Role of circulating soluble chemokines in septic shock

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Panel A: niveles de IL-8 en pg/ml respecto al tiempo en días. Panel B: niveles de MCP-1 en pg/ml respecto al tiempo en días. Panel C: niveles de MIP-1α en pg/ml respecto al tiempo en días. Panel D: niveles de RANTES en pg/ml respecto al tiempo en días. Los valores se expresan como media y como el error estándar de la media." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "R. de Pablo, J. Monserrat, A. Prieto, M. Álvarez-Mon" "autores" => array:4 [ 0 => array:2 [ "nombre" => "R." "apellidos" => "de Pablo" ] 1 => array:2 [ "nombre" => "J." "apellidos" => "Monserrat" ] 2 => array:2 [ "nombre" => "A." "apellidos" => "Prieto" ] 3 => array:2 [ "nombre" => "M." 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Celis-Rodríguez, C. Birchenall, M.Á. de la Cal, G. Castorena Arellano, A. Hernández, D. Ceraso, J.C. Díaz Cortés, C. Dueñas Castell, E.J. Jimenez, J.C. Meza, T. Muñoz Martínez, J.O. Sosa García, C. Pacheco Tovar, F. Pálizas, J.M. Pardo Oviedo, D.-I. Pinilla, F. Raffán-Sanabria, N. Raimondi, C. Righy Shinotsuka, M. Suárez, S. Ugarte, S. Rubiano" "autores" => array:22 [ 0 => array:2 [ "nombre" => "E." "apellidos" => "Celis-Rodríguez" ] 1 => array:2 [ "nombre" => "C." "apellidos" => "Birchenall" ] 2 => array:2 [ "nombre" => "M.Á." "apellidos" => "de la Cal" ] 3 => array:2 [ "nombre" => "G." "apellidos" => "Castorena Arellano" ] 4 => array:2 [ "nombre" => "A." "apellidos" => "Hernández" ] 5 => array:2 [ "nombre" => "D." "apellidos" => "Ceraso" ] 6 => array:2 [ "nombre" => "J.C." "apellidos" => "Díaz Cortés" ] 7 => array:2 [ "nombre" => "C." "apellidos" => "Dueñas Castell" ] 8 => array:2 [ "nombre" => "E.J." "apellidos" => "Jimenez" ] 9 => array:2 [ "nombre" => "J.C." 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"apellidos" => "Rubiano" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0210569113000855" "doi" => "10.1016/j.medin.2013.04.001" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0210569113000855?idApp=WMIE" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173572713001094?idApp=WMIE" "url" => "/21735727/0000003700000008/v1_201312130916/S2173572713001094/v1_201312130916/en/main.assets" ] "en" => array:21 [ "idiomaDefecto" => true "cabecera" => "Original" "titulo" => "Role of circulating soluble chemokines in septic shock" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "510" "paginaFinal" => "518" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "R. de Pablo, J. Monserrat, A. Prieto, M. Álvarez-Mon" "autores" => array:4 [ 0 => array:4 [ "nombre" => "R." "apellidos" => "de Pablo" "email" => array:1 [ 0 => "raul.depablo@uah.es" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "¿" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "J." "apellidos" => "Monserrat" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "A." "apellidos" => "Prieto" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "M." 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C: controls; ARDS: acute respiratory distress syndrome; ARF: acute renal failure; DIC: disseminated intravascular coagulation. The criteria are specified in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>." ] ] ] "textoCompleto" => "IntroductionMultiorgan failure is the main cause of death in patients with sepsis.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> The prognosis of multiorgan dysfunction syndrome (MODS) is conditioned to the number of failed organs, the severity of failure, and its duration in time. In a study published by Knaus et al., the mortality rate was 22% among patients with single organ failure lasting less than 24h, but increased to 42% when the condition persisted for 7 days. In turn, the mortality rate was found to be 80% in the case of three or more failed organs with a duration of less than 24h, and reached 100% when the condition persisted for more than four days.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>Although severity scores have been developed to characterize the degree of multiorgan dysfunction and predict mortality among patients with sepsis, understanding the physiopathology of MODS represents an ongoing challenge.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> The development of MODS is a consequence of excessive activation of the inflammatory response. To date, however, the treatments that have attempted to counter this exaggerated systemic inflammatory response have failed.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> Furthermore, most patients who survive the initial aggression of sepsis die days or weeks later as a result of multiorgan failure and in a situation of immunosuppression.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>At cellular level, a number of mechanisms contribute to the development of MODS, including microvascular thrombosis, neutrophil-induced damage, bacterial translocation, cytokine release, endothelial dysfunction, cell apoptosis, etc.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> The chemokines constitute a large family of cytokines that stimulate the movement of leukocytes and regulate their migration from the bloodstream toward the tissues. They are regarded as proinflammatory cytokines, since they induce the production and release of histamine, enzymes and defensins. However, in contrast to other cytokines, the chemokines do not induce other cytokines or produce fever or acute phase reactants. Furthermore, chemokines in large circulating concentrations exert desensitizing effects and can suppress local inflammation.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>Nuclear factor-κB (NF-κB) plays a key role in the physiopathology of sepsis and septic shock. An increase in its activity has been associated with a higher mortality rate and a poorer prognosis.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> NF-κB mediates the transcription of a range of genes encoding for inflammatory molecules such as cytokines, adhesion molecules, enzymes, immune receptors, acute phase reactants and chemokines–including interleukin-8 (IL-8), macrophage inflammatory protein 1-α (MIP-1α), type 1 monocyte chemoattractant protein (MCP-1) and RANTES (regulated on activation, normal T cell expressed and secreted) protein. The role of these chemokines when soluble in plasma in the development of organ dysfunction in patients with sepsis has not been well established to date.The present study postulates that the plasma levels of these circulating chemokines are increased in patients with septic shock, and that this in turn contributes to the development of organ dysfunction and patient mortality.Patients and methodsOn a retrospective basis and covering a period of approximately 36 months, we included those patients over 18 years of age with severe sepsis admitted to the Intensive Care Unit (ICU). Severe sepsis was diagnosed based on the presence of sepsis plus the failure of some organ, hypoperfusion or hypotension, in compliance with the criteria of the consensus conference of the American College of Chest Physicians/Society of Critical Care Medicine<a class="elsevierStyleCrossRef" href="#bib0040">8</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The demonstration of infection was also considered essential, using microbiological techniques (gram staining and/or culture), radiological techniques, or direct visualization of the infection site.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The following exclusion criteria were established:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">a)Primary or acquired immunodeficiency of any kind</li><li class="elsevierStyleListItem" id="lsti0010">b)Previous immunosuppressive or immune modulating treatment</li><li class="elsevierStyleListItem" id="lsti0015">c)Uncontrolled or actively treated neoplastic disease</li><li class="elsevierStyleListItem" id="lsti0020">d)Active autoimmune or allergic disorders</li><li class="elsevierStyleListItem" id="lsti0025">e)The need for extrarenal filtration techniques capable of affecting clearance of the different inflammatory mediators</li><li class="elsevierStyleListItem" id="lsti0030">f)Administration of experimental therapy</li></ul>We analyzed peripheral blood samples from 36 health volunteers (controls) with an age and gender distribution similar to that of the patients included in the study, in order to prevent the demographic characteristics from interfering with the interpretation of the results. The study protocol was approved by the Clinical Research Ethics Committee. The relatives of the patients and healthy controls gave informed consent to the experimental protocol.All the patients received conventional treatment. None received activated protein C, and individuals needing hydrocortisone due to refractory hypotension were excluded from the study.Blood samples were collected through the arterial catheter in tubes without anticoagulant in the first 12h after admission to the ICU (baseline sample), 48h after admission, and after 7, 14 and 28 days. An additional 10ml of blood was extracted and allowed to clot at room temperature, followed by serum separation by centrifugation at 600×g during 20min. The supernatants were collected, filtered and divided into aliquots that were stored frozen at −70°C until use.After thawing of the supernatants to room temperature, sandwich ELISA testing was carried out. The results obtained were measured with the Multititer Plus® enzymoimmunoassay reader (Tiertek Multiscan Plus, Flow Laboratories, United Kingdom), and were compared with a standard curve obtained from known concentrations of each cytokine, supplied by the manufacturer.The analysis of the different standard curves and subsequent interpolations were carried out with the Delta Soft II® version 4.1 software (Biometallies, Inc., USA) on a Macintosh® computer.The determinations of the concentrations of the different cytokines were made using the commercial formulations with a supernatant quantitation sensitivity of 25pg/ml for IL-8 (Diaclone, USA), 5pg/ml for MCP-1 (R&D System, Minneapolis, USA), 10pg/ml for MIP-1α (R&D System, Minneapolis, USA), and 10pg/ml for RANTES (R&D System, Minneapolis, USA).In relation to the statistical study, we first examined the nature of the distributions using the Shapiro–Wilk normality test. When the data obtained showed a normal distribution, comparisons of means were established using the Student t-test. In the case of data with a non-normal distribution, comparisons were made using the nonparametric Mann–Whitney U-test. Comparison of data from one same group at different time intervals was carried out with the Friedman test, while correlations between the different variables were established using the Pearson correlation coefficient.The results of the experimental studies are presented as the mean and standard error of the mean (sem). In all cases significance levels of under 5% were considered (p<0.05). The SPSS version 11.0 statistical package (SPSS Inc., Chicago, IL 60606, USA) was used throughout.Results<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> shows the flow of the 128 individuals studied, including 52 patients (all with septic shock), 40 excluded subjects and 36 healthy controls. The demographic characteristics of the patients are summarized in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.<elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Chemokine levels with respect to the control groupThe serum levels of the studied soluble chemokines (IL-8, MCP-1, MIP-1α and RANTES) showed special and individualized behavior in each case.As can be seen in panel A of <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>, IL-8 maintained extraordinarily elevated levels throughout the evolution of sepsis.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>The concentration of MCP-1 was very high in the first phase and then gradually decreased to normalization by day 28 (panel B of <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).There were no significant differences between the levels of MIP-1α among the controls and in the patients at any timepoint (panel C of <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).On the other hand, as can be seen in panel D of <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>, the RANTES levels were below those of the controls at all timepoints of the disease.Prognostic value of the soluble chemokine levelsThe mortality rate among the patients was 34.6%. In the patients with septic shock, we found no significant differences in serum chemokine levels between the survivors and those who died (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Correlation between the chemokine levels and failure of the different organsAmong the 6 organ system failures considered (cardiovascular, acute respiratory distress syndrome [ARDS], acute renal failure [ARF], coagulopathy, liver failure and neurological failure), the incidence of liver failure (n=3) and of neurological failure (n=2) was so low that no conclusions can be drawn from the data obtained. On the other hand, all the patients met criteria of cardiovascular failure and were classified as presenting septic shock. The patients with ARDS upon admission totaled 46%, while the incidence of ARF was 36%, and that of coagulopathy 19%.Analysis of the chemokine levels at the time of admission to the ICU and in relation to the different types of organ failure showed the serum levels of IL-8 to be significantly higher in the patients admitted with ARDS than in those without ARDS, and also in those with ARF compared with the patients who did not develop ARF (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). In relation to the rest of the chemokines (MCP-1, MIP-1α and RANTES), no significant differences were observed at the time of admission in those with ARDS or in those with ARF (<a class="elsevierStyleCrossRefs" href="#fig0020">Figs. 4–6</a>).<elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="fig0030"></elsevierMultimedia>The IL-8 and MIP-1α levels in the patients with coagulopathy were higher than in those without coagulopathy upon admission (<a class="elsevierStyleCrossRefs" href="#fig0015">Figs. 3 and 5</a>). Significant differences were also observed in the levels of RANTES, with lower concentrations upon admission to the ICU in patients with coagulopathy than in those without (<a class="elsevierStyleCrossRef" href="#fig0030">Fig. 6</a>).DiscussionIn the present study we found chemokines to be involved in the development of different types of organ damage. Interleukin-8 is increased in patients with septic shock, and these levels are good markers of respiratory, renal and hematological failure. Two other chemokines are also implicated in the case of patients with coagulopathy, namely MIP-1α and RANTES.Hack et al.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> were the first to report that 89% of the patients with sepsis had high IL-8 levels upon admission and during follow-up over 60h, though in contrast to our own findings, the levels decreased in the course of follow-up. The physiopathological basis for this finding is the fact that endotoxin, IL-1β, and especially TNF-α are the main stimuli for IL-8 production and release. Measurement of the serum concentrations of IL-8 has been used to predict which patients have bacteremia in a group of subjects reporting to the emergency service due to systemic inflammatory response syndrome (SIRS),<a class="elsevierStyleCrossRef" href="#bib0050">10</a> though other authors prefer to use the procalcitonin levels for this purpose.<a class="elsevierStyleCrossRef" href="#bib0055">11</a>A range of soluble molecules have been evaluated as potential prognostic markers in patients with sepsis.<a class="elsevierStyleCrossRefs" href="#bib0060">12–15</a> In this context, the prognostic usefulness of IL-8 concentration has been described by several authors.<a class="elsevierStyleCrossRefs" href="#bib0080">16,17</a>Recently, different studies using commercial multitests and simultaneously determining 17 molecules in patients with sepsis have found IL-8 to be one of the best prognostic biomarkers in patients of this kind.<a class="elsevierStyleCrossRefs" href="#bib0090">18–20</a> We and other investigators have not obtained such results.<a class="elsevierStyleCrossRef" href="#bib0105">21</a> Possibly, the reason for this discrepancy is that our patients, in contrast to those of the other studies, were in a more serious condition, with higher APACHE II scores and practically all in a state of shock–this making it more difficult to find differences in the levels of IL-8. In effect, in the studies published by Halstensen et al.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> and Damas,<a class="elsevierStyleCrossRef" href="#bib0080">16</a> patients with shock had higher levels than patients with sepsis but no cardiovascular failure.Interleukin-8 has been identified as the main chemotactic factor of polymorphonuclear neutrophils in the lungs.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> Boutten et al.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> demonstrated a correlation between the neutrophil count and the concentration of IL-8 in bronchoalveolar lavage (BAL) obtained from different lung segments in 17 patients with unilateral pneumonia. We recorded higher IL-8 concentrations in patients with ARDS upon admission to the ICU than in those without ARDS. Some studies have analyzed this point and confirm our findings.<a class="elsevierStyleCrossRefs" href="#bib0080">16,25</a> It has been shown that the IL-8 levels in bronchoalveolar lavage are increased in patients with ARDS,<a class="elsevierStyleCrossRefs" href="#bib0130">26,27</a> and are moreover correlated to chronification of the disease.<a class="elsevierStyleCrossRef" href="#bib0140">28</a>We observed significant differences in the levels of IL-8 among patients with ARF upon admission to the ICU as a consequence of sepsis. Fujishima et al.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> correlated the blood IL-8 levels to the development of ARF and mortality. The study published by Ahlström et al.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> likewise confirms our results. Interleukin-8 is probably implicated in the physiopathology of ARF in septic patients, though there are no conclusive experimental data in this respect. We therefore cannot discard the possibility that IL-8 elevation is simply a problem of renal clearance and accumulation of the molecule in situations of renal failure. In our study the IL-8 levels were higher in patients with coagulopathy at the onset of sepsis. The previously mentioned studies by Damas<a class="elsevierStyleCrossRef" href="#bib0080">16</a> and Fujishima<a class="elsevierStyleCrossRef" href="#bib0085">17</a> in septic patients confirm our data. Interleukin-8 is implicated in the induction of intravascular coagulation associated to endotoxin.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> It promotes the activation of coagulation, particularly through mediation by CD14+ monocytes.<a class="elsevierStyleCrossRef" href="#bib0155">31</a> Thrombin in turn stimulates the production of IL-8 by monocytes and endothelial cells.<a class="elsevierStyleCrossRef" href="#bib0155">31</a> An increase in blood IL-8 has also been described in coagulopathy associated to acute promyelocytic leukemia.<a class="elsevierStyleCrossRef" href="#bib0160">32</a>Type 1 monocyte chemoattractant protein (MCP-1) is a CC chemokine that acts as a mediator in monocyte and T lymphocyte tissue infiltration in a broad range of inflammatory diseases. In our study we recorded elevated MCP-1 levels upon admission compared with the control group, and these levels were seen to subsequently decrease progressively, with normalization after 28 days. These same results have been obtained by other authors.<a class="elsevierStyleCrossRefs" href="#bib0165">33,34</a> However, some investigators<a class="elsevierStyleCrossRef" href="#bib0175">35</a> have only recorded elevated MCP-1 levels in the bronchoalveolar lavage of patients with sepsis, but not in serum. In this sense, we did not record elevated concentrations in patients with ARDS or any other organ failure upon admission. On the other hand, MCP-1 is admittedly regarded as a second signal and would be implicated in monocyte infiltration; consequently, at the time of admission it might not be possible to appreciate the clinical relevance which this mediator probably has at a later stage in time.We found no differences in the serum MCP-1 levels during the first week of sepsis between the patients who died and those who survived. Similar results have been obtained by other authors.<a class="elsevierStyleCrossRef" href="#bib0170">34</a>Macrophage inflammatory protein 1-α (MIP-1α) is fundamentally a macrophage chemotactic protein, although it has also been associated with chemotactic and proadhesive effects upon other cell types. MIP-1α also exerts modulating effects upon the production of cytokines, and is an endogenous pyrogen. Although experimentally MIP-1α appears after the administration of lipopolysaccharides both in vitro<a class="elsevierStyleCrossRef" href="#bib0180">36</a> and in vivo,<a class="elsevierStyleCrossRefs" href="#bib0170">34,37</a> the results obtained on examining the serum levels in patients with severe sepsis were very notorious. In effect, we observed normal levels throughout the evolution of the disease, regardless of the prognosis. These same findings have been described by other groups.<a class="elsevierStyleCrossRefs" href="#bib0085">17,33–35,38</a>All authors appear to agree that the MIP-1α levels have no prognostic value or relation to the development of multiorgan failure.<a class="elsevierStyleCrossRefs" href="#bib0085">17,38</a> However, in our study we did observe differences in the levels of MIP-1α among the patients with coagulopathy upon admission to the ICU versus those without coagulopathy. The only study we have found in this line is the work published by Fujishima et al.,<a class="elsevierStyleCrossRef" href="#bib0085">17</a> and although a tendency toward increased levels of MIP-1α was noted in the patients with coagulopathy, statistical significance was not reached.The RANTES (regulated on activation, normal T cell expressed and secreted) protein is a CC chemokine produced by a series of cell types including platelets, lymphocytes and epithelial cells, in response to pyrogenic signals such as endotoxin, bacterial infections and TNF-α.<a class="elsevierStyleCrossRef" href="#bib0195">39</a> Its main biological function is the trafficking and activation of both inflammatory and non-inflammatory cells.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> Cavaillon et al.<a class="elsevierStyleCrossRef" href="#bib0205">41</a> reported that the levels of RANTES in sepsis are inversely proportional to the APACHE II score; the authors thus deduced that RANTES is lower among the patients who do not survive. Møller et al.<a class="elsevierStyleCrossRef" href="#bib0165">33</a> demonstrated that patients with fulminant meningococcemia had lesser RANTES concentrations than patients with other less serious meningococcal infections.We also observed extraordinarily low RANTES levels compared with the healthy controls. However, we did not find significant differences in the levels between the survivors and those patients who died. The only form of organ failure in which there were significantly lower concentrations in the patients was the presence of coagulopathy upon admission in the ICU versus those without coagulopathy. This result is difficult to interpret. It is known that bacteria can stimulate the release of RANTES,<a class="elsevierStyleCrossRef" href="#bib0195">39</a> and that the administration of 4ng/kg of endotoxin to 8 healthy volunteers resulted in a drop in RANTES levels.<a class="elsevierStyleCrossRef" href="#bib0210">42</a> On the other hand, we also know that platelets are the principal source of RANTES.<a class="elsevierStyleCrossRef" href="#bib0215">43</a> Platelets express CD40 at surface level, which interacts with the CD154 receptor of activated T lymphocytes, inducing the release of RANTES stored in the platelets.<a class="elsevierStyleCrossRef" href="#bib0215">43</a>During the inflammatory response, RANTES is released into the intravascular compartment and rapidly binds to the endothelial surface, thereby giving rise to the recruitment and retention of leukocytes–including T cells.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> This is where the interpretation difficulty lies: is the decrease in RANTES observed in coagulopathy attributable to depletion of the molecule upon binding to the vascular endothelium, or is it a consequence of a drop in the RANTES reservoir, i.e., the platelets? In hematological patients, Ellis et al.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> found that in subjects with fever, RANTES concentration is related to the presence of thrombocytopenia. We posteriorly studied the correlation between the levels of RANTES and the platelet counts in blood among patients with severe sepsis during the first day of admission to the ICU. This nonparametric association, studied by means of the Spearman test, yielded a correlation of 0.546, with p=0.007. We therefore cannot rule out the possibility that this decrease in RANTES levels among patients with coagulopathy is simply an expression of the thrombocytopenia found in these individuals.In conclusion, in this study we have demonstrated the participation of chemokines IL-8, MIP-1α and RANTES in coagulopathy associated to septic shock, as well as the usefulness of IL-8 as a biomarker of respiratory and renal failure. Nevertheless, these molecules appear to lack prognostic value in patients with septic shock.Financial supportThis study has been financed in part by the Community of Madrid, S-BIO-0189/2006, and by the Fondo de Investigación Sanitaria, PI-08-1890.Conflicts of interestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:2 [ "identificador" => "xres298987" "titulo" => array:8 [ 0 => "Abstract" 1 => "Purpose" 2 => "Design" 3 => "Setting" 4 => "Patients" 5 => "Interventions" 6 => "Results" 7 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec282030" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres298988" "titulo" => array:8 [ 0 => "Resumen" 1 => "Objetivo" 2 => "Diseño" 3 => "Ámbito" 4 => "Pacientes" 5 => "Intervenciones" 6 => "Resultados" 7 => "Conclusiones" ] ] 3 => array:2 [ "identificador" => "xpalclavsec282031" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Patients and methods" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Results" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Chemokine levels with respect to the control group" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Prognostic value of the soluble chemokine levels" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Correlation between the chemokine levels and failure of the different organs" ] ] ] 7 => array:2 [ "identificador" => "sec0035" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0040" "titulo" => "Financial support" ] 9 => array:2 [ "identificador" => "sec0045" "titulo" => "Conflicts of interest" ] 10 => array:2 [ "identificador" => "xack70558" "titulo" => "Acknowledgements" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-07-29" "fechaAceptado" => "2012-09-24" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec282030" "palabras" => array:6 [ 0 => "Chemokines" 1 => "Septic shock" 2 => "Acute respiratory distress syndrome" 3 => "Acute renal failure" 4 => "Coagulopathy" 5 => "Biomarkers" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec282031" "palabras" => array:6 [ 0 => "Quimioquinas" 1 => "Shock séptico" 2 => "Síndrome de distrés respiratorio agudo" 3 => "Fracaso renal agudo" 4 => "Coagulopatía" 5 => "Biomarcadores" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "PurposeChemokines are a large superfamily of small proteins that not only function in leukocyte trafficking, but are also necessary for linkage between innate and adaptive immunity. Little is known about their role in septic shock. We hypothesized that serum levels of the most important chemokines are related to organ failure, disease severity and outcome. DesignA prospective observational study was carried out. SettingSurgical-clinical Intensive Care Unit. PatientsNinety-two patients diagnosed with septic shock using international criteria. Forty patients were excluded due to acquired immunity disturbances. Samples from 36 healthy controls were also analyzed. InterventionsNone. ResultsIn 46% of the patients who suffered acute respiratory distress syndrome (ARDS), IL-8 levels were higher than in patients without ARDS (499.9±194.1 vs 190.8±91.7pg/ml; p=0.039). This molecule was also higher in 36% of the patients with sepsis-induced acute renal failure (ARF) (453.3±181.6 vs 201.3±95.9pg/ml; p=0.049). Coagulopathy was found in 19% of the septic shock patients with elevated serum IL-8 levels (635.8±292.3 vs 218.7±87.0pg/ml; p=0.010), elevated MIP-1α (91.4±27.3 vs 58.8±11.1pg/ml; p=0.044), and low circulating RANTES levels (8162.2±6321.0 vs 18781.8±11.1pg/ml; p=0.027). No significant differences were found between survivors and non-survivors at any time of follow-up. ConclusionsUpon admission to the ICU, IL-8 is a reliable biomarker of sepsis-induced AFR, ARDS and coagulopathy. Altered circulating MIP-1α and RANTES levels are also found in patients with septic shock and coagulopathy. However, chemokines do not appear to be good biomarkers of mortality in septic shock." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "ObjetivoLas quimioquinas son una gran familia de pequeños péptidos que tienen una participación clave no solo en el control del tráfico de los leucocitos, sino también se ha visto que son necesarios en las interacciones entre la inmunidad innata y adaptativa. El papel de estas moléculas es poco conocido en el seno del shock séptico. Nuestra hipótesis es que los niveles séricos de las principales quimioquinas tienen relación con los diferentes fallos orgánicos y con el pronóstico de los pacientes con shock séptico. DiseñoEstudio prospectivo y observacional. ÁmbitoUnidad de Cuidados Intensivos médico-quirúrgica. PacientesNoventa y dos pacientes cumplieron criterios internacionales de shock séptico con demostración de una infección, de los que se excluyeron 40 por presentar diferentes alteraciones inmunitarias adquiridas. Treinta y seis voluntarios sanos sirvieron de grupo control. IntervencionesNinguna. ResultadosEl 46% de los pacientes presentaron síndrome de distrés respiratorio agudo (SDRA) y en ellos los niveles séricos de IL-8 se encontraban elevados (499,9±194,1 vs. 190,8±91,7pg/ml; p=0,039). Esta molécula también estaba elevada en el 36% de los pacientes con shock séptico que tenían fracaso renal agudo (FRA) (453,3±181,6 vs. 201,3±95,9pg/ml; p=0,049). El 19% de los pacientes presentaron coagulopatía y en ellos se observó una elevación de los niveles de IL-8 (635,8±292,3 vs. 218,7±87,0pg/ml; p=0,010), de MIP-1α (91,4±27,3 vs. 58,8±11,1pg/ml; p=0,044) y niveles bajos de RANTES (8162,2±6321,0 vs. 18781,8±11,1pg/ml; p=0,027). No encontramos diferencias significativas en los niveles séricos de quimioquinas estudiadas en pacientes con shock séptico entre los supervivientes y los que fallecieron. ConclusionesAl ingreso en la UCI, la IL-8 es un buen biomarcador de FRA y de SDRA, así como de coagulopatía en pacientes con shock séptico. MIP-1α y RANTES también presentan niveles séricos alterados en la coagulopatía asociada a la sepsis. A pesar de esto, las quimioquinas no parecen ser buenos marcadores pronósticos en estos pacientes." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: de Pablo R, Monserrat J, Prieto A, Álvarez-Mon M. Papel de las quimioquinas solubles circulantes en el shock séptico. Med Intensiva. 2013;37:510–518." ] ] "multimedia" => array:9 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1597 "Ancho" => 1571 "Tamanyo" => 130048 ] ] "descripcion" => array:1 [ "en" => "Flow of the studied and evaluated subjects." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1917 "Ancho" => 2293 "Tamanyo" => 230577 ] ] "descripcion" => array:1 [ "en" => "Soluble chemokine levels in patients with septic shock. Panel A: levels of IL-8 in pg/ml versus time in days. Panel B: levels of MCP-1 in pg/ml versus time in days. Panel C: levels of MIP-1α in pg/ml versus time in days. Panel D: levels of RANTES in pg/ml versus time in days. The values are expressed as the mean and standard error of the mean." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1010 "Ancho" => 1307 "Tamanyo" => 53327 ] ] "descripcion" => array:1 [ "en" => "Levels of IL-8 in patients with septic shock upon admission to the ICU. C: controls; ARDS: acute respiratory distress syndrome; ARF: acute renal failure; DIC: disseminated intravascular coagulation. The criteria are specified in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 959 "Ancho" => 1222 "Tamanyo" => 50173 ] ] "descripcion" => array:1 [ "en" => "Levels of MCP-1 in patients with septic shock upon admission to the ICU. C: controls; ARDS: acute respiratory distress syndrome; ARF: acute renal failure; DIC: disseminated intravascular coagulation. The criteria are specified in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>." ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 1026 "Ancho" => 1487 "Tamanyo" => 57322 ] ] "descripcion" => array:1 [ "en" => "Levels of MIP-1α in patients with septic shock upon admission to the ICU. C: controls; ARDS: acute respiratory distress syndrome; ARF: acute renal failure; DIC: disseminated intravascular coagulation. The criteria are specified in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>." ] ] 5 => array:7 [ "identificador" => "fig0030" "etiqueta" => "Figure 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 1001 "Ancho" => 1488 "Tamanyo" => 59291 ] ] "descripcion" => array:1 [ "en" => "Levels of RANTES in patients with septic shock upon admission to the ICU. C: controls; ARDS: acute respiratory distress syndrome; ARF: acute renal failure; DIC: disseminated intravascular coagulation. The criteria are specified in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>." ] ] 6 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "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=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Criteria of sepsis: 2 or more of the following 4 criteria must be met \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fever or hypothermia: temperature >38°C or <36°C \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tachycardia: heart rate>90bpm \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hyperventilation: respiratory frequency>20rpm or partial CO2pressure<32mmHg, or minute-volume>10l/min \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Leukocytosis>12,000cells/mm3or leukopenia<4000cells/mm3, or >10% young cell forms (band cells, etc.) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Criteria of septic shock: patients with sepsis associated to hypotension, hypoperfusion or the need for circulatory support measures \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypotension: systolic blood pressure<90mmHg or a drop>40mmHg with respect to baseline in patients with a history of arterial hypertension \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypoperfusion: presence of lactic acidosis, oliguria<0.5ml/kg body weight and hour and/or altered consciousness \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Circulatory support: need for positive balance>2000ml/day without any other justifying cause, or need for the administration of vasoactive drugs \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Definition of organ failure: the following criteria must be maintained for over 24h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cardiovascular: presence of one or more of the following \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heart rate: <55bpm \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mean blood pressure: <50mmHg \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tachycardia or ventricular fibrillation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Need for vasoactive drugs \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Respiratory: criteria of acute respiratory distress syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PaO2/FiO2: <200mmHg \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bilateral infiltration on chest X-rays \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pulmonary capillary pressure: <19mmHg \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Justifying acute process \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Renal: presence of at least one of the following \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diuresis: <160ml/8h or <480ml in 24h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Blood urea nitrogen (BUN): >100mg/dl \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Plasma creatinine: >3.5mg/dl \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hematological: presence of at least one of the following \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Leukopenia: <1000/mm3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Thrombocytopenia: <20,000/mm3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hematocrit: <20% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neurological: Glasgow coma score: <7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepatic: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">INR: >1.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bilirubin: >6mg/dl \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab437829.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Criteria of sepsis, septic shock and of each type of organ failure." ] ] 7 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "The results are expressed as mean±standard error of the mean. APACHE II (Acute Physiology and Chronic Health Evaluation),<a class="elsevierStyleCrossRef" href="#bib0220">44</a> MODS (Multiple Organ Dysfunction Score),<a class="elsevierStyleCrossRef" href="#bib0225">45</a> MODS,<a class="elsevierStyleCrossRef" href="#bib0230">46</a> SOFA (Sequential Organ Failure Assessment),<a class="elsevierStyleCrossRef" href="#bib0235">47</a> and SOFA<a class="elsevierStyleCrossRef" href="#bib0240">48</a> are severity scores." "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=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age (years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">61.6±3.6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Males/females \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">36/16 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Clinical/surgical \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24/28 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">APACHE II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24.26±1.41 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MODS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7.66±0.69 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">δ-MODS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.69±0.49 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SOFA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8.89±0.74 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">δ-SOFA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.11±0.63 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab437827.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Demographic data of the patients." ] ] 8 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "The results are expressed as mean±standard error of the mean." "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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Controls (n=36) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Baseline</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">3d</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">7d</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14d \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28d \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Non-survivors (n=18) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Survivors (n=34) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Non-survivors (n=13) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Survivors (n=34) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Non-survivors (n=11) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Survivors (n=34) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Survivors (n=34) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Survivors (n=34) \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL-8 (pg/ml) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.02±0.37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">356.7±167.7<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">265.7±113.3<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">103.4±37.5<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">170.0±127.4<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">187.2±162.2<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">70.5±18.1<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">178.5±135.5<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21.96± 3.18<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="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MCP1 (pg/ml) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">204.9±59.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.774±771.7<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.020.8±670.7<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.839.9±732.3<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">917.3±218.3<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.192.4±268.5<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">640.7±151.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">568.1±143.1<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">378.9±113.9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MIP-1α (pg/ml) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38.4±2.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">59.3±18.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">67.7±12.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">56.2±17.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38.4±7.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">34.4±3.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">44.5±10.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">46.7±7.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">26.2±6.7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RANTES (pg/ml) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">58.000±3.204 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20.714±3.624<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14.758±2.105<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.914±4.919<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16.900±6.008<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8.371±8.338<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29.279±5.866<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">33.162±6.323<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28.924±4.452<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab437828.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "p<0.05 between each timepoint and the controls. 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Role of circulating soluble chemokines in septic shock

Papel de las quimioquinas solubles circulantes en el shock séptico

R. de Pabloa,b,

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raul.depablo@uah.es

Corresponding author.

, J. Monserratb, A. Prietob, M. Álvarez-Monb,c

a Unidad de Cuidados Intensivos, Hospital Universitario Príncipe de Asturias, Madrid, Spain

b Laboratorio de Enfermedades del Sistema Inmune y Oncología, Unidad asociada al Centro Nacional de Biotecnología, Departamento de Medicina, Universidad de Alcalá, Madrid, Spain

c Servicio de Enfermedades del Sistema Inmune y Oncología, Hospital Universitario Príncipe de Asturias, Madrid, Spain

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          "en" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Levels of MCP-1 in patients with septic shock upon admission to the ICU&#46; C&#58; controls&#59; ARDS&#58; acute respiratory distress syndrome&#59; ARF&#58; acute renal failure&#59; DIC&#58; disseminated intravascular coagulation&#46; The criteria are specified in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Multiorgan failure is the main cause of death in patients with sepsis&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The prognosis of multiorgan dysfunction syndrome &#40;MODS&#41; is conditioned to the number of failed organs&#44; the severity of failure&#44; and its duration in time&#46; In a study published by Knaus et al&#46;&#44; the mortality rate was 22&#37; among patients with single organ failure lasting less than 24<span class="elsevierStyleHsp" style=""></span>h&#44; but increased to 42&#37; when the condition persisted for 7 days&#46; In turn&#44; the mortality rate was found to be 80&#37; in the case of three or more failed organs with a duration of less than 24<span class="elsevierStyleHsp" style=""></span>h&#44; and reached 100&#37; when the condition persisted for more than four days&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Although severity scores have been developed to characterize the degree of multiorgan dysfunction and predict mortality among patients with sepsis&#44; understanding the physiopathology of MODS represents an ongoing challenge&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The development of MODS is a consequence of excessive activation of the inflammatory response&#46; To date&#44; however&#44; the treatments that have attempted to counter this exaggerated systemic inflammatory response have failed&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Furthermore&#44; most patients who survive the initial aggression of sepsis die days or weeks later as a result of multiorgan failure and in a situation of immunosuppression&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">At cellular level&#44; a number of mechanisms contribute to the development of MODS&#44; including microvascular thrombosis&#44; neutrophil-induced damage&#44; bacterial translocation&#44; cytokine release&#44; endothelial dysfunction&#44; cell apoptosis&#44; etc&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The chemokines constitute a large family of cytokines that stimulate the movement of leukocytes and regulate their migration from the bloodstream toward the tissues&#46; They are regarded as proinflammatory cytokines&#44; since they induce the production and release of histamine&#44; enzymes and defensins&#46; However&#44; in contrast to other cytokines&#44; the chemokines do not induce other cytokines or produce fever or acute phase reactants&#46; Furthermore&#44; chemokines in large circulating concentrations exert desensitizing effects and can suppress local inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Nuclear factor-&#954;B &#40;NF-&#954;B&#41; plays a key role in the physiopathology of sepsis and septic shock&#46; An increase in its activity has been associated with a higher mortality rate and a poorer prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> NF-&#954;B mediates the transcription of a range of genes encoding for inflammatory molecules such as cytokines&#44; adhesion molecules&#44; enzymes&#44; immune receptors&#44; acute phase reactants and chemokines&#8211;including interleukin-8 &#40;IL-8&#41;&#44; macrophage inflammatory protein 1-&#945; &#40;MIP-1&#945;&#41;&#44; type 1 monocyte chemoattractant protein &#40;MCP-1&#41; and RANTES &#40;regulated on activation&#44; normal T cell expressed and secreted&#41; protein&#46; The role of these chemokines when soluble in plasma in the development of organ dysfunction in patients with sepsis has not been well established to date&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The present study postulates that the plasma levels of these circulating chemokines are increased in patients with septic shock&#44; and that this in turn contributes to the development of organ dysfunction and patient mortality&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Patients and methods</span><p id="par0030" class="elsevierStylePara elsevierViewall">On a retrospective basis and covering a period of approximately 36 months&#44; we included those patients over 18 years of age with severe sepsis admitted to the Intensive Care Unit &#40;ICU&#41;&#46; Severe sepsis was diagnosed based on the presence of sepsis plus the failure of some organ&#44; hypoperfusion or hypotension&#44; in compliance with the criteria of the consensus conference of the American College of Chest Physicians&#47;Society of Critical Care Medicine<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The demonstration of infection was also considered essential&#44; using microbiological techniques &#40;gram staining and&#47;or culture&#41;&#44; radiological techniques&#44; or direct visualization of the infection site&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">The following exclusion criteria were established&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">a&#41;</span><p id="par0040" class="elsevierStylePara elsevierViewall">Primary or acquired immunodeficiency of any kind</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">b&#41;</span><p id="par0045" class="elsevierStylePara elsevierViewall">Previous immunosuppressive or immune modulating treatment</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">c&#41;</span><p id="par0050" class="elsevierStylePara elsevierViewall">Uncontrolled or actively treated neoplastic disease</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">d&#41;</span><p id="par0055" class="elsevierStylePara elsevierViewall">Active autoimmune or allergic disorders</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">e&#41;</span><p id="par0060" class="elsevierStylePara elsevierViewall">The need for extrarenal filtration techniques capable of affecting clearance of the different inflammatory mediators</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">f&#41;</span><p id="par0065" class="elsevierStylePara elsevierViewall">Administration of experimental therapy</p></li></ul></p><p id="par0070" class="elsevierStylePara elsevierViewall">We analyzed peripheral blood samples from 36 health volunteers &#40;controls&#41; with an age and gender distribution similar to that of the patients included in the study&#44; in order to prevent the demographic characteristics from interfering with the interpretation of the results&#46; The study protocol was approved by the Clinical Research Ethics Committee&#46; The relatives of the patients and healthy controls gave informed consent to the experimental protocol&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">All the patients received conventional treatment&#46; None received activated protein C&#44; and individuals needing hydrocortisone due to refractory hypotension were excluded from the study&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Blood samples were collected through the arterial catheter in tubes without anticoagulant in the first 12<span class="elsevierStyleHsp" style=""></span>h after admission to the ICU &#40;baseline sample&#41;&#44; 48<span class="elsevierStyleHsp" style=""></span>h after admission&#44; and after 7&#44; 14 and 28 days&#46; An additional 10<span class="elsevierStyleHsp" style=""></span>ml of blood was extracted and allowed to clot at room temperature&#44; followed by serum separation by centrifugation at 600<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">g</span> during 20<span class="elsevierStyleHsp" style=""></span>min&#46; The supernatants were collected&#44; filtered and divided into aliquots that were stored frozen at &#8722;70<span class="elsevierStyleHsp" style=""></span>&#176;C until use&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">After thawing of the supernatants to room temperature&#44; sandwich ELISA testing was carried out&#46; The results obtained were measured with the Multititer Plus<span class="elsevierStyleSup">&#174;</span> enzymoimmunoassay reader &#40;Tiertek Multiscan Plus&#44; Flow Laboratories&#44; United Kingdom&#41;&#44; and were compared with a standard curve obtained from known concentrations of each cytokine&#44; supplied by the manufacturer&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The analysis of the different standard curves and subsequent interpolations were carried out with the Delta Soft II<span class="elsevierStyleSup">&#174;</span> version 4&#46;1 software &#40;Biometallies&#44; Inc&#46;&#44; USA&#41; on a Macintosh<span class="elsevierStyleSup">&#174;</span> computer&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">The determinations of the concentrations of the different cytokines were made using the commercial formulations with a supernatant quantitation sensitivity of 25<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for IL-8 &#40;Diaclone&#44; USA&#41;&#44; 5<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for MCP-1 &#40;R&#38;D System&#44; Minneapolis&#44; USA&#41;&#44; 10<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for MIP-1&#945; &#40;R&#38;D System&#44; Minneapolis&#44; USA&#41;&#44; and 10<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for RANTES &#40;R&#38;D System&#44; Minneapolis&#44; USA&#41;&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">In relation to the statistical study&#44; we first examined the nature of the distributions using the Shapiro&#8211;Wilk normality test&#46; When the data obtained showed a normal distribution&#44; comparisons of means were established using the Student <span class="elsevierStyleItalic">t</span>-test&#46; In the case of data with a non-normal distribution&#44; comparisons were made using the nonparametric Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span>-test&#46; Comparison of data from one same group at different time intervals was carried out with the Friedman test&#44; while correlations between the different variables were established using the Pearson correlation coefficient&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The results of the experimental studies are presented as the mean and standard error of the mean &#40;sem&#41;&#46; In all cases significance levels of under 5&#37; were considered &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; The SPSS version 11&#46;0 statistical package &#40;SPSS Inc&#46;&#44; Chicago&#44; IL 60606&#44; USA&#41; was used throughout&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Results</span><p id="par0110" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> shows the flow of the 128 individuals studied&#44; including 52 patients &#40;all with septic shock&#41;&#44; 40 excluded subjects and 36 healthy controls&#46; The demographic characteristics of the patients are summarized in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Chemokine levels with respect to the control group</span><p id="par0115" class="elsevierStylePara elsevierViewall">The serum levels of the studied soluble chemokines &#40;IL-8&#44; MCP-1&#44; MIP-1&#945; and RANTES&#41; showed special and individualized behavior in each case&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">As can be seen in panel A of <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#44; IL-8 maintained extraordinarily elevated levels throughout the evolution of sepsis&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0125" class="elsevierStylePara elsevierViewall">The concentration of MCP-1 was very high in the first phase and then gradually decreased to normalization by day 28 &#40;panel B of <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">There were no significant differences between the levels of MIP-1&#945; among the controls and in the patients at any timepoint &#40;panel C of <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">On the other hand&#44; as can be seen in panel D of <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#44; the RANTES levels were below those of the controls at all timepoints of the disease&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Prognostic value of the soluble chemokine levels</span><p id="par0140" class="elsevierStylePara elsevierViewall">The mortality rate among the patients was 34&#46;6&#37;&#46; In the patients with septic shock&#44; we found no significant differences in serum chemokine levels between the survivors and those who died &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Correlation between the chemokine levels and failure of the different organs</span><p id="par0145" class="elsevierStylePara elsevierViewall">Among the 6 organ system failures considered &#40;cardiovascular&#44; acute respiratory distress syndrome &#91;ARDS&#93;&#44; acute renal failure &#91;ARF&#93;&#44; coagulopathy&#44; liver failure and neurological failure&#41;&#44; the incidence of liver failure &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#41; and of neurological failure &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#41; was so low that no conclusions can be drawn from the data obtained&#46; On the other hand&#44; all the patients met criteria of cardiovascular failure and were classified as presenting septic shock&#46; The patients with ARDS upon admission totaled 46&#37;&#44; while the incidence of ARF was 36&#37;&#44; and that of coagulopathy 19&#37;&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Analysis of the chemokine levels at the time of admission to the ICU and in relation to the different types of organ failure showed the serum levels of IL-8 to be significantly higher in the patients admitted with ARDS than in those without ARDS&#44; and also in those with ARF compared with the patients who did not develop ARF &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; In relation to the rest of the chemokines &#40;MCP-1&#44; MIP-1&#945; and RANTES&#41;&#44; no significant differences were observed at the time of admission in those with ARDS or in those with ARF &#40;<a class="elsevierStyleCrossRefs" href="#fig0020">Figs&#46; 4&#8211;6</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="fig0030"></elsevierMultimedia><p id="par0155" class="elsevierStylePara elsevierViewall">The IL-8 and MIP-1&#945; levels in the patients with coagulopathy were higher than in those without coagulopathy upon admission &#40;<a class="elsevierStyleCrossRefs" href="#fig0015">Figs&#46; 3 and 5</a>&#41;&#46; Significant differences were also observed in the levels of RANTES&#44; with lower concentrations upon admission to the ICU in patients with coagulopathy than in those without &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 6</a>&#41;&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Discussion</span><p id="par0160" class="elsevierStylePara elsevierViewall">In the present study we found chemokines to be involved in the development of different types of organ damage&#46; Interleukin-8 is increased in patients with septic shock&#44; and these levels are good markers of respiratory&#44; renal and hematological failure&#46; Two other chemokines are also implicated in the case of patients with coagulopathy&#44; namely MIP-1&#945; and RANTES&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Hack et al&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> were the first to report that 89&#37; of the patients with sepsis had high IL-8 levels upon admission and during follow-up over 60<span class="elsevierStyleHsp" style=""></span>h&#44; though in contrast to our own findings&#44; the levels decreased in the course of follow-up&#46; The physiopathological basis for this finding is the fact that endotoxin&#44; IL-1&#946;&#44; and especially TNF-&#945; are the main stimuli for IL-8 production and release&#46; Measurement of the serum concentrations of IL-8 has been used to predict which patients have bacteremia in a group of subjects reporting to the emergency service due to systemic inflammatory response syndrome &#40;SIRS&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> though other authors prefer to use the procalcitonin levels for this purpose&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">A range of soluble molecules have been evaluated as potential prognostic markers in patients with sepsis&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#8211;15</span></a> In this context&#44; the prognostic usefulness of IL-8 concentration has been described by several authors&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;17</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Recently&#44; different studies using commercial multitests and simultaneously determining 17 molecules in patients with sepsis have found IL-8 to be one of the best prognostic biomarkers in patients of this kind&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#8211;20</span></a> We and other investigators have not obtained such results&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Possibly&#44; the reason for this discrepancy is that our patients&#44; in contrast to those of the other studies&#44; were in a more serious condition&#44; with higher APACHE II scores and practically all in a state of shock&#8211;this making it more difficult to find differences in the levels of IL-8&#46; In effect&#44; in the studies published by Halstensen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> and Damas&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> patients with shock had higher levels than patients with sepsis but no cardiovascular failure&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Interleukin-8 has been identified as the main chemotactic factor of polymorphonuclear neutrophils in the lungs&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Boutten et al&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> demonstrated a correlation between the neutrophil count and the concentration of IL-8 in bronchoalveolar lavage &#40;BAL&#41; obtained from different lung segments in 17 patients with unilateral pneumonia&#46; We recorded higher IL-8 concentrations in patients with ARDS upon admission to the ICU than in those without ARDS&#46; Some studies have analyzed this point and confirm our findings&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;25</span></a> It has been shown that the IL-8 levels in bronchoalveolar lavage are increased in patients with ARDS&#44;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;27</span></a> and are moreover correlated to chronification of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">We observed significant differences in the levels of IL-8 among patients with ARF upon admission to the ICU as a consequence of sepsis&#46; Fujishima et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> correlated the blood IL-8 levels to the development of ARF and mortality&#46; The study published by Ahlstr&#246;m et al&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> likewise confirms our results&#46; Interleukin-8 is probably implicated in the physiopathology of ARF in septic patients&#44; though there are no conclusive experimental data in this respect&#46; We therefore cannot discard the possibility that IL-8 elevation is simply a problem of renal clearance and accumulation of the molecule in situations of renal failure&#46; In our study the IL-8 levels were higher in patients with coagulopathy at the onset of sepsis&#46; The previously mentioned studies by Damas<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> and Fujishima<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> in septic patients confirm our data&#46; Interleukin-8 is implicated in the induction of intravascular coagulation associated to endotoxin&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> It promotes the activation of coagulation&#44; particularly through mediation by CD14&#43; monocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> Thrombin in turn stimulates the production of IL-8 by monocytes and endothelial cells&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> An increase in blood IL-8 has also been described in coagulopathy associated to acute promyelocytic leukemia&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Type 1 monocyte chemoattractant protein &#40;MCP-1&#41; is a CC chemokine that acts as a mediator in monocyte and T lymphocyte tissue infiltration in a broad range of inflammatory diseases&#46; In our study we recorded elevated MCP-1 levels upon admission compared with the control group&#44; and these levels were seen to subsequently decrease progressively&#44; with normalization after 28 days&#46; These same results have been obtained by other authors&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#44;34</span></a> However&#44; some investigators<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> have only recorded elevated MCP-1 levels in the bronchoalveolar lavage of patients with sepsis&#44; but not in serum&#46; In this sense&#44; we did not record elevated concentrations in patients with ARDS or any other organ failure upon admission&#46; On the other hand&#44; MCP-1 is admittedly regarded as a second signal and would be implicated in monocyte infiltration&#59; consequently&#44; at the time of admission it might not be possible to appreciate the clinical relevance which this mediator probably has at a later stage in time&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">We found no differences in the serum MCP-1 levels during the first week of sepsis between the patients who died and those who survived&#46; Similar results have been obtained by other authors&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Macrophage inflammatory protein 1-&#945; &#40;MIP-1&#945;&#41; is fundamentally a macrophage chemotactic protein&#44; although it has also been associated with chemotactic and proadhesive effects upon other cell types&#46; MIP-1&#945; also exerts modulating effects upon the production of cytokines&#44; and is an endogenous pyrogen&#46; Although experimentally MIP-1&#945; appears after the administration of lipopolysaccharides both in vitro<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> and in vivo&#44;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#44;37</span></a> the results obtained on examining the serum levels in patients with severe sepsis were very notorious&#46; In effect&#44; we observed normal levels throughout the evolution of the disease&#44; regardless of the prognosis&#46; These same findings have been described by other groups&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;33&#8211;35&#44;38</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">All authors appear to agree that the MIP-1&#945; levels have no prognostic value or relation to the development of multiorgan failure&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;38</span></a> However&#44; in our study we did observe differences in the levels of MIP-1&#945; among the patients with coagulopathy upon admission to the ICU versus those without coagulopathy&#46; The only study we have found in this line is the work published by Fujishima et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> and although a tendency toward increased levels of MIP-1&#945; was noted in the patients with coagulopathy&#44; statistical significance was not reached&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">The RANTES &#40;regulated on activation&#44; normal T cell expressed and secreted&#41; protein is a CC chemokine produced by a series of cell types including platelets&#44; lymphocytes and epithelial cells&#44; in response to pyrogenic signals such as endotoxin&#44; bacterial infections and TNF-&#945;&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> Its main biological function is the trafficking and activation of both inflammatory and non-inflammatory cells&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> Cavaillon et al&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> reported that the levels of RANTES in sepsis are inversely proportional to the APACHE II score&#59; the authors thus deduced that RANTES is lower among the patients who do not survive&#46; M&#248;ller et al&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> demonstrated that patients with fulminant meningococcemia had lesser RANTES concentrations than patients with other less serious meningococcal infections&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">We also observed extraordinarily low RANTES levels compared with the healthy controls&#46; However&#44; we did not find significant differences in the levels between the survivors and those patients who died&#46; The only form of organ failure in which there were significantly lower concentrations in the patients was the presence of coagulopathy upon admission in the ICU versus those without coagulopathy&#46; This result is difficult to interpret&#46; It is known that bacteria can stimulate the release of RANTES&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> and that the administration of 4<span class="elsevierStyleHsp" style=""></span>ng&#47;kg of endotoxin to 8 healthy volunteers resulted in a drop in RANTES levels&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> On the other hand&#44; we also know that platelets are the principal source of RANTES&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> Platelets express CD40 at surface level&#44; which interacts with the CD154 receptor of activated T lymphocytes&#44; inducing the release of RANTES stored in the platelets&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">During the inflammatory response&#44; RANTES is released into the intravascular compartment and rapidly binds to the endothelial surface&#44; thereby giving rise to the recruitment and retention of leukocytes&#8211;including T cells&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> This is where the interpretation difficulty lies&#58; is the decrease in RANTES observed in coagulopathy attributable to depletion of the molecule upon binding to the vascular endothelium&#44; or is it a consequence of a drop in the RANTES reservoir&#44; i&#46;e&#46;&#44; the platelets&#63; In hematological patients&#44; Ellis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> found that in subjects with fever&#44; RANTES concentration is related to the presence of thrombocytopenia&#46; We posteriorly studied the correlation between the levels of RANTES and the platelet counts in blood among patients with severe sepsis during the first day of admission to the ICU&#46; This nonparametric association&#44; studied by means of the Spearman test&#44; yielded a correlation of 0&#46;546&#44; with <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;007&#46; We therefore cannot rule out the possibility that this decrease in RANTES levels among patients with coagulopathy is simply an expression of the thrombocytopenia found in these individuals&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">In conclusion&#44; in this study we have demonstrated the participation of chemokines IL-8&#44; MIP-1&#945; and RANTES in coagulopathy associated to septic shock&#44; as well as the usefulness of IL-8 as a biomarker of respiratory and renal failure&#46; Nevertheless&#44; these molecules appear to lack prognostic value in patients with septic shock&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Financial support</span><p id="par0230" class="elsevierStylePara elsevierViewall">This study has been financed in part by the <span class="elsevierStyleGrantSponsor" id="gs0005">Community of Madrid</span>&#44; <span class="elsevierStyleGrantNumber" refid="gs0005">S-BIO-0189&#47;2006</span>&#44; and by the <span class="elsevierStyleGrantSponsor" id="gs0010"><span class="elsevierStyleItalic">Fondo de Investigaci&#243;n Sanitaria</span></span>&#44; <span class="elsevierStyleGrantNumber" refid="gs0010">PI-08-1890</span>&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conflicts of interest</span><p id="par0235" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "titulo" => array:8 [
            0 => "Abstract"
            1 => "Purpose"
            2 => "Design"
            3 => "Setting"
            4 => "Patients"
            5 => "Interventions"
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          "titulo" => "Keywords"
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          "titulo" => array:8 [
            0 => "Resumen"
            1 => "Objetivo"
            2 => "Dise&#241;o"
            3 => "&#193;mbito"
            4 => "Pacientes"
            5 => "Intervenciones"
            6 => "Resultados"
            7 => "Conclusiones"
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          "titulo" => "Palabras clave"
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          "titulo" => "Introduction"
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          "titulo" => "Patients and methods"
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          "titulo" => "Results"
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            0 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Chemokine levels with respect to the control group"
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            1 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Prognostic value of the soluble chemokine levels"
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              "identificador" => "sec0030"
              "titulo" => "Correlation between the chemokine levels and failure of the different organs"
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          "titulo" => "Discussion"
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          "identificador" => "xack70558"
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          "titulo" => "References"
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    "fechaRecibido" => "2012-07-29"
    "fechaAceptado" => "2012-09-24"
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          "clase" => "keyword"
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          "palabras" => array:6 [
            0 => "Chemokines"
            1 => "Septic shock"
            2 => "Acute respiratory distress syndrome"
            3 => "Acute renal failure"
            4 => "Coagulopathy"
            5 => "Biomarkers"
          ]
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          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec282031"
          "palabras" => array:6 [
            0 => "Quimioquinas"
            1 => "Shock s&#233;ptico"
            2 => "S&#237;ndrome de distr&#233;s respiratorio agudo"
            3 => "Fracaso renal agudo"
            4 => "Coagulopat&#237;a"
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        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Purpose</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Chemokines are a large superfamily of small proteins that not only function in leukocyte trafficking&#44; but are also necessary for linkage between innate and adaptive immunity&#46; Little is known about their role in septic shock&#46; We hypothesized that serum levels of the most important chemokines are related to organ failure&#44; disease severity and outcome&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0015">Design</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A prospective observational study was carried out&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0020">Setting</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Surgical-clinical Intensive Care Unit&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0025">Patients</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Ninety-two patients diagnosed with septic shock using international criteria&#46; Forty patients were excluded due to acquired immunity disturbances&#46; Samples from 36 healthy controls were also analyzed&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0030">Interventions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">None&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0035">Results</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">In 46&#37; of the patients who suffered acute respiratory distress syndrome &#40;ARDS&#41;&#44; IL-8 levels were higher than in patients without ARDS &#40;499&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>194&#46;1 vs 190&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>91&#46;7<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;039&#41;&#46; This molecule was also higher in 36&#37; of the patients with sepsis-induced acute renal failure &#40;ARF&#41; &#40;453&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>181&#46;6 vs 201&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>95&#46;9<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;049&#41;&#46; Coagulopathy was found in 19&#37; of the septic shock patients with elevated serum IL-8 levels &#40;635&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>292&#46;3 vs 218&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>87&#46;0<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;010&#41;&#44; elevated MIP-1&#945; &#40;91&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>27&#46;3 vs 58&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#46;1<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;044&#41;&#44; and low circulating RANTES levels &#40;8162&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6321&#46;0 vs 18781&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#46;1<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;027&#41;&#46; No significant differences were found between survivors and non-survivors at any time of follow-up&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0040">Conclusions</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Upon admission to the ICU&#44; IL-8 is a reliable biomarker of sepsis-induced AFR&#44; ARDS and coagulopathy&#46; Altered circulating MIP-1&#945; and RANTES levels are also found in patients with septic shock and coagulopathy&#46; However&#44; chemokines do not appear to be good biomarkers of mortality in septic shock&#46;</p>"
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        "titulo" => "Resumen"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0050">Objetivo</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Las quimioquinas son una gran familia de peque&#241;os p&#233;ptidos que tienen una participaci&#243;n clave no solo en el control del tr&#225;fico de los leucocitos&#44; sino tambi&#233;n se ha visto que son necesarios en las interacciones entre la inmunidad innata y adaptativa&#46; El papel de estas mol&#233;culas es poco conocido en el seno del shock s&#233;ptico&#46; Nuestra hip&#243;tesis es que los niveles s&#233;ricos de las principales quimioquinas tienen relaci&#243;n con los diferentes fallos org&#225;nicos y con el pron&#243;stico de los pacientes con shock s&#233;ptico&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0055">Dise&#241;o</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Estudio prospectivo y observacional&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0060">&#193;mbito</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Unidad de Cuidados Intensivos m&#233;dico-quir&#250;rgica&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0065">Pacientes</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Noventa y dos pacientes cumplieron criterios internacionales de shock s&#233;ptico con demostraci&#243;n de una infecci&#243;n&#44; de los que se excluyeron 40 por presentar diferentes alteraciones inmunitarias adquiridas&#46; Treinta y seis voluntarios sanos sirvieron de grupo control&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0070">Intervenciones</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Ninguna&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0075">Resultados</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">El 46&#37; de los pacientes presentaron s&#237;ndrome de distr&#233;s respiratorio agudo &#40;SDRA&#41; y en ellos los niveles s&#233;ricos de IL-8 se encontraban elevados &#40;499&#44;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>194&#44;1 vs&#46; 190&#44;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>91&#44;7<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;039&#41;&#46; Esta mol&#233;cula tambi&#233;n estaba elevada en el 36&#37; de los pacientes con shock s&#233;ptico que ten&#237;an fracaso renal agudo &#40;FRA&#41; &#40;453&#44;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>181&#44;6 vs&#46; 201&#44;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>95&#44;9<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;049&#41;&#46; El 19&#37; de los pacientes presentaron coagulopat&#237;a y en ellos se observ&#243; una elevaci&#243;n de los niveles de IL-8 &#40;635&#44;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>292&#44;3 vs&#46; 218&#44;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>87&#44;0<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;010&#41;&#44; de MIP-1&#945; &#40;91&#44;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>27&#44;3 vs&#46; 58&#44;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#44;1<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;044&#41; y niveles bajos de RANTES &#40;8162&#44;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6321&#44;0 vs&#46; 18781&#44;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#44;1<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;027&#41;&#46; No encontramos diferencias significativas en los niveles s&#233;ricos de quimioquinas estudiadas en pacientes con shock s&#233;ptico entre los supervivientes y los que fallecieron&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0080">Conclusiones</span><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Al ingreso en la UCI&#44; la IL-8 es un buen biomarcador de FRA y de SDRA&#44; as&#237; como de coagulopat&#237;a en pacientes con shock s&#233;ptico&#46; MIP-1&#945; y RANTES tambi&#233;n presentan niveles s&#233;ricos alterados en la coagulopat&#237;a asociada a la sepsis&#46; A pesar de esto&#44; las quimioquinas no parecen ser buenos marcadores pron&#243;sticos en estos pacientes&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; de Pablo R&#44; Monserrat J&#44; Prieto A&#44; &#193;lvarez-Mon M&#46; Papel de las quimioquinas solubles circulantes en el shock s&#233;ptico&#46; Med Intensiva&#46; 2013&#59;37&#58;510&#8211;518&#46;</p>"
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          "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Levels of IL-8 in patients with septic shock upon admission to the ICU&#46; C&#58; controls&#59; ARDS&#58; acute respiratory distress syndrome&#59; ARF&#58; acute renal failure&#59; DIC&#58; disseminated intravascular coagulation&#46; The criteria are specified in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p>"
        ]
      ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Levels of MCP-1 in patients with septic shock upon admission to the ICU&#46; C&#58; controls&#59; ARDS&#58; acute respiratory distress syndrome&#59; ARF&#58; acute renal failure&#59; DIC&#58; disseminated intravascular coagulation&#46; The criteria are specified in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "fig0025"
        "etiqueta" => "Figure 5"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
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        "figura" => array:1 [
          0 => array:4 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Levels of MIP-1&#945; in patients with septic shock upon admission to the ICU&#46; C&#58; controls&#59; ARDS&#58; acute respiratory distress syndrome&#59; ARF&#58; acute renal failure&#59; DIC&#58; disseminated intravascular coagulation&#46; The criteria are specified in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "fig0030"
        "etiqueta" => "Figure 6"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
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        "figura" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Levels of RANTES in patients with septic shock upon admission to the ICU&#46; C&#58; controls&#59; ARDS&#58; acute respiratory distress syndrome&#59; ARF&#58; acute renal failure&#59; DIC&#58; disseminated intravascular coagulation&#46; The criteria are specified in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p>"
        ]
      ]
      6 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Criteria of sepsis&#58; 2 or more of the following 4 criteria must be met</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Fever or hypothermia&#58; temperature &#62;38</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#176;C or &#60;36</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#176;C</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Tachycardia&#58; heart rate</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#62;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">90</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">bpm</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Hyperventilation&#58; respiratory frequency</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#62;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">20</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">rpm or partial CO</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">2</span></span><span class="elsevierStyleItalic">pressure</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">32</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mmHg&#44; or minute-volume</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#62;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">10</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">l&#47;min</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Leukocytosis</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#62;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">12&#44;000</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">cells&#47;mm</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">3</span></span><span class="elsevierStyleItalic">or leukopenia</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">4000</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">cells&#47;mm</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">3</span></span><span class="elsevierStyleItalic">&#44; or &#62;10&#37; young cell forms &#40;band cells&#44; etc&#46;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Criteria of septic shock&#58; patients with sepsis associated to hypotension&#44; hypoperfusion or the need for circulatory support measures</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Hypotension&#58; systolic blood pressure</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">90</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mmHg or a drop</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#62;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">40</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mmHg with respect to baseline in patients with a history of arterial hypertension</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Hypoperfusion&#58; presence of lactic acidosis&#44; oliguria</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">0&#46;5</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">ml&#47;kg body weight and hour and&#47;or altered consciousness</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Circulatory support&#58; need for positive balance</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#62;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">2000</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">ml&#47;day without any other justifying cause&#44; or need for the administration of vasoactive drugs</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Definition of organ failure&#58; the following criteria must be maintained for over 24</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">h</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Cardiovascular&#58; presence of one or more of the following</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Heart rate&#58; &#60;55<span class="elsevierStyleHsp" style=""></span>bpm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Mean blood pressure&#58; &#60;50<span class="elsevierStyleHsp" style=""></span>mmHg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Tachycardia or ventricular fibrillation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Need for vasoactive drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Respiratory&#58; criteria of acute respiratory distress syndrome</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>PaO<span class="elsevierStyleInf">2</span>&#47;FiO<span class="elsevierStyleInf">2</span>&#58; &#60;200<span class="elsevierStyleHsp" style=""></span>mmHg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Bilateral infiltration on chest X-rays&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Pulmonary capillary pressure&#58; &#60;19<span class="elsevierStyleHsp" style=""></span>mmHg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Justifying acute process&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Renal&#58; presence of at least one of the following</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Diuresis&#58; &#60;160<span class="elsevierStyleHsp" style=""></span>ml&#47;8<span class="elsevierStyleHsp" style=""></span>h or &#60;480<span class="elsevierStyleHsp" style=""></span>ml in 24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Blood urea nitrogen &#40;BUN&#41;&#58; &#62;100<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Plasma creatinine&#58; &#62;3&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Hematological&#58; presence of at least one of the following</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Leukopenia&#58; &#60;1000&#47;mm<span class="elsevierStyleSup">3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Thrombocytopenia&#58; &#60;20&#44;000&#47;mm<span class="elsevierStyleSup">3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Hematocrit&#58; &#60;20&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Neurological&#58; Glasgow coma score&#58; &#60;7</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Hepatic&#58;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>INR&#58; &#62;1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Bilirubin&#58; &#62;6<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">Criteria of sepsis&#44; septic shock and of each type of organ failure&#46;</p>"
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      7 => array:7 [
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">The results are expressed as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard error of the mean&#46; APACHE II &#40;Acute Physiology and Chronic Health Evaluation&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> MODS &#40;Multiple Organ Dysfunction Score&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> MODS&#44;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> SOFA &#40;Sequential Organ Failure Assessment&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> and SOFA<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> are severity scores&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">61&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Males&#47;females&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">36&#47;16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Clinical&#47;surgical&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&#47;28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">APACHE II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&#46;26<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MODS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;66<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;69&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#948;-MODS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">2&#46;69<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;49&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#46;89<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;74&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t">&#948;-SOFA&nbsp;\t\t\t\t\t\t\n
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          "leyenda" => "<p id="spar0125" class="elsevierStyleSimplePara elsevierViewall">The results are expressed as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard error of the mean&#46;</p>"
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                0 => """
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                  \t\t\t\t\tvoid\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Controls &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>36&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">3<span class="elsevierStyleHsp" style=""></span>d</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t">14<span class="elsevierStyleHsp" style=""></span>d&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">28<span class="elsevierStyleHsp" style=""></span>d&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Non-survivors &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>18&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Survivors &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>34&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Non-survivors &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Survivors &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>34&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Non-survivors &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>11&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Survivors &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>34&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Survivors &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>34&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Survivors &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>34&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL-8 &#40;pg&#47;ml&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">2&#46;02<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;37&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">356&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>167&#46;7<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">103&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>37&#46;5<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">170&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>127&#46;4<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">187&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>162&#46;2<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">70&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>18&#46;1<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">178&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>135&#46;5<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">21&#46;96<span class="elsevierStyleHsp" style=""></span>&#177; 3&#46;18<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MCP1 &#40;pg&#47;ml&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">204&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>59&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;774<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>771&#46;7<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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;020&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>670&#46;7<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;839&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>732&#46;3<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">917&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>218&#46;3<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">640&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>151&#46;4&nbsp;\t\t\t\t\t\t\n
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                      "titulo" => "Use of the SOFA score to assess the incidence of organ dysfunction&#47;failure in intensive care units&#58; results of a multicenter&#44; prospective study&#46; Working group on &#8220;sepsis-related problems&#8221; of the European Society of Intensive Care Medicine"
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                      "titulo" => "The use of maximum SOFA score to quantify organ dysfunction&#47;failure in intensive care&#46; Results of a prospective&#44; multicentre study&#46; Working Group on Sepsis related Problems of the ESICM"
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                            2 => "R&#46; Matos"
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        "identificador" => "xack70558"
        "titulo" => "Acknowledgements"
        "texto" => "<p id="par0240" class="elsevierStylePara elsevierViewall">The authors thank the medical and nursing team of the ICU of Pr&#237;ncipe de Asturias University Hospital for their collaboration in this study&#46;</p>"
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Article information

ISSN: 21735727
Original language: English

DOI:10.1016/j.medine.2012.09.008

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Year/Month	Html	Pdf	Total

2024 November	14	12	26
2024 October	62	62	124
2024 September	43	45	88
2024 August	71	68	139
2024 July	37	43	80
2024 June	55	63	118
2024 May	60	59	119
2024 April	62	36	98
2024 March	88	31	119
2024 February	73	57	130
2024 January	69	33	102
2023 December	52	36	88
2023 November	55	55	110
2023 October	59	35	94
2023 September	61	53	114
2023 August	56	14	70
2023 July	59	30	89
2023 June	48	14	62
2023 May	64	34	98
2023 April	46	18	64
2023 March	97	37	134
2023 February	83	45	128
2023 January	101	29	130
2022 December	102	40	142
2022 November	73	44	117
2022 October	120	32	152
2022 September	83	60	143
2022 August	68	60	128
2022 July	47	45	92
2022 June	53	52	105
2022 May	54	38	92
2022 April	57	57	114
2022 March	60	54	114
2022 February	64	44	108
2022 January	73	57	130
2021 December	54	68	122
2021 November	59	45	104
2021 October	44	54	98
2021 September	39	34	73
2021 August	38	49	87
2021 July	48	32	80
2021 June	28	48	76
2021 May	37	58	95
2021 April	95	86	181
2021 March	39	16	55
2021 February	42	36	78
2021 January	43	39	82
2020 December	42	30	72
2020 November	40	22	62
2020 October	50	34	84
2020 September	38	25	63
2020 August	33	25	58
2020 July	56	13	69
2020 June	41	17	58
2020 May	23	19	42
2020 April	45	17	62
2020 March	24	13	37
2020 February	42	25	67
2020 January	40	22	62
2019 December	61	22	83
2019 November	25	21	46
2019 October	31	17	48
2019 September	35	14	49
2019 August	38	12	50
2019 July	40	21	61
2019 June	24	10	34
2019 May	36	28	64
2019 April	33	9	42
2019 March	38	19	57
2019 February	33	30	63
2019 January	37	25	62
2018 December	50	36	86
2018 November	130	69	199
2018 October	175	26	201
2018 September	47	10	57
2018 August	15	5	20
2018 July	22	5	27
2018 June	25	9	34
2018 May	12	5	17
2018 April	21	10	31
2018 March	21	3	24
2018 February	18	7	25
2018 January	33	13	46
2017 December	29	3	32
2017 November	33	10	43
2017 October	36	6	42
2017 September	24	7	31
2017 August	26	10	36
2017 July	22	6	28
2017 June	24	9	33
2017 May	26	8	34
2017 April	30	17	47
2017 March	26	8	34
2017 February	18	5	23
2017 January	13	3	16
2016 December	15	6	21
2016 November	20	13	33
2016 October	42	13	55
2016 September	39	11	50
2016 August	26	5	31
2016 July	12	9	21
2016 January	1	0	1
2015 December	2	0	2

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