Association of carbohydrate 125 antigen with sepsis mortality in critical patients

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Carbohydrate antigen 125 &#40;CA125&#41; is a glycoprotein synthesized by mesothelial cells located mainly in the pleura&#44; peritoneum&#44; pericardium&#44; and internal male and female reproductive organs&#46; It has classically been considered a marker in ovarian tumours&#59; however&#44; serum increases in this biomarker have been described in other neoplasms &#40;breast&#44; colon&#44; lung&#44; pancreas&#44; uterus&#44; endometrium&#44; cervix&#41;&#44; in benign diseases &#40;pancreatitis&#44; tuberculosis&#44; pelvic inflammatory disease&#44; endometriosis&#41;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;4</span></a> and in certain physiological conditions &#40;menstruation&#44; first trimester of pregnancy&#41;&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The pathophysiological mechanisms by which serum levels of CA125 are elevated are not fully established&#46; The increase in its synthesis has been related to the presence of serous congestion&#44; mechanical stress and&#47;or proinflammatory stimuli that would act on mesothelial cells<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#8211;7</span></a>&#46; This immuno-inflammatory activity has been demonstrated in both in vitro<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> and human<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> studies&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">There are few studies that establish a relationship between the levels of CA125 and certain acute infectious conditions&#46; Among them&#44; abdominal infections stand out&#44; proposing its use as a marker of severity in appendicitis or other conditions that involve peritoneal irritation<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#8211;12</span></a>&#46; Serum levels of CA125 in infections occurring at other sites have not been extensively studied&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Sepsis is a nosological entity characterised by&#44; among other pathophysiological features&#44; a systemic inflammatory state and a propensity for interstitial oedema<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;14</span></a>&#46; However&#44; its pathogenesis&#44; involving complex molecular-cellular-inflammatory pathways&#44; remains controversial and a subject of study&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The main objective of this study is to analyse the association of CA125 with sepsis mortality in critically ill patients&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Patients and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Study design and population</span><p id="par0030" class="elsevierStylePara elsevierViewall">A longitudinal prospective observational study was carried out in the adult medical-surgical Intensive Care Unit &#40;ICU&#41; of the Manises Hospital&#44; between January 2017 and March 2019&#46; Manises Hospital is a regional hospital with 325 beds&#44; 10 of which are for the ICU&#44; providing care for a total population of 195&#44;000 inhabitants&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The study population included all patients admitted to the ICU with a diagnosis of sepsis of any aetiology in the period under review&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The exclusion criteria were the following&#58; age under 18&#44; pregnancy or postpartum period&#44; patients with active ovarian cancer&#44; and patients with a previous &#8220;withholding&#47;withdrawal of life support&#8221; decision or order&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The design and conduct of the study complied with the recommendations on biomedical research involving human subjects contained in the Declaration of Helsinki&#44; endorsed by the General Assembly of the World Medical Association &#40;1996&#41;&#46; The investigators adhered at all times to the ethical requirements necessary to carry out the research&#46; The Research Committee of the Hospital de Manises and the Hospital Universitario y Polit&#233;cnico La Fe approved the suitability of the study&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Data collection</span><p id="par0050" class="elsevierStylePara elsevierViewall">To study the characteristics of septic patients and the potential risk factors related to their prognosis&#44; as well as the clinical impact&#44; the following variables were collected&#58; age&#44; sex&#44; patient origin &#40;classified as ED&#44; operating room&#44; ward&#41;&#44; days of ICU stay&#44; days of hospital stay&#44; clinical outcome &#40;ICU death&#44; in-hospital death or hospital discharge&#41;&#44; cardiovascular risk factors &#40;hypertension&#44; obesity&#44; dyslipidaemia&#44; diabetes mellitus&#44; smoking&#44; alcoholism&#41;&#44; the existence of previous diagnosed chronic disease &#40;COPD&#44; chronic liver disease&#44; chronic renal failure&#44; chronic ischaemic heart disease&#41; and cancer&#46; Infection data &#40;sepsis or septic <span class="elsevierStyleItalic">shock</span>&#44; site of the infection&#41;&#44; laboratory data during the first 7 days of admission &#40;CA125&#44; procalcitonin&#44; C-reactive protein&#44; white blood cells&#44; neutrophils&#44; lymphocytes&#44; lactate&#41; and severity indices in the first 24 h &#40;APACHE-II and SOFA&#41; for each patient&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Data analysis</span><p id="par0055" class="elsevierStylePara elsevierViewall">Patients with a diagnosis of sepsis&#47;septic <span class="elsevierStyleItalic">shock</span> within the first 24 h of ICU admission were identified by applying <span class="elsevierStyleItalic">The Third International Consensus Definitions for Sepsis and Septic Shock</span> &#40;Sepsis-3&#41;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The information was recorded between days 1 and 7 of admission&#44; with day 1 being the day of admission to the ICU&#46; Patients discharged from ICU before day 7 were monitored until discharge or death&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Quantitative determination in vitro of CA125 was performed on the ADVIA Centaur&#174; immunoassay system by direct chemiluminometric technology&#44; using 2 CA125-specific mouse monoclonal antibodies&#46; Serum samples were obtained according to standard procedures&#46; CA125 test results are expressed in units per millilitre &#40;U&#47;mL&#41; and its normal range consists of values below 35 U&#47;mL&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Statistical analysis</span><p id="par0070" class="elsevierStylePara elsevierViewall">Continuous variables were expressed as the mean &#177; 1 standard deviation or as the median &#40;interquartile range&#44; IQR&#41; when appropriate&#46; Discrete variables were presented as percentages&#46; The Chi-square test or Fisher&#39;s exact test was used to compare categorical variables between groups and Student&#8217;s t-test to compare continuous variables&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">In the initial analyses&#44; the effect of CA125 was assessed for each patient&#44; using summary measurements from the combination of each patient&#8217;s determinations over the first week of admission&#46; The effect of the presence of CA125 above 35 U&#47;mL in any determination during the first week of admission was estimated by calculating the relative risk using a Poisson regression analysis with consistent standard errors&#44; adjusting for age&#44; source of infection and APACHE- II at admission&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">A repeated measures analysis was performed to take into account the regularity of the samples studied&#46; Relative risks &#40;RR&#41; were calculated using Poisson regression models fitted with generalized estimating equations&#46; The effect of mean CA125 levels on mortality was analysed using linear regression models with random effects&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">All the significance tests were carried out bilaterally and the level of statistical significance was established when p &#60; 0&#46;05&#46; Statistical analysis was carried out with the STATA&#174; software&#44; version 12&#46;0 &#40;StataCorp&#46; 2009&#44; Stata Statistical Software&#58; Release 12&#44; StataCorp LP&#44; College Station&#44; Texas&#44; United States&#41;&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><p id="par0090" class="elsevierStylePara elsevierViewall">A total of 126 patients with a mean age of 66 years &#40;64&#8722;69&#41; were studied&#44; of whom 77 were men &#40;61&#46;1&#37;&#41;&#46; Data on origin&#44; associated comorbidity&#44; site of infection&#44; severity scale scores and patient outcomes are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; All the infection laboratory parameters&#44; with the exception of the lymphocyte levels&#44; were high&#46; The mean CA125 concentration was 53&#46;23 U&#47;mL &#40;37&#46;7&#8722;68&#41;&#44; levels above normal&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">A total of 86 patients had septic <span class="elsevierStyleItalic">shock</span> &#40;68&#46;5&#37;&#41;&#46; The distribution according to age&#44; sex&#44; origin&#44; comorbidities or source of infection of patients with sepsis or septic <span class="elsevierStyleItalic">shock</span> was similar to that of our overall cohort&#44; with no statistically significant differences&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Patients with septic <span class="elsevierStyleItalic">shock</span> had higher lactate levels &#40;3&#46;2 mmol&#47;l &#91;IQR 2&#46;2&#8722;4&#46;2&#93; septic <span class="elsevierStyleItalic">shock</span> vs&#46; 1&#46;2 &#91;IQR 1&#46;2&#8722;1&#46;7&#93; sepsis&#59; p &#61; 0&#46;020&#41;&#44; white blood cells &#40;15&#46;075 &#215; 10<span class="elsevierStyleSup">9</span>&#47;l &#91;IQR 13&#44;235&#8722;16&#44;915&#93; vs&#46; 12&#44;117 &#215; 10<span class="elsevierStyleSup">9</span>&#47;l &#91;IQR 10650&#8722;13584&#93;&#59; p &#61; 0&#46;043&#41; and procalcitonin &#40;98 &#956;g&#47;l &#91;IQR 51&#8722;146&#93; vs&#46; 10 &#956;g&#47;l &#91;IQR 5&#8722;15&#93;&#44; p &#61; 0&#46;0023&#41;&#46; Mean CA125 levels were high in both subgroups&#44; somewhat higher in patients with sepsis&#44; with this trend not being significant &#40;64&#46;5 U&#47;mL &#91;IQR 41&#46;6&#8722;87&#46;7&#93; sepsis vs&#46; 47&#46;9 &#91;IQR 27&#46;6&#8211;68&#93; septic <span class="elsevierStyleItalic">shock</span>&#59; p &#61; 0&#46;326&#41;&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The APACHE-II score &#40;21 &#91;IQR 20&#8722;23&#93; vs&#46; 16 &#91;IQR 14&#8211;16&#93;&#59; p &#61; 0&#46;001&#41; and SOFA &#40;8 &#91;IQR 7&#8211;9&#93; vs&#46; 6 &#91;IQR 5&#8211;7&#93;&#59; p &#61; 0&#46;0005&#41; was also higher in patients with septic <span class="elsevierStyleItalic">shock</span>&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Mortality was 34&#46;13&#37; &#40;n &#61; 43&#41;&#46; There were no statistically significant differences in the sepsis and septic <span class="elsevierStyleItalic">shock</span> subgroups &#40;30&#37; mortality in sepsis vs&#46; 36&#37; in septic <span class="elsevierStyleItalic">shock</span>&#59; p &#61; 0&#46;505&#41;&#46; Patients who died had a higher mean age &#40;72 years &#91;IQR 68&#8722;75&#93; vs&#46; 64 &#91;IQR 61&#8722;67&#93;&#59; p &#61; 0&#46;006&#41;&#44; higher mean lactate levels &#40;4&#46;6 &#91;IQR 2&#46;6&#8211;6&#46;6&#93; vs&#46; 1&#46;7 &#91;IQR 1&#46;5&#8722;1&#46;8&#93;&#59; p &#61; 0&#46;0001&#41; and CA125 &#40;77&#46;2 U&#47;mL &#91;IQR 35&#46;9&#8722;118&#46;5&#93; vs&#46; 40&#46;2 &#91;IQR 30&#8722;50&#46;9&#93;&#59; p &#61; 0&#46;027&#41;&#44; as well as a higher score on the APACHE-II severity scales &#40;23 &#91;IQR 22&#8722;25&#93; vs&#46; 17 &#91;IQR 16&#8722;19&#93;&#59; p &#61; 0&#46;001&#41; and SOFA &#40;8 &#91;IQR 7&#8211;9&#93; vs&#46; 7 &#91;IQR 6&#8211;7&#93;&#59; p &#61; 0&#46;004&#41; compared to the patients who survived &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Mean CA125 levels &#40;U&#47;mL&#41; were analysed over the 7-day study period&#46; The averages of these daily determinations are shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#46; CA125 concentrations remained consistently high&#44; above normal values and exhibited an upward trend&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">When comparing CA125 levels according to the site of infection &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41; we determined that&#44; with a statistically significant difference &#40;p &#61; 0&#46;001&#41;&#44; abdominal infections showed higher mean levels &#40;62 &#177; 55&#44; 5 U&#47;mL&#41;&#44; followed by pulmonary infections &#40;46&#46;82 &#177; 66&#46;1 U&#47;mL&#41;&#44; urinary tract infections &#40;42&#46;05 &#177; 123&#46;5 U&#47;mL&#41; and other infections &#40;35&#46;63 &#177; 36&#46;3 U&#47;mL&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0125" class="elsevierStylePara elsevierViewall">The results of the multivariate analysis showed that patients who had CA125 levels greater than 35 U&#47;mL during the 7 days of follow-up had a 3-fold increased risk of mortality compared to those who did not &#40;RR 3&#46;1&#59; 95&#37; CI 1&#46;6 to 6&#46;2&#44; p &#61; 0&#46;001&#41;&#46; The mean value of CA125 was also associated with mortality &#40;RR 1&#46;004&#59; 95&#37; CI 1&#46;001&#8211;1&#46;005&#59; p &#61; 0&#46;0001&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; This effect was not observed in those patients who had only one elevated marker in the study period &#40;RR 2&#46;4&#44; 95&#37; CI 0&#46;9&#8211;6&#46;4&#44; p &#61; 0&#46;08&#41; and&#44; similarly&#44; normal levels of this marker &#40;&#60;35 U&#47;mL&#41; during the entire week of follow-up were associated with a significant reduction in the risk of death &#40;RR 0&#46;3&#44; 95&#37; CI 0&#46;1 to 0&#46;9&#44; p &#61; 0&#46;03&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">The repeated measures analysis confirmed these results &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#44; showing that the number of samples in which patients had CA125 above 35 U&#47;mL was associated with an increased risk of mortality&#44; independent of age&#44; site of infection and APACHE-II score &#40;RR 2&#46;8&#59; 95&#37; CI 1&#46;2&#8211;6&#46;7&#59; p &#61; 0&#46;02&#41;&#46; Mean CA125 levels were 10&#37; higher in patients who died than in those who survived &#40;p &#61; 0&#46;003&#41;&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Discussion</span><p id="par0135" class="elsevierStylePara elsevierViewall">The mechanisms by which CA125 synthesis increases are connected with pathophysiological conditions that relate inflammation to systemic congestion&#44; both of which are also present in sepsis&#46; in vitro studies have shown that proinflammatory cytokines can stimulate human mesothelial cells to increase CA125 synthesis<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#46; In this regard&#44; Mi&#241;ana et al&#46;<span class="elsevierStyleSup">9</span> showed in their study that elevated levels of CA125 &#40;&#62;60 U&#47;mL&#41; in patients with acute heart failure were associated not only with higher levels of TNF-&#9001;&#44; IL-6 and IL-1&#44; but also with a lower relative lymphocyte count&#44; associating immuno-inflammatory activity with CA125 synthesis&#46; Therefore&#44; elevated CA125 concentrations could be expected in septic patients&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">On the other hand&#44; most pro-inflammatory cytokines are known to have a high temporal variability &#40;pulsatile release&#44; short half-life&#44; etc&#46;&#41; and their measurement techniques are not well standardised<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&#46; In contrast&#44; CA125 kinetics shows a half-life exceeding one week<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;18</span></a>&#44; which&#44; together with other properties such as its wide availability in routine clinical practice&#44; standardised determination&#44; pharmacokinetic reliability and low cost&#44; would give it some theoretical advantage to be proposed as a biomarker for the identification of high inflammatory activity&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">The present study showed that patients with sepsis had high mean levels of CA125 during the 7 days of determination&#44; with an increasing temporal trend&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">The most common site of infection in our study cohort was the abdominal site &#40;46&#46;7&#37;&#41;&#44; followed by the pulmonary site &#40;19&#46;86&#37;&#41;&#44; the urinary tract &#40;15&#46;07&#37;&#41; and other sites &#40;21&#46;42&#37;&#41;&#46; These results differ from those shown in other Spanish studies on the incidence of sepsis in ICU such as that of Blanco et al&#46; &#40;44&#46;8&#37; pulmonary site&#44; 31&#46;5&#37; abdominal site&#44; 6&#46;2&#37; urinary tract site&#44; 17&#46;5&#37; other sites&#41;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> and that of Esteban et al&#46; &#40;52&#37; pulmonary site&#44; 15&#46;1&#37; abdominal site&#44; 6&#46;1&#37; urinary tract site&#44; 26&#46;3&#37; other sites of infection&#41;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a>&#44; probably attributable to the polyvalent nature of the ICU where the study was carried out&#44; with both medical and surgical patients&#44; the latter accounting for 34&#46;92&#37; of admissions and with a prevalence of abdominal interventions&#46; For these reasons&#44; it could be thought that CA125 levels are elevated in our study as a consequence of a direct hyperstimulation of mesothelial cells&#44; especially peritoneal and pleural<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> cells&#46; However&#44; urinary tract sites of infection and other sites other than abdominal and pulmonary&#44; also showed elevated mean CA125 levels&#44; supporting the existence of a systemic proinflammatory mechanism involved in the increased synthesis of CA125 and not only produced and attributable to a local effect&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">When analysing mean CA125 levels according to the severity of the condition&#44; in relation to the presence of sepsis or septic <span class="elsevierStyleItalic">shock</span>&#44; high levels &#40;CA125 &#62; 35 U&#47;mL&#41; were observed in both subgroups&#44; with higher levels in those patients with a diagnosis of sepsis&#44; although this trend was not significant&#46; A larger sample size is probably needed to perform a more in-depth analysis of these findings&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">The ability to predict in-hospital mortality of the APACHE-II severity score in septic patients is unquestionable<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>&#46; The score of this scale was significantly higher in our study both in the subgroup of patients with septic <span class="elsevierStyleItalic">shock</span> &#40;p &#61; 0&#46;001&#41; and in patients who died &#40;p &#61; 0&#46;001&#41; and was an independent prognostic marker of mortality &#40;RR 1&#46;1&#59; 95&#37; CI 1&#46;1&#8211;1&#46;2&#59; p &#61; 0&#46;0001&#41;&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Our mortality data are analogous to those observed in the national study carried out by the Edusepsis group<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&#44; which showed that the implementation of an education program&#44; following the guidelines of the <span class="elsevierStyleItalic">Surviving Sepsis Campaign&#44;</span> results in decreased mortality from severe sepsis&#47;septic <span class="elsevierStyleItalic">shock</span>&#46; Mortality data in patients with septic <span class="elsevierStyleItalic">shock</span> are also similar to those provided by the systematic review and meta-analysis carried out by Vincent et al&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> However&#44; a lower mortality associated with post-surgical patients and a limited sample size could explain the lack of statistical significance when comparing mortality between the two subgroups&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Patients who died had higher serum CA125 levels &#40;p &#61; 0&#46;027&#41; and a multivariate analysis revealed an independent association of CA125 &#62; 35 U&#47;mL with an increased risk of death&#46; In addition&#44; normal CA125 levels &#40;&#60; 35 U&#47;mL&#41; were associated with a significant reduction in mortality &#40;RR 0&#46;3&#59; 95&#37; CI 0&#46;1 to 0&#46;9&#59; p &#61; 0&#46;03&#41;&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">We have found no studies in the medical literature reviewed that establish a relationship between serum CA125 values and critically ill septic patients&#46; Studies on CA125 and acute infections are mostly related to abdominal disease&#44; are inconsistent and divergent in their results&#44; making it difficult to add prognostic value to this biomarker or even to discern between severe and uncomplicated cases<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12&#44;24&#44;25</span></a>&#46; The use of CA125 as a biomarker in heart failure has recently been proposed<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;27</span></a>&#44; for its ability to quantify the degree of fluid overload and inflammation associated with this condition&#46; Elevated levels have been associated with the severity and prognosis of heart failure both in its stable phase and during acute decompensation<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#8211;28</span></a> and have even been proposed as a guide for treatment<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;30</span></a>&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">One of the strengths of our study is that having a sustained plasma elevation of CA125 may identify a population subgroup with a worse prognosis in sepsis&#46; Ideally&#44; a prognostic biomarker would detect the severity of the disease within the first 24 h of progression&#44; which is seen in our series&#44; as patients who died had the highest CA125 levels on the first day of determination&#46; However&#44; the behaviour in the different subgroups and the possible mechanisms involved in their synthesis and clearance are aspects to be considered in future studies&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">We believe that this study may have the following limitations&#58; it is an observational study conducted in a single centre&#44; which by design may be subject to different types of bias and residual confounding factors that we tried to limit by following the study protocol and the various multivariate analyses&#59; b&#41; CA125 levels may not always be determined over several consecutive days in actual practice&#59; c&#41; patient hydration status was not taken into account as a possible factor associated with CA125 synthesis&#59; and d&#41; with the current data&#44; we cannot address the complex pathogenic mechanisms that may be involved in the relationship between CA125&#44; sepsis and mortality&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">In conclusion&#44; septic patients had elevated CA125 levels during the study period&#44; with higher levels in infections with an abdominal origin compared to other infection sites&#46; Patients who died had higher CA125 levels than those observed in patients who survived&#46; In our study&#44; serial determination of CA125 is a prognostic marker of mortality independent of age&#44; site of infection or patient severity&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflict of interest</span><p id="par0195" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest&#46;</p></span></span>"
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          "titulo" => "References"
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    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2021-06-02"
    "fechaAceptado" => "2021-09-16"
    "PalabrasClave" => array:2 [
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1549049"
          "palabras" => array:5 [
            0 => "Carbohydrate 125 antigen"
            1 => "Biomarkers"
            2 => "Sepsis"
            3 => "Septic shock"
            4 => "Intensive care"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1549050"
          "palabras" => array:5 [
            0 => "Ant&#237;geno carbohidrato 125"
            1 => "Biomarcadores"
            2 => "Sepsis"
            3 => "Shock s&#233;ptico"
            4 => "Cuidados cr&#237;ticos"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">The increased synthesis of CA125 in mesothelial cells is connected with pathophysiological processes&#44; also present in sepsis&#44; that link inflammation with systemic congestion&#46; We propose to evaluate serum levels of this biomarker in patients with sepsis and to study its association with the severity and evolution of the disease&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Longitudinal retrospective observational study&#44; which included 126 patients admitted to an Intensive Care Unit with sepsis criteria&#46; The main variables analyzed were&#58; CA125 values for 7 days&#44; the variation of its levels according to the source of infection &#40;abdominal&#44; pulmonary&#44; nephrourinary and others&#41;&#44; sepsis&#44; septic shock&#44; APACHE-II score and mortality&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">CA125 levels remained elevated throughout the study period&#46; The abdominal focus presented higher mean levels of CA125 &#40;62 &#177; 55&#46;5 U&#47;mL&#59; P &#61; 0&#46;001&#41; and were higher in non-survivors &#40;77&#46;2 U&#47;mL&#59; interquartile range 35&#46;9&#8722;118&#46;5&#59; <span class="elsevierStyleItalic">P</span> &#61; 0&#46;0273&#41;&#46; CA125 levels &#62; 35 U&#47;mL throughout the weal had an independently effect on the evolution &#40;relative risk &#91;RR&#93; 3&#46;1&#59; 95&#37; confidence interval &#91;CI&#93; 1&#46;6&#8211;6&#46;2&#59; <span class="elsevierStyleItalic">P</span> &#61; 0&#46;001&#41; and the elevated mean value of CA125 was also associated with mortality &#40;RR 1&#46;004&#59; 95&#37; CI 1&#46;001&#8211;1&#46;005&#59; <span class="elsevierStyleItalic">P</span> &#61; 0&#46;0001&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Septic patients presented high levels of CA125 on the study days&#44; being higher in abdominal infections&#46; In our study&#44; serial determination of CA125 is a prognostic marker of mortality independent of age&#44; origin of infection or severity&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Introduction"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Methods"
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          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
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            "identificador" => "abst0020"
            "titulo" => "Conclusions"
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      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">La s&#237;ntesis aumentada de CA125 en las c&#233;lulas mesoteliales se asocia a procesos fisiopatol&#243;gicos presentes en la sepsis&#44; que relacionan la inflamaci&#243;n con la congesti&#243;n sist&#233;mica&#46; Proponemos evaluar los niveles s&#233;ricos de este biomarcador en la sepsis y estudiar su asociaci&#243;n con la gravedad y evoluci&#243;n de la enfermedad&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Estudio observacional prospectivo longitudinal que incluy&#243; a 126 pacientes que ingresaron en una unidad de cuidados intensivos con criterios de sepsis&#46; Las variables principales analizadas fueron&#58; valores de CA125 durante 7 d&#237;as&#44; foco causante de la infecci&#243;n &#40;abdominal&#44; pulmonar&#44; nefrourinario y otros&#41;&#44; sepsis&#44; shock s&#233;ptico&#44; escala APACHE-II y mortalidad&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Los niveles de CA125 se mantuvieron elevados en el per&#237;odo de estudio&#46; El foco abdominal present&#243; niveles medios de CA125 m&#225;s elevados &#40;62 &#177; 55&#44;5 U&#47;mL&#59; p &#61; 0&#44;001&#41; y fueron superiores en los pacientes que fallecieron &#40;77&#44;2 U&#47;mL&#59; rango intercuartil 35&#44;9&#8211;118&#44;5&#59; p &#61; 0&#44;0273&#41;&#46; Los niveles de CA125 &#62; 35 U&#47;mL durante toda la semana tuvieron un efecto sobre la evoluci&#243;n de forma independiente &#40;riesgo relativo &#91;RR&#93; 3&#44;1&#59; intervalo de confianza &#91;IC&#93; 95&#37; 1&#44;6 a 6&#44;2&#59; p &#61; 0&#44;001&#41; y el valor medio elevado de CA125 tambi&#233;n se asoci&#243; a la mortalidad &#40;RR 1&#44;004&#59; IC 95&#37; 1&#44;001&#8722;1&#44;005&#59; p &#61; 0&#44;0001&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Los pacientes s&#233;pticos presentaron unos niveles elevados de CA125 en los d&#237;as de estudio&#44; siendo superiores en infecciones de foco abdominal&#46; En nuestro estudio&#44; la determinaci&#243;n seriada de CA125 es un marcador pron&#243;stico de mortalidad independiente de la edad&#44; el origen de la infecci&#243;n o la gravedad&#46;</p></span>"
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            "identificador" => "abst0035"
            "titulo" => "Resultados"
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            "titulo" => "Conclusiones"
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      0 => array:8 [
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        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1081
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        "detalles" => array:1 [
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            "identificador" => "at0005"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Time course &#40;days 1 to 7&#41; of the mean levels of CA125 &#40;U&#47;mL&#41;&#46;</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">No&#46;&#58; number of determinations&#59; IQR&#58; interquartile range&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Variability in CA125 levels according to the site of infection&#46;</p>"
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          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">APACHE-II&#58; <span class="elsevierStyleItalic">Acute Physiology and Chronic Health Evaluation II&#59;</span> COPD&#58; chronic obstructive pulmonary disease&#59; HTN&#58; arterial hypertension&#59; CKD&#58; chronic kidney disease&#59; IQR&#58; interquartile range&#59; SOFA&#58; <span class="elsevierStyleItalic">Sequential Organ Failure Assessment&#59;</span> ICU&#58; Intensive care unit&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Data highlighted in italics refer to a statistically significant p-value &#40;p &#60; 0&#46;005&#41;&#46;</p>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Variables&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Overall &#40;N &#61; 126&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Deceased &#40;n &#61; 43&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">64 &#40;59&#8722;68&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">36 &#40;41&#46;86&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hospitalization&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Comorbidities&#44; n &#40;&#37;&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>HTN&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Diabetes mellitus&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Dyslipidemia&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Obesity&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">35 &#40;27&#46;78&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">8 &#40;22&#46;86&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Active smoker&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Alcoholism&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Liver disease&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Ischemic heart disease&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Site of infection&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Pulmonary&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Biliary&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Urinary tract&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Abdominal&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Central nervous system&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Laboratory results&#44; median &#40;IQR&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>CA125 &#40;U&#47;mL&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>WBCs &#40;&#215;10<span class="elsevierStyleSup">9</span>&#47;l&#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">14&#44;136 &#40;12&#44;787&#8722;15&#44;485&#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
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                  \t\t\t\t">12&#44;117 &#40;10&#44;650&#8722;13&#44;584&#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">15&#44;075 &#40;13&#44;235&#8722;16&#44;915&#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
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                  \t\t\t\t">0&#44;043&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">14&#44;887 &#40;131&#44;543&#8722;16&#44;619&#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">12&#44;687 &#40;10&#44;552&#8722;14&#44;822&#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">0&#46;1266&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Neutrophils &#40;mm<span class="elsevierStyleSup">3</span>&#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">11&#44;052 &#40;9868&#8722;12&#44;237&#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
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                  \t\t\t\t">9666 &#40;8335&#8722;10&#44;998&#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
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                  \t\t\t\t">11&#44;720 &#40;10&#44;088&#8722;13&#44;352&#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">0&#44;1081&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">11&#44;771 &#40;10&#44;246&#8722;13&#44;297&#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">9714 &#40;7851&#8722;11&#44;577&#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">0&#46;1013&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Lymphocytes &#40;mm<span class="elsevierStyleSup">3</span>&#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">880 &#40;777&#8722;983&#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
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                  \t\t\t\t">800 &#40;663&#8722;937&#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">918 &#40;780&#8722;1055&#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">0&#46;2959&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">909 &#40;806&#8722;1013&#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">825 &#40;592&#8722;1058&#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">0&#46;4429&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Procalcitonin &#40;&#956;g&#47;l&#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">70 &#40;37&#8722;103&#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">10 &#40;5&#8722;15&#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">98 &#40;51&#8722;146&#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
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                  \t\t\t\t"><span class="elsevierStyleItalic">0&#46;0132</span>&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">74 &#40;32&#8722;117&#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">62 &#40;7&#46;4&#8722;117&#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">0&#46;7202&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>C-reactive protein &#40;mg&#47;l&#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">213 &#40;196&#8722;230&#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">198 &#40;168&#8722;228&#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">220 &#40;200&#8722;240&#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">0&#46;2225&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">212 &#40;190&#8722;234&#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">214 &#40;189&#8722;240&#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">0&#46;9042&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">APACHE-II&#44; median &#40;IQR&#41;</span>&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">20 &#40;18&#8722;21&#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">16 &#40;14&#8722;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-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21 &#40;20&#8722;23&#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"><span class="elsevierStyleItalic">0&#46;001</span>&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">17 &#40;16&#8722;19&#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">23 &#40;22&#8722;25&#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">0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">SOFA&#44; median &#40;IQR&#41;</span>&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;49 &#40;6&#46;89&#8722;8&#46;08&#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">5&#46;9 &#40;5&#46;1&#8722;6&#46;8&#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">8&#46;19 &#40;7&#46;4&#8722;8&#46;9&#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"><span class="elsevierStyleItalic">0&#46;0005</span>&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">6&#46;8 &#40;6&#46;16&#8722;7&#46;6&#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">8&#46;6 &#40;7&#46;6&#8722;9&#46;6&#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">0&#46;0042&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">ICU stay &#40;days&#41;&#44; median &#40;IQR&#41;</span>&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">9&#46;2 &#40;3&#46;3&#8722;15&#46;07&#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">5&#46;6 &#40;3&#46;9&#8722;7&#46;29&#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">10&#46;89 &#40;2&#46;3&#8722;19&#46;4&#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">0&#46;471&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">9&#46;7 &#40;0&#46;95&#8722;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-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#46;2 &#40;4&#46;5&#8722;12&#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">0&#46;8167&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Hospital stay &#40;days&#41;&#44; median &#40;IQR&#41;</span>&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">27 &#40;15&#8722;38&#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
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