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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Ventilator-associated pneumonia &#40;VAP&#41; is defined as a type of pneumonia established 48<span class="elsevierStyleHsp" style=""></span>h after endotracheal intubation&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> VAP is a frequent complication found in intensive care patients receiving mechanical ventilation&#46; About 15&#37; of patients exposed to intubation show pneumonia symptoms<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#59; however&#44; the incidence of pneumonia can vary widely between studies&#46; A recent multicenter observational study conducted in Italy revealed that the incidence of VAP in hospitalized COVID-19 patients was estimated at 29&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Therefore&#44; the high frequency and severity of the disease make VAP one of the most important and common causes of death related to hospital-acquired conditions&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Respiratory assistance in intensive care units &#40;ICUs&#41; is necessary because of the individual&#39;s inability to breathe without mechanical assistance&#46; In this context&#44; the hospitalized patients&#39; oral microenvironment can function as a reservoir of opportunistic microorganisms&#44;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> propagating bacteria from the oral cavity toward the lungs&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Also&#44; poor oral hygiene&#44; reduced natural cleaning mechanism of the mouth&#44; and low salivary flow can contribute to the imbalance of the oral microflora&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Reducing the oral colonization of microorganisms might be a potential mechanism to control VAP&#46; Many clinical trials reported that routine oral care with chlorhexidine &#40;CHX&#41; substantially reduced the number of VAP episodes in ICU patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> CHX is a broad-spectrum antiseptic agent with bacteriostatic and bactericidal activity and a low potential for inducing dermatological reactions&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> CHX has been widely used in clinical practice for preventing VAP&#44; either as a gel or as an aqueous solution&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">However&#44; a recent systematic review by Klompas et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> revealed no significant difference in ventilator-associated pneumonia risk in double-blind studies of non-cardiac surgery patients&#46; Rabello et al&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> also showed inconsistency in a recent overview evaluating 14 systematic reviews and meta-analyses with high-quality evidence&#46; The authors showed that CHX effectively prevented nosocomial pneumonia among adults in cardiothoracic ICU but not in other clinical-surgical units&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">This systematic review evaluated randomized clinical trials of mechanically ventilated patients in ICU &#40;patients&#41;&#44; being applied any dosage form of chlorhexidine &#40;intervention&#41; in comparison to patients that did not receive any drug &#40;comparison&#41;&#46; VAP incidence&#44; all-cause mortality&#44; ICU length of stay&#44; and mechanical ventilation duration were the variables investigated &#40;outcomes&#41;&#46; Recent RCTs &#40;randomized clinical trials&#41; were included&#44; and the proposed eligibility criteria and stratification substantially reduced the sources of heterogeneity&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Methods</span><p id="par0030" class="elsevierStylePara elsevierViewall">This systematic review followed the Cochrane<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> and PRISMA<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> criteria for systematic reviews and meta-analyses&#46; Registration in the PROSPERO database was accomplished under submission&#58; CRD42020209760 and title&#58; &#34;Does oral care with chlorhexidine reduce the Incidence of ventilator-associated pneumonia and all-cause mortality in intensive care unit patients&#63; A systematic review and meta-analysis&#34;&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Data sources and searches methods</span><p id="par0035" class="elsevierStylePara elsevierViewall">The appraised databases were PubMed&#44; Cochrane Library&#44; and EMBASE&#46; An additional investigation was conducted by searching the included articles&#8217; references&#44; previous meta-analyses&#44; Google scholar&#44; and ClinicalTrials&#46;gov&#46; The selection of the terms was based on satellite articles&#46; The complete search strategy is presented in the supplementary material &#40;Table S1&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Two independent reviewers &#40;JCC and CKM&#41; screened the titles and abstracts extracted from the databases&#46; Any disagreement was addressed to a third reviewer &#40;JEVP&#41;&#46; The searches started in February 2019 and were updated on January 1st&#44; 2022&#46; Endnote software was used to manage citations and identify duplicates&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Study selection</span><p id="par0045" class="elsevierStylePara elsevierViewall">The review was based on the following PICO strategy&#58; 1&#46; <span class="elsevierStyleBold">Population&#58;</span> intensive care unit patients receiving mechanical ventilation&#59; 2&#46; <span class="elsevierStyleBold">Intervention&#58;</span> oral application of chlorhexidine&#46; 3&#46; <span class="elsevierStyleBold">Comparison&#58;</span> intubated intensive care unit patients that did not receive any pharmaceutical formulation containing antiseptic agents with proven activity&#59; 4&#46; <span class="elsevierStyleBold">Outcomes&#58;</span> all-cause mortality&#44; the incidence of VAP&#44; ICU length of stay&#44; and days of mechanical ventilation&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The studies were selected according to the search strategy with the following inclusion criteria&#58; 1&#41; randomized clinical trials applying any dosage form of chlorhexidine&#59; 2&#41; daily administration of CHX&#59; 3&#41; no restriction of date or location&#59; 4&#41; mechanically ventilated patients for at least 48<span class="elsevierStyleHsp" style=""></span>h&#59; 5&#41; publication period analysis until January 1st&#44; 2022&#46; The exclusion criteria included&#58; 1&#41; studies related to <span class="elsevierStyleItalic">in vitro</span> methodology&#59; 2&#41; studies containing chlorhexidine preparations in both control and intervention arms&#59; 3&#41; studies presented only in the abstract form&#59; 4&#41; Studies conducted in pediatric ICU&#59; 5&#41; studies containing only pre-operatively administration of CHX&#59; 6&#41; studies using substances with known antiseptic activity in the control arm&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Data extraction and quality assessment</span><p id="par0055" class="elsevierStylePara elsevierViewall">The extracted data were analyzed individually in an orderly fashion&#44; and the collected information was obtained in a standardized design&#46; The following data were gathered from the articles&#58; authorship&#44; location of study&#44; number of patients&#44; intervention&#44; and control characteristics &#40;pharmaceutical form and concentrations&#44; additional teeth brushing&#41;&#46; The data collection was entered in an Excel spreadsheet &#40;Excel&#44; Microsoft&#44; Washington&#44; USA&#41; by one author &#40;JCC&#41;&#44; and all information was verified by another reviewer &#40;JEVP&#41;&#46; No efforts were made to contact the authors regarding incomplete data&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The quality of the included trials was appraised by the Cochrane criteria<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> to assess the risk of bias in 6 domains &#40;<span class="elsevierStyleItalic">i&#46;e&#46;</span>&#44; sequence generation&#44; allocation concealment&#44; blinding&#44; incomplete outcome data&#44; selective outcome reporting&#44; and other bias&#41;&#46; Review Manager 5&#46;2&#46;7 software &#40;Cochrane Collaboration&#44; Oxford&#44; United Kingdom&#41; was used to generate the risk of bias summary and graph&#46; The funnel plot was also created to suggest reporting bias&#46; Based on the information extracted from each trial&#44; the studies were classified as high&#44; low&#44; or unclear risk of bias &#40;when not enough details were reported&#41;&#46; Two independent reviewers made these classifications &#40;JCC and CKM&#41;&#44; and any disagreements were solved by consensus&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Data synthesis and analysis</span><p id="par0065" class="elsevierStylePara elsevierViewall">The incidence of ventilator-associated pneumonia was set as the primary outcome&#46; All-cause mortality&#44; duration of mechanical ventilation&#44; and ICU length of stay were selected as the secondary outcome&#46; Subgroup analyses were performed to avoid heterogeneity&#46; The influence of the CHX concentration was also appraised by conducting an additional analysis with the studies stratified according to the antiseptic dosage&#46; The tests for subgroup differences were also appraised for this setup&#46; These further analyses aimed to facilitate the comparison with other studies and investigate the influence of clinical parameters on the VAP outcomes&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Review Manager 5&#46;2&#46;7 software &#40;Cochrane Collaboration&#44; Oxford&#44; United Kingdom&#41; was used to perform the quantitative synthesis&#46; The weighted relative risk &#40;for the incidence of VAP and mortality&#41; and mean difference &#40;for ICU length of stay and mechanical ventilation duration&#41; were calculated using the generic inverse variance random-effects model&#46; The I&#178;&#44; tau&#178; and chi&#178; statistical tests were used to estimate heterogeneity&#46; Forest plots were constructed for each outcome and all data were calculated considering a confidence interval &#40;CI&#41; of 95&#37; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; Stratification was performed based on the study&#8217;s blindness for the VAP incidence and all-cause mortality&#46; Sub-group analysis was not assessed for ICU length of stay and mechanical ventilation duration due to a lack of available data&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Results</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Description of included studies</span><p id="par0075" class="elsevierStylePara elsevierViewall">The search strategy identified 2661 studies&#44; of which 1005 were duplicates&#46; After assessing the eligibility criteria&#44; ten studies were included in the meta-analysis &#40;including 1233 patients&#41;&#46; Fig&#46; S1 shows the PRISMA flowchart for the summarized results&#46; The main characteristics of each study are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Table S2 shows detailed quantitative data of the studies included in this review&#44; and Table S3 presents the information about trials not included in the meta-analysis&#44; including the reasons for exclusion&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">Chlorhexidine concentration&#44; control arm&#44; location of studies&#44; and brushing</p><p id="par0085" class="elsevierStylePara elsevierViewall">Four studies applied 0&#46;12&#37; CHX solution&#44;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;18&#44;19&#44;23</span></a> three trials employed CHX at a concentration of 0&#46;2&#37;&#44;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;20&#44;22</span></a> and three studies used CHX at a concentration of 2&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16&#44;21</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Besides the placebo &#40;considered when the control maintained the same organoleptic conditions as the control&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;19&#44;21&#44;23</span></a> saline&#44;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;22</span></a> sterile water&#44;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> and potassium permanganate<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> solutions were also used in the control group&#46; Some studies described the control arm as &#34;usual care&#34; or oral foam&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Petroleum jelly<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> was also used as the control arm when CHX gel was administered as the intervention&#46; Two studies<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;21</span></a> described brushing the patients&#39; teeth with a toothbrush&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Studies were carried out on almost all continents&#46; America&#58; Brazil&#44;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#44;21</span></a> US&#44;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Europe&#58; Turkey&#44;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a> Netherlands<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>&#59; Asia&#58; India&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Thailand&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Iran&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> and Oceania&#58; Australia&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> Among them&#44; five &#40;Brazil&#44; India&#44; Thailand&#44; Iran&#44; and Turkey&#41; are low and middle-income countries&#44; and three &#40;US&#44; Netherlands&#44; and Australia&#41; are considered high-income countries</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Quantitative data</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Incidence of VAP</span><p id="par0100" class="elsevierStylePara elsevierViewall">Ten studies containing 1233 patients receiving oral application of CHX to prevent VAP were identified&#46; The meta-analysis showed that CHX was effective to reduce VAP &#40;0&#46;73 &#91;0&#46;55&#44; 0&#46;97&#93; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;03&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A<span class="elsevierStyleBold">&#41;</span>&#46; The heterogeneity for the analysis was&#58; Tau&#178;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;08&#59; Chi&#178;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>15&#46;27&#44; df<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;08&#41;&#59; I&#178;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>41&#37;&#46; The RR for VAP incidence assessing only double-blind studies resulted in lower RR&#58; 0&#46;65 &#91;0&#46;49&#44; 0&#46;87&#93; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0005&#46; The hetoregeneity for this assay was considered negligible&#58; Tau&#178;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;00&#59; Chi&#178;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;11&#44; df<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;68&#41;&#59; I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#37;&#46; The RR appraised for the incidence of VAP including only studies that was not fully blinded was 0&#46;85 &#91;0&#46;49&#44; 1&#46;46&#93; &#40;p&#61;0&#46;55&#41;&#46; The heterogeneity in this test was considered moderate&#58; Tau&#178;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;21&#59; Chi&#178;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#46;47&#44; df<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span> 0&#46;03&#41;&#59; I&#178;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>62&#37;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">The CHX concentration did not result in differences in VAP incidence according to the tests for subgroup differences &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;80&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">All-cause mortality</span><p id="par0110" class="elsevierStylePara elsevierViewall">Six studies involving 718 patients receiving oral application of CHX were identified&#46; CHX did not influence mortality rates in critically ill patients&#46; The RR risk of all-cause mortality for CHX were&#58; 1&#46;13 &#91;0&#46;96&#44; 1&#46;32&#93; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;14&#46; The heterogeneity was considered neglible&#58; Tau&#178;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;00&#59; Chi&#178;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;98&#44; df<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5 &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;55&#41;&#59; I&#178;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#37;&#41;&#46; The RR for the Incidence of VAP assessing only double-blind studies were&#58; 0&#46;99 &#91;0&#46;72&#44; 1&#46;36&#93; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;95 &#40;Heterogeneity&#58; Tau&#178;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;02&#59; Chi&#178;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;73&#44; df<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2 &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;26&#41;&#59; I&#178;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>27&#37;&#41;&#46; The RR appraised for the Incidence of VAP including only studies that was not fully blinded were&#58; 1&#46;20 &#91;0&#46;98&#44; 1&#46;46&#93; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;08 &#40;Heterogeneity&#58; Tau&#178;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;00&#59; Chi&#178;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;29&#44; df<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2 &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;86&#41;&#59; I&#178;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">ICU length of stay and days of mechanical ventilation</span><p id="par0115" class="elsevierStylePara elsevierViewall">CHX administration had no effect in the in the ICU length of stay &#40;mean difference 0&#46;06 &#91;1&#46;72&#44; 1&#46;68&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span> 0&#46;63&#93;&#41; <span class="elsevierStyleBold">&#40;</span><a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41; and mechanical ventilation duration &#40;mean difference 0&#46;00 &#91;-2&#46;05&#44; 2&#46;04&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;00&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41; in patients receiving endotracheal intubation&#46; No subgroup analysis was performed due to the reduced number of available data&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Risk of bias</span><p id="par0120" class="elsevierStylePara elsevierViewall">Of the total trials included&#44; five were double-blinded&#44;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16&#44;18&#44;19</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> two were single-blinded&#44;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;23</span></a> and three were open-label&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;17&#44;21</span></a> Less studies reported mortality &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#41; than VAP incidence &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41;&#44; suggesting reporting bias&#46; At least half of the included trials presented some concerns regarding missing outcome data&#46; 60&#37; of the studies showed some drawbacks in the randomization process&#46; Only 50&#37; of the RCTs presented low risk of bias &#40;overall&#41;&#46; Fig&#46; S2 shows the risk of bias summary and graph of all included studies&#46; No publication bias was observed &#40;Fig&#46; S3&#41;&#46;</p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Discussion</span><p id="par0125" class="elsevierStylePara elsevierViewall">This systematic review and meta-analysis assumed that oral care with CHX in ICU patients could be beneficial in preventing VAP&#46; Based on the available literature and the eligibility criteria&#44; our data revealed that the daily application of oral CHX resulted in a reduction of 27&#37; in the number of VAP cases&#46; These results are in accordance with other meta-analyses that showed similar RR&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;24&#44;25</span></a> The heterogeneity was considered negligible when only double-blinded trials were included &#40;I&#178;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#41; and moderate for the overall analysis &#40;I&#178;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>41&#37;&#41;&#46; Differences in the severity of the disease&#44; patient&#39;s baseline characteristics&#44; study design&#44; hospital structure&#44; frequency of CHX administration and other factors could be a source of heterogeneity between studies&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">To evaluate the influence of the CHX concentration on the VAP outcomes&#44; an additional investigation was also conducted&#46; However&#44; the percentage of CHX in the formulations did not affect the overall analysis &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;80&#41;&#46; In this context&#44; even the lower concentrations of CHX &#40;0&#46;12&#37;&#41; afforded a significant reduction in the number of VAP episodes&#46; Although CHX in the concentration of 0&#46;2 and 2&#37; did not show a statistically significant reduction in VAP incidence&#44; it might be related to the number of enrolled studies&#46; Therefore&#44; a definitive statement about the best percentage of CHX was not claimed &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B&#41;&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Concerning mortality&#44; the safety of routine oral care with CHX to reduce VAP incidence must be interpreted with awareness&#46; Although the proximity of the lower limit of the confidence interval observed in the overall analysis &#40;1&#46;13 &#91;0&#46;96&#44; 1&#46;32&#93;&#41; revealed a sign that CHX could negatively affect mortality&#44; the double-blinded studies indicated no effect in the mortality ratios &#40;0&#46;99 &#91;0&#46;72&#44; 1&#46;36&#93;&#41;&#46; However&#44; our analysis revealed that some studies did not report mortality rates&#46; While VAP is complex to assess due to subjectivity&#44; high inter-observer variability&#44; and false positives&#59; mortality is an objective outcome and is simpler and more patient-centered&#46; Therefore&#44; the discrepancy in the number of articles reporting both effects might suggest a reporting bias&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Moreover&#44; some authors state that the antiseptic activity of CHX might select resistant bacteria towards the lungs&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;27</span></a> Kampf<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> showed that exposure to sub-lethal CHX concentrations might enhance resistance in <span class="elsevierStyleItalic">Acinetobacter</span> spp&#46;&#44; <span class="elsevierStyleItalic">K&#46; pneumoniae</span>&#44; and <span class="elsevierStyleItalic">Pseudomonas</span> spp&#46; &#40;known species for emerging antibiotic resistance and high mortality rate&#41;&#46; Zhang et al&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> also showed increased resistance to chlorhexidine and colistin in <span class="elsevierStyleItalic">Klebsiella</span> strains&#46; The cepA gene expression was upregulated in the adapted strains&#44; suggesting a cross-sectional adaptive resistance to chlorhexidine&#46; Another potential explanation for the CHX harm is that some patients may aspirate small amounts of chlorhexidine&#44; leading to acute lung injury and acute respiratory distress syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">The results related to mortality could be conflicting because the evaluated patients in the trials involved in this review were critically ill by trauma&#44; surgery&#44; or other condition&#46; In this context&#44; the mortality ratios could be more related to the severity of the disease rather than the development of a respiratory infection&#44; especially in non-blinded and small studies&#46; Therefore&#44; we propose that new trials focus on the safety of CHX in further studies&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">No significant difference regarding the mean duration of mechanical ventilation and ICU length of stay was observed&#46; These results might be underpowered due to the lack of available evidence&#46; Some studies reported these outcomes as the median and the interquartile ranges&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;21&#44;23</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Our review showed similar results compared to a recent meta-analysis<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> evaluating the impact of CHX on preventing VAP&#46; Differences in effects could be related to the eligibility criteria&#46; We decided not to include patients in pediatric ICU and receiving a pre-operatively application of CHX as it could lead to a potential source of heterogeneity&#46; Although the review by Klompas et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> showed no benefit of using CHX to prevent VAP&#44; this article included only a few trials due to the restricted inclusion criteria &#40;double-blind studies with non-cardiac patients&#41;&#44; giving wide confidence intervals&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Also&#44; other reviews included patients that were expected &#40;but not mandatory&#41; to be mechanically ventilated for at least 48<span class="elsevierStyleHsp" style=""></span>h &#40;which is the minimum time required for a VAP diagnostic&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;25</span></a> Therefore&#44; some patients &#40;especially those who underwent cardiac surgery&#41; might have been extubated within one day&#44; which could interfere with the number of patients able to be diagnosed with VAP&#44; compromising the meta-analysis&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;25&#44;30&#8211;32</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">Although the analysis showed clear benefits of oral care with CHX to prevent ventilator-associated pneumonia in critically ill patients&#44; our study presented several limitations&#46; First&#44; some papers could be missed as they were not available in English&#46; In addition&#44; the studies included in this meta-analysis reported different subjective diagnostic criteria to characterize VAP&#46; This lack of pattern could cause significant variations across trials&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Currently&#44; the CDC &#40;Centers for diseases control&#41; has developed a more objective criterion&#44; namely VAE &#40;ventilator-associated events&#41;&#44; to diagnose worsening oxygenation in mechanically ventilated patients&#46; This new outcome has been suggested to replace VAP for monitoring intubated patients&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Different protocols were also used concerning the CHX application&#46; While some articles described the application of CHX &#40;either in solution or as a gel&#41; in gauzes or swabs&#44; other studies brushed the patient&#39;s teeth several times&#46; In this context&#44; some studies have stratified their data according to brushing&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> However&#44; recent meta-analyses revealed that brushing does not affect the incidence of VAP or all-cause mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;24&#44;34</span></a> Even though brushing is an important issue&#44; our study focused only on whether adding any concentration of CHX was beneficial compared to oral care alone&#46; Therefore&#44; our review did not compare oral regimens and brushing frequency differences&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Besides study blinding&#44; incomplete data was also a major limiting factor&#46; Regarding the duration of mechanical ventilation and ICU length of stay&#44; only a fraction of the articles reported these outcomes&#46; Some studies did not report mortality ratios&#44;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16&#44;20&#44;23</span></a> which is more accessible and objective than VAP incidence&#44; suggesting reporting bias&#46; Also&#44; we identified that the randomization process was also a source of limitation&#46; In most trials&#44; information about sequence generation and allocation concealment was not properly reported&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">As only a few studies presented high risk of bias&#44; we believe that the quality of the evidence remained moderate concerning the application of CHX to reduce the VAP incidence&#46; For all-cause mortality&#44; we support that this outcome had a very low quality of evidence&#46; First&#44; we identified that some articles did not declare mortality ratios&#46; Also&#44; the confidence interval of this outcome was very large and the number of events was low&#44; suggesting significant imprecision&#46; For the duration of mechanical ventilation and ICU length of stay&#44; we state that the quality of evidence was deficient as few articles were included&#44; and the information regarding the patient&#39;s discharge was unclear in most studies&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Future research should adhere to the Consolidated Standards of Reporting Trials &#40;CONSORT&#41; statement to improve study quality and report mortality and incidence ratios related to VAE instead of VAP&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Concluding remarks</span><p id="par0195" class="elsevierStylePara elsevierViewall">This systematic review and meta-analysis showed that CHX was beneficial in preventing VAP in critically ill patients&#46; However&#44; no conclusion could be made on mortality rates because the quality of the evidence was very low&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Authors contribution</span><p id="par0200" class="elsevierStylePara elsevierViewall">Conceptualization&#58; Jonas Cruz&#44; Carolina Martins&#44; Jonathas Piassi&#44; Idelmo j&#250;nior&#44; Joel J&#250;nior&#44; Leonardo Faverani</p><p id="par0205" class="elsevierStylePara elsevierViewall">Methodology&#58; Jonas Cruz&#44; Carolina Martins&#44; Jonathas Piassi&#44;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Formal analysis&#58; Jonas Cruz&#44; Carolina Martins&#44; Jonathas Piassi&#44; Idelmo j&#250;nior&#44; Joel J&#250;nior&#44; Leonardo Faverani</p><p id="par0215" class="elsevierStylePara elsevierViewall">Investigation&#58; Jonas Cruz&#44; Carolina Martins&#44; Jonathas Piassi&#44; Idelmo j&#250;nior&#44; Joel J&#250;nior&#44; Leonardo Faverani</p><p id="par0220" class="elsevierStylePara elsevierViewall">Writing original&#58; Jonas Cruz&#44; Carolina Martins&#44; Jonathas Piassi&#44; Idelmo j&#250;nior&#44; Joel J&#250;nior&#44; Leonardo Faverani</p><p id="par0225" class="elsevierStylePara elsevierViewall">Writing review&#58; Jonas Cruz&#44; Joel J&#250;nior&#44; Leonardo Faverani</p><p id="par0230" class="elsevierStylePara elsevierViewall">Project administration&#58; Jonas Cruz&#44; Joel J&#250;nior&#44; Leonardo Faverani</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0185">Role of funding source</span><p id="par0235" class="elsevierStylePara elsevierViewall">This work was supported financially by the Funda&#231;&#227;o de Amparo &#224; Pesquisa do Estado de S&#227;o Paulo &#40;FAPESP&#44; S&#227;oPaulo&#44; Brazil&#41;&#44; the Conselho Nacional de Desenvolvimento Cient&#237;fico e Tecnol&#243;gico &#40;CNPq&#44; Bras&#237;lia&#44; Brazil&#41;&#46; The funding sources had no impact in the design&#44; conduct&#44; or reporting of the article or the decision to publish the study&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0190">Conflict of interest</span><p id="par0240" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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            3 => "Neumon&#237;a asociada a ventilador"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">This study aimed to investigate chlorhexidine&#8217;s efficacy in preventing ventilator-associated pneumonia &#40;VAP&#41;&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Design</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">A systematic review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Settings</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">The data were obtained from Pubmed&#44; Cochrane Library&#44; and EMBASE&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Patients or participants</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Only mechanically ventilated patients for at least 48<span class="elsevierStyleHsp" style=""></span>h were included&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Interventions</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Randomized clinical trials applying any dosage form of chlorhexidine were eligible&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Main variables of interest</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">The relative risk &#40;RR&#41; of the VAP incidence and all-cause mortality was assessed using the random-effects model&#46; The mean difference in days of mechanical ventilation duration and intensive care unit &#40;ICU&#41; length of stay were also appraised&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Results</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Ten studies involving 1233 patients were included in the meta-analysis&#46; The oral application of CHX reduced the incidence of VAP &#40;RR&#44; 0&#46;73 &#91;95&#37; CI&#44; 0&#46;55&#44; 0&#46;97&#93;&#41; and did not show an increase in all-cause mortality &#40;RR&#44; 1&#46;13 &#91;95&#37; CI&#44; 0&#46;96&#44; 1&#46;32&#93;&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conclusions</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">CHX proved effective to prevent VAP&#46; However&#44; a conclusion on mortality rates could not be drawn because the quality of the evidence was very low for this outcome&#46;</p></span>"
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        "resumen" => "<span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Objetivo</span><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Este estudio tuvo como objetivo investigar la eficacia de la clorhexidina en la prevenci&#243;n de la neumon&#237;a asociada al ventilador &#40;NAV&#41;&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Dise&#241;o</span><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">se realiz&#243; una revisi&#243;n sistem&#225;tica y un metan&#225;lisis siguiendo los elementos de informe &#40;PRISMA&#41; Preferred Reporting Items for Systematic Reviews and Meta-Analyses&#46;</p></span> <span id="abst0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">&#193;mbito</span><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Los datos se obtuvieron de Pubmed&#44; Cochrane Library y EMBASE&#46;</p></span> <span id="abst0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Pacientes o participantes</span><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">solo se incluyeron pacientes con ventilaci&#243;n mec&#225;nica durante al menos 48 horas&#46;</p></span> <span id="abst0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Intervenciones</span><p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Fueron elegibles los ensayos cl&#237;nicos aleatorios que aplicaban cualquier forma de dosificaci&#243;n de clorhexidina&#46;</p></span> <span id="abst0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Variables de inter&#233;s principales</span><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Se evalu&#243; el riesgo relativo &#40;RR&#41; de incidencia de NAVM y mortalidad por todas las causas mediante el modelo de efectos aleatorios&#46; Tambi&#233;n se evalu&#243; la diferencia media en los d&#237;as de duraci&#243;n de la ventilaci&#243;n mec&#225;nica y la duraci&#243;n de la estancia en la unidad de cuidados intensivos &#40;UCI&#41;&#46;</p></span> <span id="abst0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Resultados</span><p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Diez estudios con 1233 pacientes se incluyeron en el metan&#225;lisis&#46; La aplicaci&#243;n oral de CHX redujo la incidencia de VAP &#40;RR&#44; 0&#44;73 &#91;IC 95&#37;&#44; 0&#44;55&#44; 0&#44;97&#93;&#41; y no mostr&#243; un aumento en la mortalidad por todas las causas &#40;RR&#44; 1&#44;13 &#91;IC 95&#37;&#44; 0&#44;96&#44; 1&#44;32&#93;&#46;</p></span> <span id="abst0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conclusiones</span><p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">CHX demostr&#243; ser eficaz para prevenir la VAP&#46; Sin embargo&#44; no se pudo establecer una conclusi&#243;n sobre las tasas de mortalidad porque la calidad de la evidencia fue muy baja para este resultado&#46;</p></span>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Forest plot of the mechanical ventilation duration&#46;</p>"
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            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="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Reference&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Country&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Intervention&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Control&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Brushing&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Blindness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Koeman et al&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Netherlands&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#37; gel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vaseline petroleum jelly&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Double&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tantipong et al&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Thailland&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#37; solution &#40;4&#215;&#47;day&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Saline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Double&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Panchabhai et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">India&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;2&#37; solution &#40;twice&#47;day&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Potassium permangnate 0&#46;01&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Open&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Scannapieco et al&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">USA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;12&#37; solution &#40;twice&#47;day&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oral foam&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Double&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bellissimo-Rodrigues et al&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Brazil&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;12&#37; solution &#40;3&#215;&#47;day&#59; 15<span class="elsevierStyleHsp" style=""></span>ml&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Double&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Berry et al&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Autralia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;2&#37; solution &#40;twice&#47;day&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sterile water&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Single&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Meinberg et al&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Brazil&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#37; gel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Open&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#214;z&#231;aka et al&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Turkey&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;2&#37; solution &#40;4&#215;&#47;day&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Saline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Double&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Meidani et al&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Iran&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;12&#37; solution &#40;3&#215;&#47;day&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Open&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Kes et al&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Turkey&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;12&#37; solution &#40;3&#215;&#47;day&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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