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array:23 [ "pii" => "S2173572722003162" "issn" => "21735727" "doi" => "10.1016/j.medine.2022.03.006" "estado" => "S300" "fechaPublicacion" => "2023-05-01" "aid" => "1776" "copyright" => "Elsevier España, S.L.U. and SEMICYUC" "copyrightAnyo" => "2022" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Med Intensiva. 2023;47:267-79" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:18 [ "pii" => "S2173572722003174" "issn" => "21735727" "doi" => "10.1016/j.medine.2022.02.022" "estado" => "S300" "fechaPublicacion" => "2023-05-01" "aid" => "1764" "copyright" => "Elsevier España, S.L.U. and SEMICYUC" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Med Intensiva. 2023;47:280-8" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Long-term functional outcomes of children after critical illnesses: A cohort study" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "280" "paginaFinal" => "288" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Resultados funcionales a largo plazo de los niños después de enfermedades críticas: un estudio de cohorte" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1906 "Ancho" => 1505 "Tamanyo" => 192094 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Flowchart of patient selection. 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Sánchez-García, P. Martínez-López, A.M. Gómez-González, J. Rodriguez-Capitán, R.J. Jiménez-López, J.M. García Almeida, E. Avanesi-Molina, N. Zamboschi, C. Rueda-Molina, V. Doncel-Abad, A.I. Molina-Ramos, E. Cabrera-César, I. Ben-Abdellatif, M. Gordillo-Resina, E. Pérez-Mesa, M. Nieto-González, P. Nuevo-Ortega, C. Reina-Artacho, P.L. Sánchez Fernández, M.F. Jiménez-Navarro, M.A. Estecha-Foncea" "autores" => array:21 [ 0 => array:2 [ "nombre" => "A.M." "apellidos" => "Sánchez-García" ] 1 => array:2 [ "nombre" => "P." "apellidos" => "Martínez-López" ] 2 => array:2 [ "nombre" => "A.M." "apellidos" => "Gómez-González" ] 3 => array:2 [ "nombre" => "J." "apellidos" => "Rodriguez-Capitán" ] 4 => array:2 [ "nombre" => "R.J." "apellidos" => "Jiménez-López" ] 5 => array:2 [ "nombre" => "J.M." "apellidos" => "García Almeida" ] 6 => array:2 [ "nombre" => "E." "apellidos" => "Avanesi-Molina" ] 7 => array:2 [ "nombre" => "N." "apellidos" => "Zamboschi" ] 8 => array:2 [ "nombre" => "C." "apellidos" => "Rueda-Molina" ] 9 => array:2 [ "nombre" => "V." "apellidos" => "Doncel-Abad" ] 10 => array:2 [ "nombre" => "A.I." "apellidos" => "Molina-Ramos" ] 11 => array:2 [ "nombre" => "E." "apellidos" => "Cabrera-César" ] 12 => array:2 [ "nombre" => "I." "apellidos" => "Ben-Abdellatif" ] 13 => array:2 [ "nombre" => "M." "apellidos" => "Gordillo-Resina" ] 14 => array:2 [ "nombre" => "E." "apellidos" => "Pérez-Mesa" ] 15 => array:2 [ "nombre" => "M." "apellidos" => "Nieto-González" ] 16 => array:2 [ "nombre" => "P." "apellidos" => "Nuevo-Ortega" ] 17 => array:2 [ "nombre" => "C." "apellidos" => "Reina-Artacho" ] 18 => array:2 [ "nombre" => "P.L." "apellidos" => "Sánchez Fernández" ] 19 => array:2 [ "nombre" => "M.F." "apellidos" => "Jiménez-Navarro" ] 20 => array:2 [ "nombre" => "M.A." "apellidos" => "Estecha-Foncea" ] ] ] ] "resumen" => array:1 [ 0 => array:3 [ "titulo" => "Graphical abstract" "clase" => "graphical" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall"><elsevierMultimedia ident="fig0010"></elsevierMultimedia></p></span>" ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0210569122003394" "doi" => "10.1016/j.medin.2022.11.002" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0210569122003394?idApp=WMIE" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173572722003484?idApp=WMIE" "url" => "/21735727/0000004700000005/v1_202304261213/S2173572722003484/v1_202304261213/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Halogenated anesthetics vs intravenous hypnotics for short and long term sedation in the intensive care unit: A meta-analysis" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "267" "paginaFinal" => "279" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "V. Likhvantsev, G. Landoni, N. Ermokhina, M. Yadgarov, L. Berikashvili, K. Kadantseva, O. Grebenchikov, L. Okhinko, A. Kuzovlev" "autores" => array:9 [ 0 => array:4 [ "nombre" => "V." "apellidos" => "Likhvantsev" "email" => array:1 [ 0 => "lik0704@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "G." "apellidos" => "Landoni" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 2 => array:3 [ "nombre" => "N." "apellidos" => "Ermokhina" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "M." "apellidos" => "Yadgarov" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "L." "apellidos" => "Berikashvili" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 5 => array:3 [ "nombre" => "K." "apellidos" => "Kadantseva" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] 6 => array:3 [ "nombre" => "O." "apellidos" => "Grebenchikov" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 7 => array:3 [ "nombre" => "L." "apellidos" => "Okhinko" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] ] ] 8 => array:3 [ "nombre" => "A." "apellidos" => "Kuzovlev" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "V. Negovsky Reanimatology Research Institute, Moscow, Russia" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Vita-Salute San Raffaele University, Milan, Italy" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "A. Loginov Moscow Clinical Scientific Center, Moscow, Russia" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "V. Demikhov Municipal Hospital №. 68, Moscow, Russia" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Anestésicos halogenados vs. hipnóticos intravenosos para sedación a corto y largo plazo en la unidad de cuidados intensivos: un metaanálisis" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2159 "Ancho" => 2925 "Tamanyo" => 520036 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Forest plot for hospital mortality representing the odd's ratio for volatile vs. intravenous sedation effects on all-cause mortality for the included studies. The plot displays the study, sample size, odds ratio (OR), confidence interval (CI), and <span class="elsevierStyleItalic">p</span>-value. The size of the squares indicates the weight of the studies (taking into account sample size and standard deviations); the diamond represents the pooled OR with CI. Hi-QOL – studies with low–moderate risk of bias.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Sedation, ‘the act of calming patients by the administration of sedative medications’,<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> is frequently used in intensive care units (ICUs) to prevent arouse and delirium associated harm, relieve anxiety, and reduce the stress of being mechanically ventilated.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Since agitation and anxiety occurs in about 30%–80% of patients being treated in ICU settings,<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> sedation is a highly sought strategy for ICU patients.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Volatile anesthetics (VA) sedation uses isoflurane or sevoflurane to achieve the desired level of sedation.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> It is a more recent and a less frequently used strategy than the traditional intravenous strategy in the ICU setting.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> However, with the adoption of user friendly devices for VA delivery – AnaConDa (Sedana Medical, Danderyd Sweden) and MIRUS (Pall Medical, Dreieich, Germany) – VA have become increasingly popular among ICU practitioners.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,6</span></a> There are potential lungs protective properties<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7,8</span></a> and anti-inflammatory activity<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9,10</span></a> coupled with the intended endothelium-saving effect,<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,12</span></a> that contribute to an increased use of VA in the ICU. Malignant hyperthermia and possible environmental pollution are the most common drawbacks of using VA.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13,14</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Early studies confirmed safety and feasibility of VA in the ICU settings<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15,16</span></a> and a meta-analysis of randomized trials found a significant reduction in time to extubation<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> with findings confirmed in more recent systematic reviews.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The aim of this systematic review and meta-analysis was to comprehensively assess published randomized and non-randomized peer-reviewed studies which compared VA and i/v anesthetics for ICU sedation, with the hypothesis that the type of sedation may have an impact on mortality and other clinically relevant outcomes.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">This study was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Meta-analysis is registered in PROSPERO (ID: CRD42021277313).</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Search strategy</span><p id="par0030" class="elsevierStylePara elsevierViewall">A systematic search of studies published over the past 10 years (2011–2021) was carried out in PubMed, Medline, Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Google Scholar and the Russian Science Citation Index (RSCI) by four independent researchers (NE, LB, MY and KK). The search was carried out in the form of queries with details available in the supplemental material (Supplemental appendix 1). Additionally, the authors used the backward snowballing method (analysis of references of included articles and retrieved reviews) for further studies. We did not restrict search by language. Medical Subject Headings (MeSH) terms were applied.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Study selection</span><p id="par0035" class="elsevierStylePara elsevierViewall">The links obtained from the database were first independently examined at the title/annotation level by two researchers (NE and LB). Randomized controlled trials, prospective and retrospective cohort studies comparing inhaled (volatile) versus i/v sedation in the intensive care unit were considered. After removing duplicates, the appropriate publications were selected. The final decision on inclusion in this study was made based on the analysis of full-text articles. Divergences were resolved by consensus.</p><p id="par0040" class="elsevierStylePara elsevierViewall">For this study, the following inclusion criteria were used: adult patients (≥18 years) who underwent inhalation or i/v sedation in the intensive care unit (no restrictions on dose or time of administration). The exclusion criteria were mixed groups (both inhaled and i/v sedation were used), small sample size (less than 25 patients in two groups), duplicate publications, animal studies, clinical guidelines, articles without a comparison group.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Outcome measures and data extraction</span><p id="par0045" class="elsevierStylePara elsevierViewall">Basic information about the study (design, sample size, intervention plan, inclusion criteria), information about the study objects (age, gender, underlying disease and surgery), types of anesthetics and doses, target sedation level, anesthetic-conserving device, ICU treatment outcomes (mortality, duration of mechanical ventilation, troponin level at 1 postoperative day, ventilator-free days, time to extubation, awakening time, length of stay (LOS) in ICU, hospital LOS, catecholamine requirements) was collected. We have not considered the type of anesthetic used in the surgery room. The data were independently extracted by two researchers (NE and MY) and subsequently compared with each other for verification. The primary outcome of this study was all-cause mortality (30-day mortality). Secondary endpoints were: length of stay in ICU and length of hospitalization (days), duration of mechanical ventilation (days) and ventilator-free days, catecholamine requirements, cardiac troponin levels on the first postoperative day, time to extubation (min), and awakening time (min).</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Internal validity and risk of bias assessment</span><p id="par0050" class="elsevierStylePara elsevierViewall">The internal validity and risk of bias of the included studies were assessed by two peer reviewers (MY and LB) and peer-reviewed by a third (VL) according to the latest version of the “ROB 2” (the Cochrane tool for assessing risk of bias in randomized trials) and “ROBINS-I” (Risk Of Bias In Non-randomized Studies of Interventions) tools.<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20,21</span></a> Discrepancies in assessment were resolved by consensus. Publication bias was assessed using the Egger's test (MedCalc Statistical Software, version 19.5.6),<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22,23</span></a> and also by visual examination of the “funnel plot” charts. We also used a GRADE systematic approach to rate the certainty of evidence.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Two review authors (MY and LB) worked independently to assess the quality of evidence, disagreements were resolved by consensus.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Data analysis and synthesis</span><p id="par0055" class="elsevierStylePara elsevierViewall">To calculate and visualize the results of the meta-analysis in forest plots, the Cochrane tool “RevMan, version 5.3” was used. The heterogeneity of studies was assessed using the Cochran's <span class="elsevierStyleItalic">Q</span> test, and the degree of statistical agreement was measured using the coefficient of heterogeneity <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span>. The quantitative results of individual studies were brought to the form “mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>standard deviation” and the standardized difference of mean values (SMD) and its 95% confidence interval were calculated. Since many quantitative parameters in this meta-analysis a priori have a deeply skewed distribution, we used the log transformation for summary data of ventilator-free days, time to extubation, time to awakening and ICU/hospital length of stay.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> We used Cochrane handbook recommendations to re-express SMDs using rules of thumb for effect sizes (<0.40<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>small effect, 0.40–0.70<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>moderate effect, >0.70<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>large effect).<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> Binary research results were used to calculate the odds ratio with the corresponding 95% confidence interval (CI) using the inverse variance method (Mantel–Haenszel method). For a pooled estimate of the magnitude of the standardized mean difference, two models were used: a fixed-effects model (in the case of low statistical inconsistency, <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>50%) and a random-effects model (<span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>50% and/or <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05). Statistical significance was set at 0.05 for hypothesis testing.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Sensitivity analysis</span><p id="par0060" class="elsevierStylePara elsevierViewall">Sensitivity analyses were performed by considering additional subgroups – analyzing only studies with a low or moderate risk of bias (Hi-QOL studies), only RCT/non-randomized studies and by sequentially removing each study and reanalyzing the remaining data set (producing a new analysis for each study removed). Additionally, a subgroup of studies which used a prolonged sedation (>12<span class="elsevierStyleHsp" style=""></span>h) regimen was evaluated.</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Results</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Study characteristics</span><p id="par0065" class="elsevierStylePara elsevierViewall">During the initial search, 427 articles were found, of which 31 were eligible. Upon careful reading of the full-text articles, 16 studies were excluded (Supplemental Table 1). Ultimately, 15 full-text articles published between January 2011 and July 2021were included in the meta-analysis. A flowchart illustrating the study selection process is presented in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">The characteristics of the included studies are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">The meta-analysis included 1520 patients: VA (628 patients); i/v sedation (892 patients). Among the 15 included studies, 9 were RCTs. The following settings were represented: seven studies in sedation in postoperative cardiac surgery patients,<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27–29,31,34,37,39</span></a> two articles in postoperative surgical patients,<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26,32</span></a> one study in patients who were assigned to more than 24<span class="elsevierStyleHsp" style=""></span>h of mechanical ventilation sedation,<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> five studies in the intensive care unit critically ill patients (non-traumatic cardiac arrest and successful CPR,<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33,40</span></a> sepsis-associated delirium<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> and moderate to severe ARDS<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">30,35</span></a>).</p><p id="par0085" class="elsevierStylePara elsevierViewall">Fourteen included studies used the AnaConDa device in the ICU for inhaled sedation, and only one study used MIRUS.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Among the 15 included studies, 10 compared sevoflurane with propofol, 4 compared isoflurane with propofol and midazolam, and one study had multiple comparisons.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Four studies<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">30,32,36,38</span></a> used long-term sedation (12<span class="elsevierStyleHsp" style=""></span>h or more). Five of 9 RCTs and two of six non-randomized studies had medium or high quality (Supplemental Figures 1 and 2).</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Quantitative data synthesis</span><p id="par0095" class="elsevierStylePara elsevierViewall">Fourteen studies (8 RCTs) including 1453 patients reported mortality data which were not different between groups 112/609 (18.4%) in the VA group versus 202/844 (23.9%) in the i/v group (Odds Ratio (OR)<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.82 [0.60–1.12]; <span class="elsevierStyleItalic">p</span>-value for effect is 0.20; <span class="elsevierStyleItalic">p</span>-value for heterogeneity<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.15; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>34%, <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Analysis of subgroups of RCTs, non-randomized, Hi-QOL studies (studies with low–moderate risk of bias) and studies with long-term sedation did not reveal an association of sedation with mortality. Funnel plot for mortality is presented in Supplement (Supplemental Figure 3).</p><p id="par0105" class="elsevierStylePara elsevierViewall">A pooled analysis of data from five studies (606 patients, four studies with short-term sedation, two RCTs) showed that patients on VA had an increase in ventilator-free days (moderate effect size: SMD<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.46 [0.28–0.64]; <span class="elsevierStyleItalic">p</span>-value for the effect <0.001; <span class="elsevierStyleItalic">p</span>-value for heterogeneity<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.79; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0%, <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). The results were confirmed in all sub-analyses: RCTs (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.003), non-randomized (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001) and Hi-QOL studies (2 trials, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.004).</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">A pooled analysis of 987 patients (9 studies, 5 RCTs) showed that sedation with VA was associated with a reduction in duration of mechanical ventilation (SMD<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>−0.46 [−0.88 to −0.04] – moderate effect size; <span class="elsevierStyleItalic">p</span>-value for effect<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.03; <span class="elsevierStyleItalic">p</span>-value for heterogeneity <0.001; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>88%, Supplemental Figure 4, <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). The results were confirmed in Hi-QOL studies (5 trials, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001), but not when considering only RCTs (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.09) or non-randomized studies (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.29) (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). When considering only studies using prolonged sedation there was also no significant effect (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.51).</p><p id="par0115" class="elsevierStylePara elsevierViewall">Four studies with short-term sedation using sevoflurane (3 RCTs, 350 patients) reported cardiac troponin levels (1 day after surgery) with postoperative cardiac surgery patients on VA having a statistically significantly lower troponin levels (moderate effect size: SMD<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>−0.52 [from −0.84 to −0.20]; <span class="elsevierStyleItalic">p</span>-value for effect 0.001; <span class="elsevierStyleItalic">p</spa