Meta-analysis of the effects of normal saline on mortality in intensive care | Revista Española de Anestesiología y Reanimación (English Edition)

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"apellidos" => "Dierssen-Soto" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Medicina Intensiva, Hospital Universitario Marqués de Valdecilla, Santander, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Departamento de Medicina Preventiva y Salud Pública, Facultad de Medicina de la Universidad de Cantabria, Santander, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Metaanálisis de los efectos del suero salino en la mortalidad en cuidados intensivos" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1769 "Ancho" => 2502 "Tamanyo" => 162977 ] ] "descripcion" => array:1 [ "en" => "Forest plot showing the fluid therapy-kidney failure correlation." ] ] ] "textoCompleto" => "IntroductionSaline solution (SS) has been the most widely used resuscitation and maintenance fluid in intensive care units (ICU) for several decades<a class="elsevierStyleCrossRef" href="#bib0150">1</a>; however, like other fluids, its safety and efficacy has not been formally evaluated.<a class="elsevierStyleCrossRef" href="#bib0155">2</a> Now, deeper understanding of the physiopathology of fluids and glycocalyx<a class="elsevierStyleCrossRef" href="#bib0160">3</a> and of hyperchloraemia, metabolic acidosis and acute renal failure associated with their use has reversed this trend.<a class="elsevierStyleCrossRefs" href="#bib0165">4,5</a> The use of balanced crystalloid solutions, which are more similar to the electrolytic composition of plasma, can have benefits due in part to their lower chlorine content.<a class="elsevierStyleCrossRefs" href="#bib0175">6,7</a>However, the results of studies aimed at identifying clinical differences between the use of SS and balanced solutions have been inconsistent. Some show that balanced solutions, compared with fluids with a high chlorine content, reduced the risk of acute renal failure, the need for renal replacement therapies, coagulopathy, and the need for blood transfusion. Others, however, have shown no benefit.<a class="elsevierStyleCrossRefs" href="#bib0185">8–11</a>The aim of this meta-analysis has been to evaluate the effect of SS on mortality compared with balanced solutions in an intensive care unit (ICU).Material and methodsWe performed a sequential meta-analysis of controlled, randomized clinical trials and prospective studies evaluating mortality rates in ICU patients receiving SS. Studies performed in adults (age 18 years or over) admitted to the ICU were included. The study intervention was the administration of crystalloids (balanced or unbalanced) for fluid maintenance or resuscitation. The primary outcome measure was any cause mortality in the ICU or hospital. The most frequent cutoff points were 28- or 60-day mortality.The following bibliographic search engines were used: Medline, Embase, Cochrane Library, ISI Proceedings, and Web of Science, using the following MeSH terms: “saline”, “normal saline”, “isotonic saline”, “balanced crystalloids”, “balanced solutions” and “adult”, combined with the “AND” operator. The following limits were applied: “Adult-all”, “Human” and “Clinical Trial-all”. The search was extended to include related terms, based on the bibliography initially retrieved (“low-chloride solutions”, “high-chloride solutions”, etc.). Initially, all articles published up to December 2017 that met the inclusion criteria were selected.The search was performed by 2 researchers independently, with no language limitations. Any discrepancies were resolved by a third investigator. Finally, a complementary search was performed of the bibliography of the foregoing sources.Exclusion criteria were: irrelevant studies (no information on the fluid therapy used); review studies, such as commentaries or editorials; and studies with no mortality data or studies not performed in the ICU setting.Data extractionData were extracted independently by 2 researchers (AGC, MOL); any disagreements were resolved by consensus within the group.The data from each article was calculated according to a standardized formula. The odds ratio (OR) of each trial was included, together with its 95% confidence intervals (95% CI).We assessed the risk of bias for each trial using the Cochrane risk of bias tool.<a class="elsevierStyleCrossRef" href="#bib0205">12</a>Data analysisThe OR and its 95% CI was calculated by weighting the inverse of the variance. Heterogeneity was measured with I2, using the fixed effects model for I2 of less than 25% and the random effect model for I2 above this level.<a class="elsevierStyleCrossRefs" href="#bib0210">13,14</a> Publication bias was detected using the Egger test,<a class="elsevierStyleCrossRef" href="#bib0220">15</a> with significance set at p<0.01, and graphically using funnel plot analysis.<a class="elsevierStyleCrossRef" href="#bib0225">16</a> To verify the influence of individual studies on the overall result, we performed a “leave one out” sensitivity analysis, repeating our calculations after studies were eliminated one by one. Data analysis was performed using STATA v. 14.ResultsUsing our search criteria, after eliminating duplicates, 187 publications were identified, of which 71 were eligible for more detailed evaluation. After checking the methodology, 63 articles did not meet any of the inclusion criteria and were excluded, leaving 8 studies for the analysis of mortality (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>The risk of bias of each study is shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Two of the selected studies (Wu et al.<a class="elsevierStyleCrossRef" href="#bib0230">17</a> and Van Zyl et al.<a class="elsevierStyleCrossRef" href="#bib0235">18</a>), although providing mortality data, did not contribute to the final results of the meta-analysis because no deaths were recorded in any of the study groups.The 8 articles included in the meta-analysis were Wu et al.<a class="elsevierStyleCrossRef" href="#bib0230">17</a>, Van Zyl et al.<a class="elsevierStyleCrossRef" href="#bib0235">18</a>, Yunos et al.<a class="elsevierStyleCrossRef" href="#bib0195">10</a>, Young et al.<a class="elsevierStyleCrossRef" href="#bib0240">19</a>, Young et al.<a class="elsevierStyleCrossRef" href="#bib0200">11</a>, Semler et al.<a class="elsevierStyleCrossRef" href="#bib0245">20</a>, Verma et al.<a class="elsevierStyleCrossRef" href="#bib0250">21</a>, and Semler et al.<a class="elsevierStyleCrossRef" href="#bib0255">22</a>. <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> summarizes the main characteristics of the selected articles.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>A meta-analysis of the results showed that administration of SS increased the risk of death (OR 1.08, 95% CI 1.005–1.17) vs. administration of balanced crystalloids (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Given the significant heterogeneity of the studies included (I2=0%), we used a fixed effects model. The Egger test showed no statistically significant differences (p=0.539) (funnel plot in <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). In the sensitivity analysis (<a class="elsevierStyleCrossRef" href="#sec0045">Supplementary Table 1</a> available online), none of the studies substantially modified the overall result when it was eliminated from the meta-analysis.<elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia>The meta-analysis of kidney failure outcomes showed no association between the use of SS and the development of kidney failure (OR 1.00, 95% CI 0.99–1.09) (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>). The results of the comparative analysis are shown in <a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>.<elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia>DiscussionThis meta-analysis shows a significant increase in ICU mortality associated with the use of SS in the ICU compared to the administration of balanced crystalloids.These results are consistent with earlier studies that,<a class="elsevierStyleCrossRef" href="#bib0260">23</a> after analysing the choice of fluids in the initial phases of sepsis, showed that combining a balanced solution with saline for resuscitation reduced in-hospital mortality of septic shock patients from 20.2% to 17.17% (p>0.001) without increasing costs or length of hospital stay.<a class="elsevierStyleCrossRef" href="#bib0185">8</a> In this respect, concerns have already been raised regarding the use of SS in the resuscitation of critical patients.<a class="elsevierStyleCrossRef" href="#bib0265">24</a>From a physiological point of view, the fact that balanced fluids are more similar to the homeostatic composition of bodily fluids than unbalanced fluids seems a sufficiently sound biological reason for lower mortality with balanced crystalloid solutions vs. SS.<a class="elsevierStyleCrossRefs" href="#bib0185">8,25</a>In this context, there is solid evidence that administering resuscitation solutions with above normal levels of chlorine to critical patients causes hyperchloraemia and acidosis. These solutions increased the incidence of kidney failure and mortality in our patients.<a class="elsevierStyleCrossRef" href="#bib0235">18</a> However, our data did not clarify the relationship between the development of renal failure and the use of SS. Further evidence is provided by the observation that hyperchloraemia has been associated with mortality irrespective of the volume of resuscitation fluids administered.<a class="elsevierStyleCrossRef" href="#bib0275">26</a>Based on the clinical implications of these effects, the British Consensus Guidelines on Intravenous Fluid Therapy for Adult Surgical Patients recommends that balanced crystalloids be used routinely instead of isotonic saline in most settings.<a class="elsevierStyleCrossRef" href="#bib0280">27</a>Our study has several limitations that must be considered. The greatest limitation derives from the fact that blinding was inadequate in half the studies analyzed. In fact, double blinding, considered appropriate, has been used in only 3 studies, which account for less that 10% of the meta-analysis.<a class="elsevierStyleCrossRefs" href="#bib0190">9,11,13,15</a> It is also important to point out that in many of the studies performed in intensive care, the patients’ primary diagnosis differed greatly from their underlying disease. A particular treatment may be beneficial for one subset of patients, but detrimental for another.<a class="elsevierStyleCrossRef" href="#bib0285">28</a>Although SS is undoubtedly needed in intensive care units, it is no less true, in the light of our results and those of recent studies,<a class="elsevierStyleCrossRef" href="#bib0290">29</a> that its effects should not be underestimated, and it use should be protocolised.In other words, eliminating the routine use of a predetermined resuscitation and maintenance fluid could be the only measure needed to increase patient survival. The greatest advantage of this measure is its cost-effectiveness, which is far removed from the major expenditure that is often needed to introduce new treatment technologies (extracorporeal circulation systems, organ replacement therapy devices, etc.).In conclusion, based on our results, SS should be used with due caution in the ICU.Conflicts of interestDr Alejandro González-Castro acknowledges a possible conflict of interest in having collaborated with the Baxter company. The authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres1135238" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and method" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1067336" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1135237" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción y objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y método" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1067337" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Material and methods" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Data extraction" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Data analysis" ] ] ] 6 => array:2 [ "identificador" => "sec0025" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0030" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0035" "titulo" => "Conflicts of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-02-26" "fechaAceptado" => "2018-06-26" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1067336" "palabras" => array:5 [ 0 => "Normal saline" 1 => "Balanced crystalloids" 2 => "Meta-analysis" 3 => "Mortality" 4 => "Fluids" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1067337" "palabras" => array:5 [ 0 => "Suero salino" 1 => "Cristaloides balanceados" 2 => "Metaanálisis" 3 => "Mortalidad" 4 => "Fluidos" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Introduction and objectiveTo evaluate, by means of a meta-analysis, the effect of normal saline on mortality in intensive care patients, when compared with the use of balanced crystalloids. Material and methodPublished controlled clinical trials, randomized and sequential prospective studies in time, evaluating the mortality when physiological saline was used in patients admitted to intensive care units. Electronic search was performed in Medline, Embase, Cochrane Library, ISI Proceedings, and Web of Science, as well as a manual search of selected references. An independent evaluation was performed by 2 investigators. Discrepancies were resolved by consensus in the working group. Contingency tables were performed, and the OR with confidence intervals of each study were obtained. Heterogeneity was assessed by I2. Publication bias was assessed using funnel plot and Egger test. ResultsA total of 8 articles were selected for the meta-analysis of mortality, which included a total of 20,684 patients. A significant association was observed between the use of saline and mortality in intensive care patients (OR 1.0972; 95% CI 1.0049–1.1979), when compared to the use of balanced crystalloids. No statistical evidence of publication bias (Egger, P=.5349) was found. In the sensitivity analysis, none of the studies substantially modified the overall outcome if it was eliminated from the meta-analysis. ConclusionsThere may be an increase in mortality associated with the use of saline in patients admitted to intensive care when comparing with the use of balanced crystalloids." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and method" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "Introducción y objetivoEvaluar, mediante un metaanálisis, el efecto del suero salino sobre la mortalidad en los pacientes de cuidados intensivos, cuando se compara su uso con el de cristaloides balanceados. Material y métodoSe ha realizado un metaanálisis de ensayos clínicos controlados, aleatorizados y estudios prospectivos secuenciales en el tiempo, publicados, que evaluaron la mortalidad del suero salino en enfermos ingresados en unidades de cuidados intensivos. Se llevó a cabo una búsqueda electrónica en Medline, Embase, biblioteca Cochrane, ISI Proceedings y Web of Science y una búsqueda manual sobre las referencias seleccionadas. La extracción de datos fue realizada de forma independiente por 2 investigadores. Las discrepancias se resolvieron por consenso en el grupo de trabajo. El cálculo de la OR y su intervalo de confianza se realizó ponderando por el inverso de la varianza. La heterogeneidad se evaluó mediante I2. El sesgo de publicación se valoró mediante funnel plot y test de Egger. ResultadosSe seleccionaron 8 artículos para el metaanálisis de mortalidad, que incluían un total de 20.684 pacientes. Se objetivó una asociación entre el uso de suero salino y la mortalidad en los enfermos de cuidados intensivos (OR 1,0972; IC 95%:1,0049–1,1979) cuando se comparaba con el uso de cristaloides balanceados. No se encontró evidencia de sesgo de publicación (prueba de Egger p=0,5349). En el análisis de sensibilidad ninguno de los estudios modificó sustancialmente el resultado global si se eliminaba del metaanálisis. ConclusionesEs posible que exista un aumento de la mortalidad asociada al empleo de suero salino en los pacientes ingresados en cuidados intensivos cuando se compara con el empleo de cristaloides balanceados." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción y objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y método" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: González-Castro A, Ortiz-Lasa M, Rodriguez-Borregan JC, Escudero-Acha P, Chicote E, Suberviola B, et al. Metaanálisis de los efectos del suero salino en la mortalidad en cuidados intensivos. Rev Esp Anestesiol Reanim. 2019;66:3–9." ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "This article is part of the Anaesthesiology and Resuscitation Continuing Medical Education Program. An evaluation of the questions on this article can be made through the Internet by accessing the Education Section of the following web page: <a class="elsevierStyleInterRef" target="_blank" id="intr0010" href="https://www.elsevier.es/redar">https://doi.org/www.elsevier.es/redar</a>" ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "The following are the supplementary data to this article:<elsevierMultimedia ident="upi0005"></elsevierMultimedia>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0045" ] ] ] ] "multimedia" => array:50 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1578 "Ancho" => 1585 "Tamanyo" => 97410 ] ] "descripcion" => array:1 [ "en" => "Study flow chart." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1740 "Ancho" => 2502 "Tamanyo" => 156349 ] ] "descripcion" => array:1 [ "en" => "Forest plot showing the fluid therapy-mortality correlation." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1152 "Ancho" => 1583 "Tamanyo" => 60675 ] ] "descripcion" => array:1 [ "en" => "Funnel plot showing the fluid therapy-mortality correlation." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1769 "Ancho" => 2502 "Tamanyo" => 162977 ] ] "descripcion" => array:1 [ "en" => "Forest plot showing the fluid therapy-kidney failure correlation." ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 1152 "Ancho" => 1583 "Tamanyo" => 61543 ] ] "descripcion" => array:1 [ "en" => "Funnel plot showing the fluid therapy-kidney failure correlation." ] ] 5 => array:9 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: Higgins et al.<a class="elsevierStyleCrossRef" href="#bib0205">12</a>" "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Red: high risk of bias. Green: low risk of bias. ?: Uncertain risk of bias" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Wu et al.<a class="elsevierStyleCrossRef" href="#bib0230">17</a>, 2011 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Yunos et al.<a class="elsevierStyleCrossRef" href="#bib0205">12</a>, 2012 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Van Zyl et al.<a class="elsevierStyleCrossRef" href="#bib0235">18</a>, 2012 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Young et al.<a class="elsevierStyleCrossRef" href="#bib0240">19</a>, 2014 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Young et al.<a class="elsevierStyleCrossRef" href="#bib0200">11</a>, 2015 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Verma et al.<a class="elsevierStyleCrossRef" href="#bib0250">21</a>, 2016 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Semler et al.<a class="elsevierStyleCrossRef" href="#bib0245">20</a>, 2016 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Semler et al.<a class="elsevierStyleCrossRef" href="#bib0255">22</a>, 2018 \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sequence generation (selection bias) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="201901100607335461"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="201901100607335462"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="201901100607335463"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="201901100607335464"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="201901100607335465"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="201901100607335466"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="201901100607335467"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="201901100607335468"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Allocation concealment (selection bias) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="201901100607335469"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354610"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354611"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354612"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354613"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354614"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354615"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354616"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Blinding of participants and staff (execution bias) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354617"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354618"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354619"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354620"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354621"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354622"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354623"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354624"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Blinding of outcome assessment (detection bias) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354625"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">? \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354626"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">? \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">? \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">? \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">? \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">? \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Incomplete outcome data (withdrawal bias) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354627"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354628"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354629"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354630"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354631"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354632"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354633"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354634"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Selective outcome reports (information bias) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354635"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354636"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354637"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354638"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354639"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354640"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354641"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><elsevierMultimedia ident="2019011006073354642"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1936715.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Assessment of the risk of bias in each trial using the Cochrane tool." ] ] 6 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "DKA: diabetic ketoacidosis; MC: multicentre: PL: Plasmalyte; RL: Ringer Lactate; SC: single centre." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Authors \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Year \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Number of patients \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Number of study centres \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Disease studied \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of balanced solution \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Follow-up period \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Wu et al.<a class="elsevierStyleCrossRef" href="#bib0230">17</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2011 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pancreatitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hospitalization \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Van Zyl et al.<a class="elsevierStyleCrossRef" href="#bib0235">18</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2012 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">57 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DKA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hospitalization \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Yunos et al.<a class="elsevierStyleCrossRef" href="#bib0195">10</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2012 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1533 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">UC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Combination \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RL+PL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hospitalization \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Young et al.<a class="elsevierStyleCrossRef" href="#bib0240">19</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2014 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">65 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Trauma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30 days \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Young et al.<a class="elsevierStyleCrossRef" href="#bib0200">11</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2015 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2262 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Combination \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hospitalization \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Semler et al.<a class="elsevierStyleCrossRef" href="#bib0245">20</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2016 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">974 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Combination \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RL or PL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30 days \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Verma et al.<a class="elsevierStyleCrossRef" href="#bib0250">21</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2016 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">70 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Combination \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hospitalization \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Semler et al.<a class="elsevierStyleCrossRef" href="#bib0255">22</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2017 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15,802 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Combination \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RL or PL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hospitalization \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1936714.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Main characteristics of the studies included in the meta-analysis." ] ] 7 => array:5 [ 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Original article

Meta-analysis of the effects of normal saline on mortality in intensive care

Metaanálisis de los efectos del suero salino en la mortalidad en cuidados intensivos

A. González-Castroa,

Corresponding author

e409@humv.es

Corresponding author.

, M. Ortiz-Lasaa, J.C. Rodriguez-Borregana, P. Escudero-Achaa, E. Chicotea, B. Suberviolaa, C. Blancoa, Y. Peñascoa, A. Jiménez Alfonsoa, J. Llorcab, T. Dierssen-Sotob

a Servicio de Medicina Intensiva, Hospital Universitario Marqués de Valdecilla, Santander, Spain

b Departamento de Medicina Preventiva y Salud Pública, Facultad de Medicina de la Universidad de Cantabria, Santander, Spain

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      "es" => array:1 [
        "titulo" => "Metaan&#225;lisis de los efectos del suero salino en la mortalidad en cuidados intensivos"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Forest plot showing the fluid therapy-kidney failure correlation&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Saline solution &#40;SS&#41; has been the most widely used resuscitation and maintenance fluid in intensive care units &#40;ICU&#41; for several decades<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a>&#59; however&#44; like other fluids&#44; its safety and efficacy has not been formally evaluated&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">2</span></a> Now&#44; deeper understanding of the physiopathology of fluids and glycocalyx<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">3</span></a> and of hyperchloraemia&#44; metabolic acidosis and acute renal failure associated with their use has reversed this trend&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">4&#44;5</span></a> The use of balanced crystalloid solutions&#44; which are more similar to the electrolytic composition of plasma&#44; can have benefits due in part to their lower chlorine content&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">6&#44;7</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">However&#44; the results of studies aimed at identifying clinical differences between the use of SS and balanced solutions have been inconsistent&#46; Some show that balanced solutions&#44; compared with fluids with a high chlorine content&#44; reduced the risk of acute renal failure&#44; the need for renal replacement therapies&#44; coagulopathy&#44; and the need for blood transfusion&#46; Others&#44; however&#44; have shown no benefit&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">8&#8211;11</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The aim of this meta-analysis has been to evaluate the effect of SS on mortality compared with balanced solutions in an intensive care unit &#40;ICU&#41;&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and methods</span><p id="par0020" class="elsevierStylePara elsevierViewall">We performed a sequential meta-analysis of controlled&#44; randomized clinical trials and prospective studies evaluating mortality rates in ICU patients receiving SS&#46; Studies performed in adults &#40;age 18 years or over&#41; admitted to the ICU were included&#46; The study intervention was the administration of crystalloids &#40;balanced or unbalanced&#41; for fluid maintenance or resuscitation&#46; The primary outcome measure was any cause mortality in the ICU or hospital&#46; The most frequent cutoff points were 28- or 60-day mortality&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The following bibliographic search engines were used&#58; Medline&#44; Embase&#44; Cochrane Library&#44; ISI Proceedings&#44; and Web of Science&#44; using the following MeSH terms&#58; &#8220;saline&#8221;&#44; &#8220;normal saline&#8221;&#44; &#8220;isotonic saline&#8221;&#44; &#8220;balanced crystalloids&#8221;&#44; &#8220;balanced solutions&#8221; and &#8220;adult&#8221;&#44; combined with the &#8220;AND&#8221; operator&#46; The following limits were applied&#58; &#8220;Adult-all&#8221;&#44; &#8220;Human&#8221; and &#8220;Clinical Trial-all&#8221;&#46; The search was extended to include related terms&#44; based on the bibliography initially retrieved &#40;&#8220;low-chloride solutions&#8221;&#44; &#8220;high-chloride solutions&#8221;&#44; etc&#46;&#41;&#46; Initially&#44; all articles published up to December 2017 that met the inclusion criteria were selected&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The search was performed by 2 researchers independently&#44; with no language limitations&#46; Any discrepancies were resolved by a third investigator&#46; Finally&#44; a complementary search was performed of the bibliography of the foregoing sources&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Exclusion criteria were&#58; irrelevant studies &#40;no information on the fluid therapy used&#41;&#59; review studies&#44; such as commentaries or editorials&#59; and studies with no mortality data or studies not performed in the ICU setting&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Data extraction</span><p id="par0040" class="elsevierStylePara elsevierViewall">Data were extracted independently by 2 researchers &#40;AGC&#44; MOL&#41;&#59; any disagreements were resolved by consensus within the group&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The data from each article was calculated according to a standardized formula&#46; The odds ratio &#40;OR&#41; of each trial was included&#44; together with its 95&#37; confidence intervals &#40;95&#37; CI&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">We assessed the risk of bias for each trial using the Cochrane risk of bias tool&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">12</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Data analysis</span><p id="par0055" class="elsevierStylePara elsevierViewall">The OR and its 95&#37; CI was calculated by weighting the inverse of the variance&#46; Heterogeneity was measured with <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span>&#44; using the fixed effects model for <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span> of less than 25&#37; and the random effect model for <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span> above this level&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">13&#44;14</span></a> Publication bias was detected using the Egger test&#44;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">15</span></a> with significance set at <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#60;</span><span class="elsevierStyleHsp" style=""></span>0&#46;01&#44; and graphically using funnel plot analysis&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">16</span></a> To verify the influence of individual studies on the overall result&#44; we performed a &#8220;leave one out&#8221; sensitivity analysis&#44; repeating our calculations after studies were eliminated one by one&#46; Data analysis was performed using STATA v&#46; 14&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Results</span><p id="par0060" class="elsevierStylePara elsevierViewall">Using our search criteria&#44; after eliminating duplicates&#44; 187 publications were identified&#44; of which 71 were eligible for more detailed evaluation&#46; After checking the methodology&#44; 63 articles did not meet any of the inclusion criteria and were excluded&#44; leaving 8 studies for the analysis of mortality &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">The risk of bias of each study is shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Two of the selected studies &#40;Wu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a> and Van Zyl et al&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">18</span></a>&#41;&#44; although providing mortality data&#44; did not contribute to the final results of the meta-analysis because no deaths were recorded in any of the study groups&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">The 8 articles included in the meta-analysis were Wu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a>&#44; Van Zyl et al&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">18</span></a>&#44; Yunos et al&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">10</span></a>&#44; Young et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">19</span></a>&#44; Young et al&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">11</span></a>&#44; Semler et al&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">20</span></a>&#44; Verma et al&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a>&#44; and Semler et al&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">22</span></a>&#46; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> summarizes the main characteristics of the selected articles&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">A meta-analysis of the results showed that administration of SS increased the risk of death &#40;OR 1&#46;08&#44; 95&#37; CI 1&#46;005&#8211;1&#46;17&#41; vs&#46; administration of balanced crystalloids &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Given the significant heterogeneity of the studies included &#40;<span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#37;&#41;&#44; we used a fixed effects model&#46; The Egger test showed no statistically significant differences &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;539&#41; &#40;funnel plot in <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; In the sensitivity analysis &#40;<a class="elsevierStyleCrossRef" href="#sec0045">Supplementary Table 1</a> available online&#41;&#44; none of the studies substantially modified the overall result when it was eliminated from the meta-analysis&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">The meta-analysis of kidney failure outcomes showed no association between the use of SS and the development of kidney failure &#40;OR 1&#46;00&#44; 95&#37; CI 0&#46;99&#8211;1&#46;09&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46; The results of the comparative analysis are shown in <a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Discussion</span><p id="par0090" class="elsevierStylePara elsevierViewall">This meta-analysis shows a significant increase in ICU mortality associated with the use of SS in the ICU compared to the administration of balanced crystalloids&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">These results are consistent with earlier studies that&#44;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">23</span></a> after analysing the choice of fluids in the initial phases of sepsis&#44; showed that combining a balanced solution with saline for resuscitation reduced in-hospital mortality of septic shock patients from 20&#46;2&#37; to 17&#46;17&#37; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#62;</span><span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; without increasing costs or length of hospital stay&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">8</span></a> In this respect&#44; concerns have already been raised regarding the use of SS in the resuscitation of critical patients&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">24</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">From a physiological point of view&#44; the fact that balanced fluids are more similar to the homeostatic composition of bodily fluids than unbalanced fluids seems a sufficiently sound biological reason for lower mortality with balanced crystalloid solutions vs&#46; SS&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">8&#44;25</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">In this context&#44; there is solid evidence that administering resuscitation solutions with above normal levels of chlorine to critical patients causes hyperchloraemia and acidosis&#46; These solutions increased the incidence of kidney failure and mortality in our patients&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">18</span></a> However&#44; our data did not clarify the relationship between the development of renal failure and the use of SS&#46; Further evidence is provided by the observation that hyperchloraemia has been associated with mortality irrespective of the volume of resuscitation fluids administered&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">26</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Based on the clinical implications of these effects&#44; the British Consensus Guidelines on Intravenous Fluid Therapy for Adult Surgical Patients recommends that balanced crystalloids be used routinely instead of isotonic saline in most settings&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">27</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Our study has several limitations that must be considered&#46; The greatest limitation derives from the fact that blinding was inadequate in half the studies analyzed&#46; In fact&#44; double blinding&#44; considered appropriate&#44; has been used in only 3 studies&#44; which account for less that 10&#37; of the meta-analysis&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">9&#44;11&#44;13&#44;15</span></a> It is also important to point out that in many of the studies performed in intensive care&#44; the patients&#8217; primary diagnosis differed greatly from their underlying disease&#46; A particular treatment may be beneficial for one subset of patients&#44; but detrimental for another&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">28</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Although SS is undoubtedly needed in intensive care units&#44; it is no less true&#44; in the light of our results and those of recent studies&#44;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">29</span></a> that its effects should not be underestimated&#44; and it use should be protocolised&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">In other words&#44; eliminating the routine use of a predetermined resuscitation and maintenance fluid could be the only measure needed to increase patient survival&#46; The greatest advantage of this measure is its cost-effectiveness&#44; which is far removed from the major expenditure that is often needed to introduce new treatment technologies &#40;extracorporeal circulation systems&#44; organ replacement therapy devices&#44; etc&#46;&#41;&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">In conclusion&#44; based on our results&#44; SS should be used with due caution in the ICU&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflicts of interest</span><p id="par0135" class="elsevierStylePara elsevierViewall">Dr Alejandro Gonz&#225;lez-Castro acknowledges a possible conflict of interest in having collaborated with the Baxter company&#46; The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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            0 => "Suero salino"
            1 => "Cristaloides balanceados"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To evaluate&#44; by means of a meta-analysis&#44; the effect of normal saline on mortality in intensive care patients&#44; when compared with the use of balanced crystalloids&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and method</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Published controlled clinical trials&#44; randomized and sequential prospective studies in time&#44; evaluating the mortality when physiological saline was used in patients admitted to intensive care units&#46; Electronic search was performed in Medline&#44; Embase&#44; Cochrane Library&#44; ISI Proceedings&#44; and Web of Science&#44; as well as a manual search of selected references&#46; An independent evaluation was performed by 2 investigators&#46; Discrepancies were resolved by consensus in the working group&#46; Contingency tables were performed&#44; and the OR with confidence intervals of each study were obtained&#46; Heterogeneity was assessed by <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span>&#46; Publication bias was assessed using funnel plot and Egger test&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A total of 8 articles were selected for the meta-analysis of mortality&#44; which included a total of 20&#44;684 patients&#46; A significant association was observed between the use of saline and mortality in intensive care patients &#40;OR 1&#46;0972&#59; 95&#37; CI 1&#46;0049&#8211;1&#46;1979&#41;&#44; when compared to the use of balanced crystalloids&#46; No statistical evidence of publication bias &#40;Egger&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;5349&#41; was found&#46; In the sensitivity analysis&#44; none of the studies substantially modified the overall outcome if it was eliminated from the meta-analysis&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">There may be an increase in mortality associated with the use of saline in patients admitted to intensive care when comparing with the use of balanced crystalloids&#46;</p></span>"
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      "es" => array:3 [
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n y objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Evaluar&#44; mediante un metaan&#225;lisis&#44; el efecto del suero salino sobre la mortalidad en los pacientes de cuidados intensivos&#44; cuando se compara su uso con el de cristaloides balanceados&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todo</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se ha realizado un metaan&#225;lisis de ensayos cl&#237;nicos controlados&#44; aleatorizados y estudios prospectivos secuenciales en el tiempo&#44; publicados&#44; que evaluaron la mortalidad del suero salino en enfermos ingresados en unidades de cuidados intensivos&#46; Se llev&#243; a cabo una b&#250;squeda electr&#243;nica en Medline&#44; Embase&#44; biblioteca Cochrane&#44; ISI Proceedings y Web of Science y una b&#250;squeda manual sobre las referencias seleccionadas&#46; La extracci&#243;n de datos fue realizada de forma independiente por 2 investigadores&#46; Las discrepancias se resolvieron por consenso en el grupo de trabajo&#46; El c&#225;lculo de la OR y su intervalo de confianza se realiz&#243; ponderando por el inverso de la varianza&#46; La heterogeneidad se evalu&#243; mediante I<span class="elsevierStyleSup">2</span>&#46; El sesgo de publicaci&#243;n se valor&#243; mediante funnel plot y test de Egger&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se seleccionaron 8 art&#237;culos para el metaan&#225;lisis de mortalidad&#44; que inclu&#237;an un total de 20&#46;684 pacientes&#46; Se objetiv&#243; una asociaci&#243;n entre el uso de suero salino y la mortalidad en los enfermos de cuidados intensivos &#40;OR 1&#44;0972&#59; IC 95&#37;&#58;1&#44;0049&#8211;1&#44;1979&#41; cuando se comparaba con el uso de cristaloides balanceados&#46; No se encontr&#243; evidencia de sesgo de publicaci&#243;n &#40;prueba de Egger p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;5349&#41;&#46; En el an&#225;lisis de sensibilidad ninguno de los estudios modific&#243; sustancialmente el resultado global si se eliminaba del metaan&#225;lisis&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Es posible que exista un aumento de la mortalidad asociada al empleo de suero salino en los pacientes ingresados en cuidados intensivos cuando se compara con el empleo de cristaloides balanceados&#46;</p></span>"
        "secciones" => array:4 [
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            "identificador" => "abst0025"
            "titulo" => "Introducci&#243;n y objetivo"
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          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Material y m&#233;todo"
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          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
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          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusiones"
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    "NotaPie" => array:2 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Gonz&#225;lez-Castro A&#44; Ortiz-Lasa M&#44; Rodriguez-Borregan JC&#44; Escudero-Acha P&#44; Chicote E&#44; Suberviola B&#44; et al&#46; Metaan&#225;lisis de los efectos del suero salino en la mortalidad en cuidados intensivos&#46; Rev Esp Anestesiol Reanim&#46; 2019&#59;66&#58;3&#8211;9&#46;</p>"
      ]
      1 => array:2 [
        "etiqueta" => "&#9734;&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0006">This article is part of the Anaesthesiology and Resuscitation Continuing Medical Education Program&#46; An evaluation of the questions on this article can be made through the Internet by accessing the Education Section of the following web page&#58; <a class="elsevierStyleInterRef" target="_blank" id="intr0010" href="https://www.elsevier.es/redar">https&#58;&#47;&#47;doi&#46;org&#47;www&#46;elsevier&#46;es&#47;redar</a></p>"
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            "apendice" => "<p id="par0145" class="elsevierStylePara elsevierViewall">The following are the supplementary data to this article&#58;<elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary data"
            "identificador" => "sec0045"
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        ]
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Study flow chart&#46;</p>"
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        "etiqueta" => "Figure 2"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Forest plot showing the fluid therapy-mortality correlation&#46;</p>"
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        "etiqueta" => "Figure 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Funnel plot showing the fluid therapy-mortality correlation&#46;</p>"
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        "etiqueta" => "Figure 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Forest plot showing the fluid therapy-kidney failure correlation&#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="spar0065" class="elsevierStyleSimplePara elsevierViewall">Funnel plot showing the fluid therapy-kidney failure correlation&#46;</p>"
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        "etiqueta" => "Table 1"
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        "fuente" => "<span class="elsevierStyleItalic">Source</span>&#58; Higgins et al&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">12</span></a>"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Red&#58; high risk of bias&#46; Green&#58; low risk of bias&#46; &#63;&#58; Uncertain risk of bias</p>"
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                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Wu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a>&#44; 2011&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Yunos et al&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">12</span></a>&#44; 2012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Van Zyl et al&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">18</span></a>&#44; 2012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Young et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">19</span></a>&#44; 2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Young et al&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">11</span></a>&#44; 2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Verma et al&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a>&#44; 2016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Semler et al&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">20</span></a>&#44; 2016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Semler et al&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">22</span></a>&#44; 2018&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sequence generation &#40;selection bias&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="201901100607335463"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="201901100607335464"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="201901100607335465"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="201901100607335467"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="201901100607335468"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Allocation concealment &#40;selection bias&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354612"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354613"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354614"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354615"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354616"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Blinding of participants and staff &#40;execution bias&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354624"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Blinding of outcome assessment &#40;detection bias&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354625"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354626"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">&#63;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">&#63;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">&#63;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">&#63;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">&#63;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Incomplete outcome data &#40;withdrawal bias&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354628"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354629"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354630"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354631"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354632"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354633"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354634"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Selective outcome reports &#40;information bias&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354635"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354636"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354637"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354638"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354639"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354640"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354641"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><elsevierMultimedia ident="2019011006073354642"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Authors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Number of patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Number of study centres&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Disease studied&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of balanced solution&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Follow-up period&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Wu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2011&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pancreatitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hospitalization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Van Zyl et al&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">18</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">57&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DKA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hospitalization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Yunos et al&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">10</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1533&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">UC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Combination&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hospitalization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Young et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">19</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Trauma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Young et al&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">11</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2262&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Combination&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hospitalization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Semler et al&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">20</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">974&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Combination&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RL or PL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Verma et al&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Combination&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hospitalization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Semler et al&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">22</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2017&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15&#44;802&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Combination&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RL or PL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hospitalization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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