#44; the animal was intubated using a 16<span class="elsevierStyleHsp" style=""></span>G polyethylene catheter &#40;Abbott Ireland&#44; Sligo&#44; Republic of Ireland&#41;&#44; using the otoscope method<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">19</span></a> to connect the catheter to the semi-closed anesthesia breathing system &#40;Julian&#44; Dr&#228;ger&#44; L&#252;beck&#44; Germany&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Following this&#44; pressure-controlled mechanical ventilation was started&#44; with a peak inspiratory pressure &#40;PIP&#41; of 12<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O&#44; PEEP of 3<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O&#44; an FiO<span class="elsevierStyleInf">2</span> of 0&#46;5&#44; and a breathing rate of 30<span class="elsevierStyleHsp" style=""></span>rpm&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The trachea was dissected by means of a medial incision in the neck&#46; The airway was tied off using suture thread&#44; a line was placed in the left carotid artery &#40;24<span class="elsevierStyleHsp" style=""></span>G polyethylene catheter&#44; Abbott Ireland&#41; to monitor heart rate &#40;HR&#41; and mean arterial pressure with a calibrated pressure transducer&#44; and arterial blood samples were taken to determine pH&#44; PaO<span class="elsevierStyleInf">2</span> and PaCO<span class="elsevierStyleInf">2</span>&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">A 24<span class="elsevierStyleHsp" style=""></span>G polyethylene catheter &#40;Abbott Ireland&#41; was placed in the tail vein to administer 10<span class="elsevierStyleHsp" style=""></span>mL&#47;kg&#47;h 0&#46;9&#37; physiological saline solution&#44; and a temperature probe was placed in the rectum&#46; An air heater set to 45<span class="elsevierStyleHsp" style=""></span>&#176;C was used to maintain room temperature within physiological limits &#40;37&#8211;38<span class="elsevierStyleHsp" style=""></span>&#176;C&#41;&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Following this&#44; the animals were randomized to one of two study groups&#58; CONTROL &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41;&#44; which did not receive sevoflurane&#44; and SEV &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41;&#44; which were ventilated with 3&#37; sevoflurane vaporized in 1<span class="elsevierStyleHsp" style=""></span>l&#47;min of oxygen&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">After 30<span class="elsevierStyleHsp" style=""></span>min &#40;BASELINE time&#41;&#44; VILI was induced by increasing PIP to 35<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O with a driving pressure of 35<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O for 20<span class="elsevierStyleHsp" style=""></span>min &#40;INJURY time&#41;&#46; Following this&#44; ventilation continued for 30<span class="elsevierStyleHsp" style=""></span>min at the initial setting of 12<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O peak pressure and 3<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O PEEP &#40;POSTINJURY time&#41; in order to allow time for proinflammatory cytokine levels in lung tissue to increase&#46; During this process&#44; the SEV group continued to receive 3&#37; sevoflurane&#46; At the end of each experiment&#44; the animals were sacrificed with 50<span class="elsevierStyleHsp" style=""></span>meq&#47;kg of intravenous potassium chloride and the lungs were removed to study cytokine levels&#44; the wet&#47;dry weight ratio&#44; and to perform histopathological studies&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Hemodynamic and blood gas parameters</span><p id="par0065" class="elsevierStylePara elsevierViewall">HR&#44; mean arterial pressure and arterial blood gases &#40;pH&#44; PaO<span class="elsevierStyleInf">2</span> and PaCO<span class="elsevierStyleInf">2</span>&#41; were measured immediately prior to lung injury induction &#40;baseline&#41;&#44; 20<span class="elsevierStyleHsp" style=""></span>min after start of VILI&#44; and at the end of the study &#40;30<span class="elsevierStyleHsp" style=""></span>min POSTINJURY&#41;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Determination of the wet&#47;dry lung weight ratio</span><p id="par0070" class="elsevierStylePara elsevierViewall">The wet&#47;dry weight ratio was calculated in the whole left lungs of all study animals&#46; Lungs were dehydrated in a thermostat-controlled chamber at 80<span class="elsevierStyleHsp" style=""></span>&#176;C for 72<span class="elsevierStyleHsp" style=""></span>h and the dry weight was measured&#46; The wet&#47;dry weight ratio was calculated to evaluate the percentage of pulmonary edema&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Determination of TNF-&#945;&#44; IL-1&#946; and IL-6 in lung tissue</span><p id="par0075" class="elsevierStylePara elsevierViewall">The same lung segment &#40;lower right lobe&#41; was excised from all rats and stored at &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C until needed for study&#46; TNF-&#945;&#44; IL-1&#946; and IL-6 in lung tissue was measured&#46; The segment was place in saline solution and centrifuged for 10<span class="elsevierStyleHsp" style=""></span>min at 10&#44;000<span class="elsevierStyleHsp" style=""></span>rpm&#44; at 4<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; Cytokine levels were measured in the supernatant by means of an ELISA test&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Histopathological analysis</span><p id="par0080" class="elsevierStylePara elsevierViewall">The upper right lobes of all rats was excised and fixed in 10&#37; formaldehyde&#46; They were then stained with hematoxylin and eosin and embedded in paraffin for study by a histopathologist blinded to the study&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">A 4-point qualitative ordinal variable injury scale &#40;negative<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44; minor<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#44; moderate<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#44; severe<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#41; was used to evaluate each of the following characteristics&#46; The 4 main characteristics based on 15 individual items are&#58; atelectasis&#44; edema &#40;septal edema&#44; interstitial edema&#44; lymphangiectasia&#44; intra-alveolar exudate&#41;&#44; inflammation &#40;alveolar neutrophil infiltration&#44; interstitial neutrophil infiltration&#44; interstitial lymphocyte infiltration&#44; granulocyte adhesion&#41;&#44; and other &#40;alveolar hemorrhage&#44; hyperemia&#44; thrombocyte aggregation&#44; fibrin deposits&#44; hyaline membrane formation&#44; peeling of the bronchial and bronchiolar epithelium&#41;&#46; A summary of the results obtained for each parameter in all animals is given below&#46; The sum of all 15 parameters was then divided by the number of animals in each group to obtain the total injury score&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistical analysis</span><p id="par0090" class="elsevierStylePara elsevierViewall">Statistical analysis of study data was performed on SPSS<span class="elsevierStyleSup">&#174;</span> v&#46; 15&#46;0 &#40;SPSS Inc&#46;&#44; Chicago&#44; IL&#44; USA&#41;&#46; Based on the findings of earlier studies conducted by our group&#44; we determined that each group should comprise 7 animals in order to detect a difference in HR of 50<span class="elsevierStyleHsp" style=""></span>bpm or over&#44; with a <span class="elsevierStyleItalic">p</span> value of 0&#46;05&#44; a statistical power of 95&#37; in a bilateral comparison&#44; and a loss to follow-up or 0&#37;&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">All data were grouped and summarized as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation&#46; Hemodynamic and blood gas parameters were analyzed using Shapiro&#8211;Wilk normality testing&#44; followed by repeated measures analysis of variance &#40;ANOVA&#41; testing and a Bonferroni multiple comparison test&#46; For inter-group comparison of wet&#47;dry weight ratio&#44; TNF-&#945;&#44; IL-1&#946; and IL-6&#44; the unpaired <span class="elsevierStyleItalic">t</span>-test was used&#46; Statistical significance was set at <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Hemodynamic and blood gas parameters</span><p id="par0100" class="elsevierStylePara elsevierViewall">Arterial blood gas analysis showed respiratory alkalosis in both groups at VILI time vs baseline time &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Difference between CONTROLs and the SEV group were not statistically significant&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">Mean arterial pressure in the CONTROL group was significantly higher at the 3 study time points vs the SEV group &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; No statistically significant differences in HR were observed&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Determination of the wet&#47;dry lung weight ratio</span><p id="par0110" class="elsevierStylePara elsevierViewall">Wet&#47;dry lung weight ratio as an indicator of the percentage of pulmonary edema was significantly lower in the SEV group vs CONTROLs &#40;79&#46;49&#37;<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;78&#37; vs 84&#46;97&#37;<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;69&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Determination of TNF-&#945;&#44; IL-1&#946; and IL-6 in lung tissue</span><p id="par0115" class="elsevierStylePara elsevierViewall">TNF-&#945; and IL-6 levels in lung tissue were significantly lower in the SEV group vs CONTROLs &#40;144<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>25 vs 243<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>51<span class="elsevierStyleHsp" style=""></span>pg&#47;mL for IL-6 &#91;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#93; and 14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4 vs 23<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4<span class="elsevierStyleHsp" style=""></span>pg&#47;mL for TNF-&#945; &#91;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#93;&#41; &#40;<a class="elsevierStyleCrossRefs" href="#fig0010">Figs&#46; 2 and 3</a>&#41;&#59; however&#44; no statistically significant differences in changes in IL-1&#946; levels in lung tissue were found between groups &#40;128<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>92 in CONTROL vs 115<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>69<span class="elsevierStyleHsp" style=""></span>pg&#47;mL in SEV&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;715&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Histopathological analysis</span><p id="par0120" class="elsevierStylePara elsevierViewall">Histopathological findings were similar in the sevoflurane group &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41; and the CONTROL group &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#41;&#44; and showed peribronchial inflammatory injury&#44; edema&#44; and centrilobular emphysema&#46; The extent of injury was based on the score obtained from the 4-point qualitative ordinal variable scale&#58; the CONTROL group had a mean score of 1&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;33&#44; with the SEV group scoring 0&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;36&#44; which describes a minor injury with no statistically significant difference between groups&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Discussion</span><p id="par0125" class="elsevierStylePara elsevierViewall">Following induction of VILI with an inflation pressure of 35<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O for 20<span class="elsevierStyleHsp" style=""></span>min&#44; neither study group showed any clinically significant severe histopathological injuries or oxygen deficit on examination&#46; This indicates that neither the pressure nor the duration of delivery was sufficient to induce severe histopathological lung injury&#44; or that postinjury time was not sufficient for these changes to show up on histopathological analysis&#46; Nevertheless&#44; the wet&#47;dry lung weight ratio&#44; which quantifies mechanical stress markers &#40;pulmonary edema and IL-6 and TNF-&#945; levels&#41;&#44; shows significantly less pulmonary edema and inflammatory response in the SEV group vs CONTROLs&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Other experimental studies have shown that mechanical ventilation with a driving pressure of 14<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O does not induce histological changes in the lung&#44; while subjects receiving driving pressures of between 30 and 45<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O present significant perivascular and alveolar edema after 30<span class="elsevierStyleHsp" style=""></span>min of delivery&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">1&#44;2&#44;20</span></a> In our study&#44; we observed similar histopathological injuries using a driving pressure of 35<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O for 20<span class="elsevierStyleHsp" style=""></span>min&#44; although in this case the injuries were not as severe as those reported in the foregoing studies&#46; This shows that the time of exposure to high pressure &#40;increased from 20 to 30<span class="elsevierStyleHsp" style=""></span>min&#41; and the inflation pressure within this high pressure range &#40;30&#44; 35 or 40<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O&#41; are both key factors in determining the severity of lung injury&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">In our study&#44; the quantification of pulmonary edema by means of the wet&#47;dry lung weight ratio&#44; and the quantification and measurement of proinflammatory cytokine levels were shown to be more sensitive early markers of inflation pressure-induced lung injury than histopathological injury&#44; as this latter requires a more prolonged exposure to high pressures&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Reduction in the extent of pulmonary edema in the sevoflurane group coincides with the findings obtained from pulmonary ischemia-reperfusion injury<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">14</span></a> and in sepsis-induced pulmonary injury models&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleItalic">In vitro</span>&#44; sevoflurane stimulates the Na&#43;&#47;K&#43;-ATPase activity in injury-induced type <span class="elsevierStyleSmallCaps">ii</span> alveolar epithelial cells&#44; one of the functions of which is to regulate transport of ClNa and H<span class="elsevierStyleInf">2</span>O into the alveolar space&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">21</span></a> In <span class="elsevierStyleItalic">in vivo</span> experiments&#44; however&#44; there is evidence that sevoflurane does not affect water reabsorption and edema resolution&#44; but could contribute to edema formation&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">17</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">The antiinflammatory effect of volatile anesthetics has been explained by their involvement in preconditioning&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">9</span></a> Pharmacological preconditioning is a protection mechanism that makes cells relatively resistant to the myocellular death resulting from ischemia-reperfusion injury&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">15</span></a> In the lung&#44; volatile anesthetic-induced preconditioning protects against injury caused by both ischemia-reperfusion<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">13&#44;14</span></a> and sepsis&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">9&#44;15&#8211;17</span></a> Both types of injury are characterized by activation of proinflammatory cytokines&#44; such as TNF-&#945;&#44; IL-1&#946; and IL-6&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">No significant differences in proinflammatory cytokines concentrations in bronchoalveolar lavage were found during mechanical ventilation with sevoflurane or pentobarbital<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">22</span></a>&#59; however&#44; VILI-induced inflammatory response is characterized by activation of these proinflammatory cytokines&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">3</span></a> The pulmonary homogenate obtained in our study shows less proinflammatory cytokine secretion in all cytokine secreting alveolar cells &#40;TNF-&#945; and IL-6&#44; but not IL-1&#946;&#41; in animals ventilated with sevoflurane&#46; This confirms that the same anti-inflammatory and cell protective action of sevoflurane reported in other lung injury models is also found in healthy lungs&#44; where it protects alveoli against damage induce by mechanical ventilation with high driving pressure&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Many alveolar cells involved in cytokine secretion&#44; such as alveolar macrophages<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">22</span></a> and polymorphonuclear leukocytes&#44;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">16</span></a> can be affected by volatile anesthetics&#46; Type <span class="elsevierStyleSmallCaps">ii</span> alveolar epithelial cells&#44; together with inflammatory alveolar cells&#44; form part of the intra-alveolar cytokine network&#44; secreting IL-6&#44;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">23</span></a> TNF-&#945;&#44;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">24</span></a> and other interleukins&#46; Giraud et al&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">25</span></a> showed <span class="elsevierStyleItalic">in vitro</span> that volatile anesthetics in general&#44; and halotane in particular&#44; reduce secretion of TNF-&#945; and IL-6 in type <span class="elsevierStyleSmallCaps">ii</span> epithelial cells&#46; Subsequent <span class="elsevierStyleItalic">in vitro</span> experiments have shown the pre- and postconditioning with sevoflurane reduces expression of inflammatory mediators in alveolar epithelial cells&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">18</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">In contrast to our results&#44; isoflurane and sevoflurane were found to reduce plasma concentrations of IL-1&#946; in a sepsis-induced lung injury model&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">15</span></a> We believe that no significant intra-group differences in IL-1&#946; levels were found in our study because samples were taken too soon to enable measurement of IL peaks in lung tissue &#40;30<span class="elsevierStyleHsp" style=""></span>min POSTINJURY&#41;&#46; This time frame was chosen to prevent loss of the IL-6 and TNF-&#945; peaks&#44; which occur earlier&#44; because alveolar macrophages secrete IL-1&#946; 8<span class="elsevierStyleHsp" style=""></span>h following lipopolysaccharide stimulation&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">26</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">This study is subject to the limitation typical of any experimental study in rats&#46; This means that the results cannot be directly extrapolated to clinical practice in humans&#44; and more experimental studies are needed to confirm these preliminary findings&#46; Ultimately&#44; clinical trials should be conducted in human subjects to confirm our results&#46; Furthermore&#44; the VILI model used in our study was subject to a short injury exposure time &#40;20<span class="elsevierStyleHsp" style=""></span>min&#41;&#46; This means that although lung injury occurred&#44; it had no significant clinical impact on gas exchange&#46; Studies using higher pressure settings should be conducted&#44; above all with longer exposure times&#44; to show whether sevoflurane continues to exert an anti-inflammatory and cell protection effect even when lung damage is more severe and the clinical impact greater&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">In conclusion&#44; our study shows that sevoflurane attenuates VILI in health lungs in a subclinical rat model of VILI&#46; Our findings suggest that further experimental and clinical studies are needed before the real clinical benefit of the cytoprotective effects of this anesthetic can be confirmed&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Funding</span><p id="par0175" class="elsevierStylePara elsevierViewall">This study has been fully funded by departmental research funds managed by the <span class="elsevierStyleGrantSponsor" id="gs1">Instituto de Investigaci&#243;n del Hospital Puerta de Hierro</span>&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conflict of interest</span><p id="par0180" class="elsevierStylePara elsevierViewall">The authors declare they have no conflict of interest&#46;</p></span></span>"
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              "titulo" => "Determination of the wet&#47;dry lung weight ratio"
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              "titulo" => "Determination of TNF-&#945;&#44; IL-1&#946; and IL-6 in lung tissue"
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              "titulo" => "Histopathological analysis"
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              "titulo" => "Determination of TNF-&#945;&#44; IL-1&#946; and IL-6 in lung tissue"
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              "titulo" => "Histopathological analysis"
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          "titulo" => "Discussion"
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    "fechaRecibido" => "2015-01-10"
    "fechaAceptado" => "2015-04-13"
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          "clase" => "keyword"
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            0 => "Anesthesia"
            1 => "Lung injury"
            2 => "Mechanical ventilation"
            3 => "Inflammation"
            4 => "Sevoflurane"
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            0 => "Anestesia"
            1 => "Da&#241;o pulmonar"
            2 => "Ventilaci&#243;n mec&#225;nica"
            3 => "Inflamaci&#243;n"
            4 => "Sevoflurano"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Ventilator-induced lung injury &#40;VILI&#41; causes a systemic inflammatory response in tissues&#44; with an increase in IL-1&#44; IL-6 and TNF-&#945; in blood and tissues&#46; Cytoprotective effects of sevoflurane in different experimental models are well known&#44; and this protective effect can also be observed in VILI&#46; The objective of this study was to assess the effects of sevoflurane in VILI&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A prospective&#44; randomized&#44; controlled study was designed&#46; Twenty female rats were studied&#46; The animals were mechanically ventilated&#44; without sevoflurane in the control group and sevoflurane 3&#37; in the treated group &#40;SEV group&#41;&#46; VILI was induced applying a maximal inspiratory pressure of 35<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O for 20<span class="elsevierStyleHsp" style=""></span>min without any positive end-expiratory pressure for 20<span class="elsevierStyleHsp" style=""></span>min &#40;INJURY time&#41;&#46; The animals were then ventilated 30<span class="elsevierStyleHsp" style=""></span>min with a maximal inspiratory pressure of 12<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O and 3<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O positive end-expiratory pressure &#40;time 30<span class="elsevierStyleHsp" style=""></span>min POST-INJURY&#41;&#44; at which time the animals were euthanized and pathological and biomarkers studies were performed&#46; Heart rate&#44; invasive blood pressure&#44; pH&#44; PaO<span class="elsevierStyleInf">2</span>&#44; and PaCO<span class="elsevierStyleInf">2</span> were recorded&#46; The lung wet-to-dry weight ratio was used as an index of lung edema&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">No differences were found in the blood gas analysis parameters or heart rate between the 2 groups&#46; Blood pressure was statistically higher in the control group&#44; but still within the normal clinical range&#46; The percentage of pulmonary edema and concentrations of TNF-&#945; and IL-6 in lung tissue in the SEV group were lower than in the control group&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Sevoflurane attenuates VILI in a previous healthy lung in an experimental subclinical model in rats&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Introduction and objective"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Material and methods"
          ]
          2 => array:2 [
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            "titulo" => "Results"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n y objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El da&#241;o pulmonar inducido por la ventilaci&#243;n mec&#225;nica &#40;VILI&#41; provoca una respuesta inflamatoria sist&#233;mica&#44; con elevaci&#243;n en sangre y tejidos de IL-1&#44; IL-6 y TNF-&#945;&#46; Conocidos los efectos citoprotectores de sevoflurano en diferentes modelos experimentales&#44; este podr&#237;a tener un comportamiento similar ante el VILI&#46; El objetivo de este estudio es valorar el efecto de sevoflurano en el VILI&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio experimental&#44; prospectivo&#44; controlado y aleatorizado&#46; Se utilizaron 20 ratas hembra&#46; Los animales fueron ventilados mec&#225;nicamente sin sevoflurano en el grupo control y con sevoflurano al 3&#37; en el grupo tratado &#40;grupo SEV&#41;&#46; Se provoc&#243; el VILI mediante una presi&#243;n inspiratoria m&#225;xima de 35<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O sin presi&#243;n positiva al final de la expiraci&#243;n durante 20<span class="elsevierStyleHsp" style=""></span>min &#40;tiempo LESI&#211;N&#41;&#46; Despu&#233;s&#44; los animales fueron ventilados 30<span class="elsevierStyleHsp" style=""></span>min con una presi&#243;n inspiratoria m&#225;xima de 12<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O y 3<span class="elsevierStyleHsp" style=""></span>cmH<span class="elsevierStyleInf">2</span>O de presi&#243;n positiva al final de la expiraci&#243;n &#40;tiempo 30<span class="elsevierStyleHsp" style=""></span>min POSLESI&#211;N&#41;&#46; Se registraron la frecuencia cardiaca&#44; las presiones arteriales sist&#243;lica&#44; diast&#243;lica y media&#44; el pH&#44; la PaO<span class="elsevierStyleInf">2</span> y la PaCO<span class="elsevierStyleInf">2</span>&#46; Se analiz&#243; la ratio peso h&#250;medo&#47;seco del tejido pulmonar&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">No existieron diferencias estad&#237;sticamente significativas en los par&#225;metros gasom&#233;tricos ni en la frecuencia cardiaca entre los 2 grupos en estudio&#46; La PAM fue significativamente mayor en el grupo control&#44; pero dentro de l&#237;mites cl&#237;nicos normales&#46; El porcentaje de edema pulmonar y las concentraciones de TNF-&#945; e IL-6 en tejido pulmonar en el grupo de animales ventilados con sevoflurano fueron menores que en el grupo control&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Sevoflurano aten&#250;a el VILI en pulm&#243;n previamente sano&#44; en un modelo experimental de VILI subcl&#237;nico en ratas&#46;</p></span>"
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            "titulo" => "Material y m&#233;todos"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Please cite this article as&#58; Romero A&#44; Moreno A&#44; Garc&#237;a J&#44; S&#225;nchez C&#44; Santos M&#44; Garc&#237;a J&#46; Efectos de sevoflurano en la lesi&#243;n pulmonar inducida por la ventilaci&#243;n mec&#225;nica en un modelo experimental de pulm&#243;n sano&#46; Rev Esp Anestesiol Reanim&#46; 2016&#59;63&#58;22&#8211;28&#46;</p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Wet&#47;dry lung weight ratio as a marker of the percentage of pulmonary edema following establishment of a mechanical ventilation-induced lung injury in rat models anesthetized with &#40;SEV&#41; or without &#40;CONTROL&#41; sevoflurane&#46; &#42;Statistically significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; with respect to the CONTROL group&#46;</p>"
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Peribronchial inflammatory injury in the CONTROL group&#46;</p>"
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          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Data expressed as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation&#46;</p>"
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                  \t\t\t\t\tvoid\n
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                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">CONTROL&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;337<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;047&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;287<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;021&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>INJURY&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;482<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;026<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;442<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;123<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>min POSTINJURY&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;306<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;041&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;268<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;145&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">230<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">232<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>INJURY&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">258<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">256<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>22<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>min POSTINJURY&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">218<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">206<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">PaCO</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">2</span></span><span class="elsevierStyleItalic">&#40;mmHg&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Baseline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">30&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>INJURY&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;0<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;3<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>min POSTINJURY&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">31&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Heart rate &#40;bpm&#41;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Baseline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">368<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">342<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>37&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>INJURY&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">357<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">333<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>min POSTINJURY&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">385<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>27&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">362<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>27&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Mean arterial pressure &#40;mmHg&#41;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Baseline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">93<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">80<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>INJURY&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">86<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">74<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>13<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>min POSTINJURY&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">101<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">81<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>19<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Statistically significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; with respect to CONTROL group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p>"
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          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Physiological parameters at baseline&#44; VILI&#44; and the end of the experiment in rats treated with &#40;SEV&#41; and without &#40;CONTROL&#41; sevoflurane&#46;</p>"
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      ]
    ]
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      "titulo" => "References"
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        0 => array:2 [
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            0 => array:3 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ventilator-induced lung injury&#58; lessons from experimental studies"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "D&#46; Dreyfuss"
                            1 => "G&#46; Saumon"
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                    0 => array:2 [
                      "doi" => "10.1164/ajrccm.157.1.9604014"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "1998"
                        "volumen" => "157"
                        "paginaInicial" => "294"
                        "paginaFinal" => "323"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9445314"
                            "web" => "Medline"
                          ]
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              "identificador" => "bib0140"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ventilator-induced lung injury"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "J&#46;D&#46; Ricard"
                            1 => "D&#46; Dreyfuss"
                            2 => "G&#46; Saumon"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Opin Crit Care"
                        "fecha" => "2002"
                        "volumen" => "8"
                        "paginaInicial" => "12"
                        "paginaFinal" => "20"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12205401"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0145"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ventilation-induced chemokine and cytokine release is associated with activation of nuclear factor-kappaB and is blocked by steroids"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "H&#46;D&#46; Held"
                            1 => "S&#46; Boettcher"
                            2 => "L&#46; Hamann"
                            3 => "S&#46; Uhlig"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/ajrccm.163.3.2003001"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "2001"
                        "volumen" => "163"
                        "paginaInicial" => "711"
                        "paginaFinal" => "716"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11254529"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Inflammatory cytokines in patients with persistence of the acute respiratory distress syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46;B&#46; Goodman"
                            1 => "R&#46;M&#46; Strieter"
                            2 => "D&#46;P&#46; Martin"
                            3 => "K&#46;P&#46; Steinberg"
                            4 => "J&#46;A&#46; Milberg"
                            5 => "R&#46;J&#46; Maunder"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/ajrccm.154.3.8810593"
                      "Revista" => array:7 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "1996"
                        "volumen" => "154"
                        "numero" => "3 Pt 1"
                        "paginaInicial" => "602"
                        "paginaFinal" => "611"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8810593"
                            "web" => "Medline"
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            4 => array:3 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Experimental pulmonary edema due to intermittent positive pressure ventilation with high inflation pressures&#46; Protection by positive end-expiratory pressure"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "H&#46;H&#46; Webb"
                            1 => "D&#46;F&#46; Tierney"
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/arrd.1974.110.5.556"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am Rev Respir Dis"
                        "fecha" => "1974"
                        "volumen" => "110"
                        "paginaInicial" => "556"
                        "paginaFinal" => "565"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/4611290"
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Article information

ISSN: 23411929
Original language: English

DOI:10.1016/j.redare.2015.09.002

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