Does chlorhexidine reduce the incidence of ventilator-associated pneumonia in ICU patients? A systematic review and meta-analysis

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A systematic review and meta-analysis" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "437" "paginaFinal" => "444" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "J.C. Cruz, C.K. Martins, J.E.V. Piassi, I.R. Garcia Júnior, J.F. Santiago Junior, L.P. Faverani" "autores" => array:6 [ 0 => array:4 [ "nombre" => "J.C." "apellidos" => "Cruz" "email" => array:1 [ 0 => "jonas-cruz@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "C.K." "apellidos" => "Martins" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "J.E.V." "apellidos" => "Piassi" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "I.R." 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Una revisión sistemática y metanálisis" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1314 "Ancho" => 3350 "Tamanyo" => 333239 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0090" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Forest plot of VAP mortality." ] ] ] "textoCompleto" => "IntroductionVentilator-associated pneumonia (VAP) is defined as a type of pneumonia established 48h after endotracheal intubation.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> VAP is a frequent complication found in intensive care patients receiving mechanical ventilation. About 15% of patients exposed to intubation show pneumonia symptoms<a class="elsevierStyleCrossRef" href="#bib0010">2</a>; however, the incidence of pneumonia can vary widely between studies. A recent multicenter observational study conducted in Italy revealed that the incidence of VAP in hospitalized COVID-19 patients was estimated at 29%.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> Therefore, 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.<a class="elsevierStyleCrossRefs" href="#bib0010">2,4</a>Respiratory assistance in intensive care units (ICUs) is necessary because of the individual's inability to breathe without mechanical assistance. In this context, the hospitalized patients' oral microenvironment can function as a reservoir of opportunistic microorganisms,<a class="elsevierStyleCrossRef" href="#bib0025">5</a> propagating bacteria from the oral cavity toward the lungs.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> Also, poor oral hygiene, reduced natural cleaning mechanism of the mouth, and low salivary flow can contribute to the imbalance of the oral microflora.<a class="elsevierStyleCrossRef" href="#bib0035">7</a>Reducing the oral colonization of microorganisms might be a potential mechanism to control VAP. Many clinical trials reported that routine oral care with chlorhexidine (CHX) substantially reduced the number of VAP episodes in ICU patients.<a class="elsevierStyleCrossRefs" href="#bib0040">8,9</a> CHX is a broad-spectrum antiseptic agent with bacteriostatic and bactericidal activity and a low potential for inducing dermatological reactions.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> CHX has been widely used in clinical practice for preventing VAP, either as a gel or as an aqueous solution.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>However, a recent systematic review by Klompas et al.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> revealed no significant difference in ventilator-associated pneumonia risk in double-blind studies of non-cardiac surgery patients. Rabello et al.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> also showed inconsistency in a recent overview evaluating 14 systematic reviews and meta-analyses with high-quality evidence. The authors showed that CHX effectively prevented nosocomial pneumonia among adults in cardiothoracic ICU but not in other clinical-surgical units.This systematic review evaluated randomized clinical trials of mechanically ventilated patients in ICU (patients), being applied any dosage form of chlorhexidine (intervention) in comparison to patients that did not receive any drug (comparison). VAP incidence, all-cause mortality, ICU length of stay, and mechanical ventilation duration were the variables investigated (outcomes). Recent RCTs (randomized clinical trials) were included, and the proposed eligibility criteria and stratification substantially reduced the sources of heterogeneity.MethodsThis systematic review followed the Cochrane<a class="elsevierStyleCrossRef" href="#bib0065">13</a> and PRISMA<a class="elsevierStyleCrossRef" href="#bib0070">14</a> criteria for systematic reviews and meta-analyses. Registration in the PROSPERO database was accomplished under submission: CRD42020209760 and title: "Does oral care with chlorhexidine reduce the Incidence of ventilator-associated pneumonia and all-cause mortality in intensive care unit patients? A systematic review and meta-analysis".Data sources and searches methodsThe appraised databases were PubMed, Cochrane Library, and EMBASE. An additional investigation was conducted by searching the included articles’ references, previous meta-analyses, Google scholar, and ClinicalTrials.gov. The selection of the terms was based on satellite articles. The complete search strategy is presented in the supplementary material (Table S1).Two independent reviewers (JCC and CKM) screened the titles and abstracts extracted from the databases. Any disagreement was addressed to a third reviewer (JEVP). The searches started in February 2019 and were updated on January 1st, 2022. Endnote software was used to manage citations and identify duplicates.Study selectionThe review was based on the following PICO strategy: 1. Population: intensive care unit patients receiving mechanical ventilation; 2. Intervention: oral application of chlorhexidine. 3. Comparison: intubated intensive care unit patients that did not receive any pharmaceutical formulation containing antiseptic agents with proven activity; 4. Outcomes: all-cause mortality, the incidence of VAP, ICU length of stay, and days of mechanical ventilation.The studies were selected according to the search strategy with the following inclusion criteria: 1) randomized clinical trials applying any dosage form of chlorhexidine; 2) daily administration of CHX; 3) no restriction of date or location; 4) mechanically ventilated patients for at least 48h; 5) publication period analysis until January 1st, 2022. The exclusion criteria included: 1) studies related to in vitro methodology; 2) studies containing chlorhexidine preparations in both control and intervention arms; 3) studies presented only in the abstract form; 4) Studies conducted in pediatric ICU; 5) studies containing only pre-operatively administration of CHX; 6) studies using substances with known antiseptic activity in the control arm.Data extraction and quality assessmentThe extracted data were analyzed individually in an orderly fashion, and the collected information was obtained in a standardized design. The following data were gathered from the articles: authorship, location of study, number of patients, intervention, and control characteristics (pharmaceutical form and concentrations, additional teeth brushing). The data collection was entered in an Excel spreadsheet (Excel, Microsoft, Washington, USA) by one author (JCC), and all information was verified by another reviewer (JEVP). No efforts were made to contact the authors regarding incomplete data.The quality of the included trials was appraised by the Cochrane criteria<a class="elsevierStyleCrossRef" href="#bib0065">13</a> to assess the risk of bias in 6 domains (i.e., sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other bias). Review Manager 5.2.7 software (Cochrane Collaboration, Oxford, United Kingdom) was used to generate the risk of bias summary and graph. The funnel plot was also created to suggest reporting bias. Based on the information extracted from each trial, the studies were classified as high, low, or unclear risk of bias (when not enough details were reported). Two independent reviewers made these classifications (JCC and CKM), and any disagreements were solved by consensus.Data synthesis and analysisThe incidence of ventilator-associated pneumonia was set as the primary outcome. All-cause mortality, duration of mechanical ventilation, and ICU length of stay were selected as the secondary outcome. Subgroup analyses were performed to avoid heterogeneity. The influence of the CHX concentration was also appraised by conducting an additional analysis with the studies stratified according to the antiseptic dosage. The tests for subgroup differences were also appraised for this setup. These further analyses aimed to facilitate the comparison with other studies and investigate the influence of clinical parameters on the VAP outcomes.Review Manager 5.2.7 software (Cochrane Collaboration, Oxford, United Kingdom) was used to perform the quantitative synthesis. The weighted relative risk (for the incidence of VAP and mortality) and mean difference (for ICU length of stay and mechanical ventilation duration) were calculated using the generic inverse variance random-effects model. The I², tau² and chi² statistical tests were used to estimate heterogeneity. Forest plots were constructed for each outcome and all data were calculated considering a confidence interval (CI) of 95% (p<0.05). Stratification was performed based on the study’s blindness for the VAP incidence and all-cause mortality. Sub-group analysis was not assessed for ICU length of stay and mechanical ventilation duration due to a lack of available data.ResultsDescription of included studiesThe search strategy identified 2661 studies, of which 1005 were duplicates. After assessing the eligibility criteria, ten studies were included in the meta-analysis (including 1233 patients). Fig. S1 shows the PRISMA flowchart for the summarized results. The main characteristics of each study are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. Table S2 shows detailed quantitative data of the studies included in this review, and Table S3 presents the information about trials not included in the meta-analysis, including the reasons for exclusion.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Chlorhexidine concentration, control arm, location of studies, and brushingFour studies applied 0.12% CHX solution,<a class="elsevierStyleCrossRefs" href="#bib0045">9,18,19,23</a> three trials employed CHX at a concentration of 0.2%,<a class="elsevierStyleCrossRefs" href="#bib0085">17,20,22</a> and three studies used CHX at a concentration of 2%.<a class="elsevierStyleCrossRefs" href="#bib0075">15,16,21</a>Besides the placebo (considered when the control maintained the same organoleptic conditions as the control),<a class="elsevierStyleCrossRefs" href="#bib0045">9,19,21,23</a> saline,<a class="elsevierStyleCrossRefs" href="#bib0080">16,22</a> sterile water,<a class="elsevierStyleCrossRef" href="#bib0100">20</a> and potassium permanganate<a class="elsevierStyleCrossRef" href="#bib0085">17</a> solutions were also used in the control group. Some studies described the control arm as "usual care" or oral foam.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> Petroleum jelly<a class="elsevierStyleCrossRef" href="#bib0075">15</a> was also used as the control arm when CHX gel was administered as the intervention. Two studies<a class="elsevierStyleCrossRefs" href="#bib0100">20,21</a> described brushing the patients' teeth with a toothbrush.Studies were carried out on almost all continents. America: Brazil,<a class="elsevierStyleCrossRefs" href="#bib0095">19,21</a> US,<a class="elsevierStyleCrossRef" href="#bib0090">18</a> Europe: Turkey,<a class="elsevierStyleCrossRefs" href="#bib0110">22,23</a> Netherlands<a class="elsevierStyleCrossRef" href="#bib0075">15</a>; Asia: India,<a class="elsevierStyleCrossRef" href="#bib0085">17</a> Thailand,<a class="elsevierStyleCrossRef" href="#bib0080">16</a> Iran,<a class="elsevierStyleCrossRef" href="#bib0080">16</a> and Oceania: Australia.<a class="elsevierStyleCrossRef" href="#bib0100">20</a> Among them, five (Brazil, India, Thailand, Iran, and Turkey) are low and middle-income countries, and three (US, Netherlands, and Australia) are considered high-income countriesQuantitative dataIncidence of VAPTen studies containing 1233 patients receiving oral application of CHX to prevent VAP were identified. The meta-analysis showed that CHX was effective to reduce VAP (0.73 [0.55, 0.97] p=0.03) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A). The heterogeneity for the analysis was: Tau²=0.08; Chi²=15.27, df=9 (p=0.08); I²=41%. The RR for VAP incidence assessing only double-blind studies resulted in lower RR: 0.65 [0.49, 0.87] p=0.0005. The hetoregeneity for this assay was considered negligible: Tau²=0.00; Chi²=3.11, df=5 (p=0.68); I2=0%. The RR appraised for the incidence of VAP including only studies that was not fully blinded was 0.85 [0.49, 1.46] (p=0.55). The heterogeneity in this test was considered moderate: Tau²=0.21; Chi²=10.47, df=4 (p= 0.03); I²=62%.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>The CHX concentration did not result in differences in VAP incidence according to the tests for subgroup differences (p=0.80) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B).All-cause mortalitySix studies involving 718 patients receiving oral application of CHX were identified. CHX did not influence mortality rates in critically ill patients. The RR risk of all-cause mortality for CHX were: 1.13 [0.96, 1.32] p=0.14. The heterogeneity was considered neglible: Tau²=0.00; Chi²=3.98, df=5 (p=0.55); I²=0%). The RR for the Incidence of VAP assessing only double-blind studies were: 0.99 [0.72, 1.36] p=0.95 (Heterogeneity: Tau²=0.02; Chi²=2.73, df=2 (p=0.26); I²=27%). The RR appraised for the Incidence of VAP including only studies that was not fully blinded were: 1.20 [0.98, 1.46] p=0.08 (Heterogeneity: Tau²=0.00; Chi²=0.29, df=2 (p=0.86); I²=0%) (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>ICU length of stay and days of mechanical ventilationCHX administration had no effect in the in the ICU length of stay (mean difference 0.06 [1.72, 1.68; p= 0.63]) (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>) and mechanical ventilation duration (mean difference 0.00 [-2.05, 2.04; p=1.00]) (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>) in patients receiving endotracheal intubation. No subgroup analysis was performed due to the reduced number of available data.<elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia>Risk of biasOf the total trials included, five were double-blinded,<a class="elsevierStyleCrossRefs" href="#bib0075">15,16,18,19</a>,<a class="elsevierStyleCrossRef" href="#bib0110">22</a> two were single-blinded,<a class="elsevierStyleCrossRefs" href="#bib0100">20,23</a> and three were open-label.<a class="elsevierStyleCrossRefs" href="#bib0045">9,17,21</a> Less studies reported mortality (n=6) than VAP incidence (n=10), suggesting reporting bias. At least half of the included trials presented some concerns regarding missing outcome data. 60% of the studies showed some drawbacks in the randomization process. Only 50% of the RCTs presented low risk of bias (overall). Fig. S2 shows the risk of bias summary and graph of all included studies. No publication bias was observed (Fig. S3).DiscussionThis systematic review and meta-analysis assumed that oral care with CHX in ICU patients could be beneficial in preventing VAP. Based on the available literature and the eligibility criteria, our data revealed that the daily application of oral CHX resulted in a reduction of 27% in the number of VAP cases. These results are in accordance with other meta-analyses that showed similar RR.<a class="elsevierStyleCrossRefs" href="#bib0030">6,24,25</a> The heterogeneity was considered negligible when only double-blinded trials were included (I²=0) and moderate for the overall analysis (I²=41%). Differences in the severity of the disease, patient's baseline characteristics, study design, hospital structure, frequency of CHX administration and other factors could be a source of heterogeneity between studies.To evaluate the influence of the CHX concentration on the VAP outcomes, an additional investigation was also conducted. However, the percentage of CHX in the formulations did not affect the overall analysis (p=0.80). In this context, even the lower concentrations of CHX (0.12%) afforded a significant reduction in the number of VAP episodes. Although CHX in the concentration of 0.2 and 2% did not show a statistically significant reduction in VAP incidence, it might be related to the number of enrolled studies. Therefore, a definitive statement about the best percentage of CHX was not claimed (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B).Concerning mortality, the safety of routine oral care with CHX to reduce VAP incidence must be interpreted with awareness. Although the proximity of the lower limit of the confidence interval observed in the overall analysis (1.13 [0.96, 1.32]) revealed a sign that CHX could negatively affect mortality, the double-blinded studies indicated no effect in the mortality ratios (0.99 [0.72, 1.36]). However, our analysis revealed that some studies did not report mortality rates. While VAP is complex to assess due to subjectivity, high inter-observer variability, and false positives; mortality is an objective outcome and is simpler and more patient-centered. Therefore, the discrepancy in the number of articles reporting both effects might suggest a reporting bias.Moreover, some authors state that the antiseptic activity of CHX might select resistant bacteria towards the lungs.<a class="elsevierStyleCrossRefs" href="#bib0130">26,27</a> Kampf<a class="elsevierStyleCrossRef" href="#bib0140">28</a> showed that exposure to sub-lethal CHX concentrations might enhance resistance in Acinetobacter spp., K. pneumoniae, and Pseudomonas spp. (known species for emerging antibiotic resistance and high mortality rate). Zhang et al.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> also showed increased resistance to chlorhexidine and colistin in Klebsiella strains. The cepA gene expression was upregulated in the adapted strains, suggesting a cross-sectional adaptive resistance to chlorhexidine. Another potential explanation for the CHX harm is that some patients may aspirate small amounts of chlorhexidine, leading to acute lung injury and acute respiratory distress syndrome.<a class="elsevierStyleCrossRef" href="#bib0055">11</a>The results related to mortality could be conflicting because the evaluated patients in the trials involved in this review were critically ill by trauma, surgery, or other condition. In this context, the mortality ratios could be more related to the severity of the disease rather than the development of a respiratory infection, especially in non-blinded and small studies. Therefore, we propose that new trials focus on the safety of CHX in further studies.No significant difference regarding the mean duration of mechanical ventilation and ICU length of stay was observed. These results might be underpowered due to the lack of available evidence. Some studies reported these outcomes as the median and the interquartile ranges.<a class="elsevierStyleCrossRefs" href="#bib0085">17,21,23</a>Our review showed similar results compared to a recent meta-analysis<a class="elsevierStyleCrossRef" href="#bib0120">24</a> evaluating the impact of CHX on preventing VAP. Differences in effects could be related to the eligibility criteria. 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. Although the review by Klompas et al.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> showed no benefit of using CHX to prevent VAP, this article included only a few trials due to the restricted inclusion criteria (double-blind studies with non-cardiac patients), giving wide confidence intervals.Also, other reviews included patients that were expected (but not mandatory) to be mechanically ventilated for at least 48h (which is the minimum time required for a VAP diagnostic).<a class="elsevierStyleCrossRefs" href="#bib0030">6,25</a> Therefore, some patients (especially those who underwent cardiac surgery) might have been extubated within one day, which could interfere with the number of patients able to be diagnosed with VAP, compromising the meta-analysis.<a class="elsevierStyleCrossRefs" href="#bib0030">6,25,30–32</a>Although the analysis showed clear benefits of oral care with CHX to prevent ventilator-associated pneumonia in critically ill patients, our study presented several limitations. First, some papers could be missed as they were not available in English. In addition, the studies included in this meta-analysis reported different subjective diagnostic criteria to characterize VAP. This lack of pattern could cause significant variations across trials.Currently, the CDC (Centers for diseases control) has developed a more objective criterion, namely VAE (ventilator-associated events), to diagnose worsening oxygenation in mechanically ventilated patients. This new outcome has been suggested to replace VAP for monitoring intubated patients.<a class="elsevierStyleCrossRef" href="#bib0165">33</a>Different protocols were also used concerning the CHX application. While some articles described the application of CHX (either in solution or as a gel) in gauzes or swabs, other studies brushed the patient's teeth several times. In this context, some studies have stratified their data according to brushing.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> However, recent meta-analyses revealed that brushing does not affect the incidence of VAP or all-cause mortality.<a class="elsevierStyleCrossRefs" href="#bib0030">6,24,34</a> Even though brushing is an important issue, our study focused only on whether adding any concentration of CHX was beneficial compared to oral care alone. Therefore, our review did not compare oral regimens and brushing frequency differences.Besides study blinding, incomplete data was also a major limiting factor. Regarding the duration of mechanical ventilation and ICU length of stay, only a fraction of the articles reported these outcomes. Some studies did not report mortality ratios,<a class="elsevierStyleCrossRefs" href="#bib0075">15,16,20,23</a> which is more accessible and objective than VAP incidence, suggesting reporting bias. Also, we identified that the randomization process was also a source of limitation. In most trials, information about sequence generation and allocation concealment was not properly reported.As only a few studies presented high risk of bias, we believe that the quality of the evidence remained moderate concerning the application of CHX to reduce the VAP incidence. For all-cause mortality, we support that this outcome had a very low quality of evidence. First, we identified that some articles did not declare mortality ratios. Also, the confidence interval of this outcome was very large and the number of events was low, suggesting significant imprecision. For the duration of mechanical ventilation and ICU length of stay, we state that the quality of evidence was deficient as few articles were included, and the information regarding the patient's discharge was unclear in most studies.Future research should adhere to the Consolidated Standards of Reporting Trials (CONSORT) statement to improve study quality and report mortality and incidence ratios related to VAE instead of VAP.Concluding remarksThis systematic review and meta-analysis showed that CHX was beneficial in preventing VAP in critically ill patients. However, no conclusion could be made on mortality rates because the quality of the evidence was very low.Authors contributionConceptualization: Jonas Cruz, Carolina Martins, Jonathas Piassi, Idelmo júnior, Joel Júnior, Leonardo FaveraniMethodology: Jonas Cruz, Carolina Martins, Jonathas Piassi,Formal analysis: Jonas Cruz, Carolina Martins, Jonathas Piassi, Idelmo júnior, Joel Júnior, Leonardo FaveraniInvestigation: Jonas Cruz, Carolina Martins, Jonathas Piassi, Idelmo júnior, Joel Júnior, Leonardo FaveraniWriting original: Jonas Cruz, Carolina Martins, Jonathas Piassi, Idelmo júnior, Joel Júnior, Leonardo FaveraniWriting review: Jonas Cruz, Joel Júnior, Leonardo FaveraniProject administration: Jonas Cruz, Joel Júnior, Leonardo FaveraniRole of funding sourceThis work was supported financially by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, SãoPaulo, Brazil), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brasília, Brazil). The funding sources had no impact in the design, conduct, or reporting of the article or the decision to publish the study.Conflict of interestThe authors declare no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres1942593" "titulo" => "Abstract" "secciones" => array:8 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Design" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Settings" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Patients or participants" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Interventions" ] 5 => array:2 [ "identificador" => "abst0030" "titulo" => "Main variables of interest" ] 6 => array:2 [ "identificador" => "abst0035" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1673765" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1942594" "titulo" => "Resumen" "secciones" => array:8 [ 0 => array:2 [ "identificador" => "abst0045" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0050" "titulo" => "Diseño" ] 2 => array:2 [ "identificador" => "abst0055" "titulo" => "Ámbito" ] 3 => array:2 [ "identificador" => "abst0060" "titulo" => "Pacientes o participantes" ] 4 => array:2 [ "identificador" => "abst0065" "titulo" => "Intervenciones" ] 5 => array:2 [ "identificador" => "abst0070" "titulo" => "Variables de interés principales" ] 6 => array:2 [ "identificador" => "abst0075" "titulo" => "Resultados" ] 7 => array:2 [ "identificador" => "abst0080" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1673764" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Data sources and searches methods" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Study selection" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Data extraction and quality assessment" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Data synthesis and analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0035" "titulo" => "Results" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Description of included studies" ] 1 => array:3 [ "identificador" => "sec0045" "titulo" => "Quantitative data" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Incidence of VAP" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "All-cause mortality" ] 2 => array:2 [ "identificador" => "sec0060" "titulo" => "ICU length of stay and days of mechanical ventilation" ] ] ] 2 => array:2 [ "identificador" => "sec0065" "titulo" => "Risk of bias" ] ] ] 7 => array:2 [ "identificador" => "sec0070" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0075" "titulo" => "Concluding remarks" ] 9 => array:2 [ "identificador" => "sec0080" "titulo" => "Authors contribution" ] 10 => array:2 [ "identificador" => "sec0085" "titulo" => "Role of funding source" ] 11 => array:2 [ "identificador" => "sec0090" "titulo" => "Conflict of interest" ] 12 => array:2 [ "identificador" => "xack680828" "titulo" => "Acknowledgment" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2022-07-06" "fechaAceptado" => "2022-10-20" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1673765" "palabras" => array:4 [ 0 => "Antimicrobial agents" 1 => "Meta-analysis" 2 => "Chlorhexidine" 3 => "Ventilator-associated pneumonia" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1673764" "palabras" => array:4 [ 0 => "Agentes antimicrobianos" 1 => "Metanálisis" 2 => "Clorhexidina" 3 => "Neumonía asociada a ventilador" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "ObjectiveThis study aimed to investigate chlorhexidine’s efficacy in preventing ventilator-associated pneumonia (VAP). DesignA systematic review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. SettingsThe data were obtained from Pubmed, Cochrane Library, and EMBASE. Patients or participantsOnly mechanically ventilated patients for at least 48h were included. InterventionsRandomized clinical trials applying any dosage form of chlorhexidine were eligible. Main variables of interestThe relative risk (RR) of the VAP incidence and all-cause mortality was assessed using the random-effects model. The mean difference in days of mechanical ventilation duration and intensive care unit (ICU) length of stay were also appraised. ResultsTen studies involving 1233 patients were included in the meta-analysis. The oral application of CHX reduced the incidence of VAP (RR, 0.73 [95% CI, 0.55, 0.97]) and did not show an increase in all-cause mortality (RR, 1.13 [95% CI, 0.96, 1.32]). ConclusionsCHX proved effective to prevent VAP. However, a conclusion on mortality rates could not be drawn because the quality of the evidence was very low for this outcome." "secciones" => array:8 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Design" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Settings" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Patients or participants" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Interventions" ] 5 => array:2 [ "identificador" => "abst0030" "titulo" => "Main variables of interest" ] 6 => array:2 [ "identificador" => "abst0035" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "ObjetivoEste estudio tuvo como objetivo investigar la eficacia de la clorhexidina en la prevención de la neumonía asociada al ventilador (NAV). Diseñose realizó una revisión sistemática y un metanálisis siguiendo los elementos de informe (PRISMA) Preferred Reporting Items for Systematic Reviews and Meta-Analyses. ÁmbitoLos datos se obtuvieron de Pubmed, Cochrane Library y EMBASE. Pacientes o participantessolo se incluyeron pacientes con ventilación mecánica durante al menos 48 horas. IntervencionesFueron elegibles los ensayos clínicos aleatorios que aplicaban cualquier forma de dosificación de clorhexidina. Variables de interés principalesSe evaluó el riesgo relativo (RR) de incidencia de NAVM y mortalidad por todas las causas mediante el modelo de efectos aleatorios. También se evaluó la diferencia media en los días de duración de la ventilación mecánica y la duración de la estancia en la unidad de cuidados intensivos (UCI). ResultadosDiez estudios con 1233 pacientes se incluyeron en el metanálisis. La aplicación oral de CHX redujo la incidencia de VAP (RR, 0,73 [IC 95%, 0,55, 0,97]) y no mostró un aumento en la mortalidad por todas las causas (RR, 1,13 [IC 95%, 0,96, 1,32]. ConclusionesCHX demostró ser eficaz para prevenir la VAP. Sin embargo, no se pudo establecer una conclusión sobre las tasas de mortalidad porque la calidad de la evidencia fue muy baja para este resultado." "secciones" => array:8 [ 0 => array:2 [ "identificador" => "abst0045" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0050" "titulo" => "Diseño" ] 2 => array:2 [ "identificador" => "abst0055" "titulo" => "Ámbito" ] 3 => array:2 [ "identificador" => "abst0060" "titulo" => "Pacientes o participantes" ] 4 => array:2 [ "identificador" => "abst0065" "titulo" => "Intervenciones" ] 5 => array:2 [ "identificador" => "abst0070" "titulo" => "Variables de interés principales" ] 6 => array:2 [ "identificador" => "abst0075" "titulo" => "Resultados" ] 7 => array:2 [ "identificador" => "abst0080" "titulo" => "Conclusiones" ] ] ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "The following are Supplementary data to this article:<elsevierMultimedia ident="upi0005"></elsevierMultimedia><elsevierMultimedia ident="upi0010"></elsevierMultimedia><elsevierMultimedia ident="upi0015"></elsevierMultimedia><elsevierMultimedia ident="upi0020"></elsevierMultimedia><elsevierMultimedia ident="upi0025"></elsevierMultimedia><elsevierMultimedia ident="upi0030"></elsevierMultimedia>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0100" ] ] ] ] "multimedia" => array:11 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3706 "Ancho" => 3350 "Tamanyo" => 897528 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0085" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Forest plot of the VAP incidence: (a) stratified according to study design (a) stratified by CHX concentration." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1314 "Ancho" => 3350 "Tamanyo" => 333239 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0090" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Forest plot of VAP mortality." ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 599 "Ancho" => 3342 "Tamanyo" => 182813 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0095" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Forest plot of the ICU length of stay." ] ] 3 => array:8 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 600 "Ancho" => 3342 "Tamanyo" => 181912 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0100" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Forest plot of the mechanical ventilation duration." ] ] 4 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0105" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><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 \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 \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 \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 \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 \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 \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.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Netherlands \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% gel \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 \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 \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 \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.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Thailland \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% solution (4×/day) \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 \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 \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 \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.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">India \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">0.2% solution (twice/day) \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 0.01% \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 \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 \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.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">USA \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">0.12% solution (twice/day) \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 \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 \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 \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.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Brazil \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">0.12% solution (3×/day; 15ml) \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 \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 \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 \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.<a class="elsevierStyleCrossRef" href="#bib0100">20</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Autralia \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">0.2% solution (twice/day) \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 \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 \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 \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.<a class="elsevierStyleCrossRef" href="#bib0105">21</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Brazil \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% gel \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 \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 \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 \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">Özçaka et al.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Turkey \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">0.2% solution (4×/day) \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 \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 \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 \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.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Iran \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">0.12% solution (3×/day) \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 \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 \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 \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.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Turkey \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">0.12% solution (3×/day) \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 \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 \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 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3236348.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Characteristics of the included studies." ] ] 5 => array:5 [ "identificador" => "upi0010" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc2.pdf" "ficheroTamanyo" => 411030 ] ] 6 => array:5 [ "identificador" => "upi0015" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc3.pdf" "ficheroTamanyo" => 27792 ] ] 7 => array:5 [ "identificador" => "upi0020" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc4.docx" "ficheroTamanyo" => 16354 ] ] 8 => array:5 [ "identificador" => "upi0025" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc5.docx" "ficheroTamanyo" => 31725 ] ] 9 => array:5 [ "identificador" => "upi0030" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc6.docx" "ficheroTamanyo" => 77271 ] ] 10 => array:5 [ "identificador" => "upi0005" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "mmc1.jpeg" "Alto" => 1782 "Ancho" => 2508 "Tamanyo" => 114815 ] ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:34 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.C. Kalil" 1 => "M.L. Metersky" 2 => "M. Klompas" 3 => "J. Muscedere" 4 => "D.A. Sweeney" 5 => "L.B. Palmer" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/cid/ciw353" "Revista" => array:6 [ "tituloSerie" => "Clin Infect Dis" "fecha" => "2016" "volumen" => "63" "paginaInicial" => "e61" "paginaFinal" => "e111" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27418577" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Incidence of and risk factors for ventilator-associated pneumonia in critically ill patients" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.J. Cook" 1 => "S.D. Walter" 2 => "R.J. Cook" 3 => "L.E. Griffith" 4 => "G.H. Guyatt" 5 => "D. 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"vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/02105691/0000004700000008/v1_202308021407/S0210569122003047/v1_202308021407/en/main.assets" "Apartado" => array:4 [ "identificador" => "434" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Originales" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/02105691/0000004700000008/v1_202308021407/S0210569122003047/v1_202308021407/en/main.pdf?idApp=WMIE&text.app=https://medintensiva.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0210569122003047?idApp=WMIE"]

Estadísticas

Original article

Does chlorhexidine reduce the incidence of ventilator-associated pneumonia in ICU patients? A systematic review and meta-analysis

¿El cuidado bucal de rutina con clorhexidina reduce la incidencia de neumonía asociada al ventilador en pacientes de la UCI? Una revisión sistemática y metanálisis

J.C. Cruza,

Autor para correspondencia

jonas-cruz@hotmail.com

Corresponding author.

, C.K. Martinsb, J.E.V. Piassic, I.R. Garcia Júniorc, J.F. Santiago Juniord, L.P. Faveranic

a University of São Paulo (USP), Ribeirão Preto, Brazil

b Department of Medicine, University of Ribeirão Preto (UNAERP), Ribeirão Preto, Brazil

c Division of Oral and Maxillofacial Surgery, Department of Diagnosis and Surgery, São Paulo State University (UNESP), School of Dentistry, Araçatuba, São Paulo, Brazil

d Department of Health Sciences. Dentistry Course, Unisagrado: Centro Universitário Sagrado Coração, Bauru, SP, Brazil

Leído

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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Forest plot of VAP mortality&#46;</p>"
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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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        "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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            "titulo" => "Dise&#241;o"
          ]
          2 => array:2 [
            "identificador" => "abst0055"
            "titulo" => "&#193;mbito"
          ]
          3 => array:2 [
            "identificador" => "abst0060"
            "titulo" => "Pacientes o participantes"
          ]
          4 => array:2 [
            "identificador" => "abst0065"
            "titulo" => "Intervenciones"
          ]
          5 => array:2 [
            "identificador" => "abst0070"
            "titulo" => "Variables de inter&#233;s principales"
          ]
          6 => array:2 [
            "identificador" => "abst0075"
            "titulo" => "Resultados"
          ]
          7 => array:2 [
            "identificador" => "abst0080"
            "titulo" => "Conclusiones"
          ]
        ]
      ]
    ]
    "apendice" => array:1 [
      0 => array:1 [
        "seccion" => array:1 [
          0 => array:4 [
            "apendice" => "<p id="par0255" class="elsevierStylePara elsevierViewall">The following are Supplementary data to this article&#58;<elsevierMultimedia ident="upi0005"></elsevierMultimedia><elsevierMultimedia ident="upi0010"></elsevierMultimedia><elsevierMultimedia ident="upi0015"></elsevierMultimedia><elsevierMultimedia ident="upi0020"></elsevierMultimedia><elsevierMultimedia ident="upi0025"></elsevierMultimedia><elsevierMultimedia ident="upi0030"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary data"
            "identificador" => "sec0100"
          ]
        ]
      ]
    ]
    "multimedia" => array:11 [
      0 => array:8 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 3706
            "Ancho" => 3350
            "Tamanyo" => 897528
          ]
        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0085"
            "detalle" => "Figure "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Forest plot of the VAP incidence&#58; &#40;a&#41; stratified according to study design &#40;a&#41; stratified by CHX concentration&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 1314
            "Ancho" => 3350
            "Tamanyo" => 333239
          ]
        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0090"
            "detalle" => "Figure "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Forest plot of VAP mortality&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "fig0015"
        "etiqueta" => "Figure 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 599
            "Ancho" => 3342
            "Tamanyo" => 182813
          ]
        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0095"
            "detalle" => "Figure "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Forest plot of the ICU length of stay&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "fig0020"
        "etiqueta" => "Figure 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr4.jpeg"
            "Alto" => 600
            "Ancho" => 3342
            "Tamanyo" => 181912
          ]
        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0100"
            "detalle" => "Figure "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Forest plot of the mechanical ventilation duration&#46;</p>"
        ]
      ]
      4 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0105"
            "detalle" => "Table "
            "rol" => "short"
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        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><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
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                        0 => array:2 [
                          "etal" => true
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                            0 => "A&#46;C&#46; Kalil"
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                            2 => "M&#46; Klompas"
                            3 => "J&#46; Muscedere"
                            4 => "D&#46;A&#46; Sweeney"
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                        "fecha" => "2016"
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                            0 => "D&#46;J&#46; Cook"
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                            2 => "E&#46;M&#46; Enrile"
                            3 => "C&#46; Dentone"
                            4 => "A&#46; Vena"
                            5 => "C&#46; Robba"
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                            2 => "P&#46;S&#46; d S&#46; Santos"
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                          "etal" => false
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                            2 => "M&#46;D&#46; Howell"
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                            4 => "S&#46;M&#46; Berenholtz"
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                      "doi" => "10.1001/jamainternmed.2014.359"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effectiveness of oral chlorhexidine for the prevention of nosocomial pneumonia and ventilator-associated pneumonia in intensive care units&#58; overview of systematic reviews"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "F&#46; Rabello"
                            1 => "V&#46;E&#46; Ara&#250;jo"
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                      ]
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                      "Revista" => array:5 [
                        "tituloSerie" => "Int J Dent Hyg"
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                          "etal" => true
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                            0 => "J&#46;P&#46; Higgins"
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                            3 => "M&#46; Cumpston"
                            4 => "T&#46; Li"
                            5 => "M&#46;J&#46; Page"
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Información del artículo

ISSN: 02105691
Idioma original: Inglés

DOI:10.1016/j.medin.2022.10.002

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