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Combination of toothbrushing and chlorhexidine compared with exclusive use of chlorhexidine to reduce the risk of ventilator-associated pneumonia: A systematic review with meta-analysis

Abstract

This study aimed to compare the effectiveness of 0.12% chlorhexidine alone and 0.12% chlorhexidine in combination with toothbrushing to prevent ventilator-associated pneumonia (VAP) in mechanically ventilated patients.

The Embase, Latin American and Caribbean Health Science Literature, PubMed, Scientific Electronic Library Online, Scopus, LIVIVO, Web of Science, Cochrane Library, OpenThesis, and Open Access Thesis and Dissertations databases were used. Only randomized controlled trials without restrictions on the year or language of publication were included. Two reviewers assessed the risk of bias using the Joanna Briggs Institute Critical Appraisal Tool. A meta-analysis using a random-effects model estimated the combined relative risk (RR). The Grading of Recommendations, Assessment, Development and Evaluations approach was used to assess the certainty of the evidence.

Initially, 2,337 studies were identified, of which 4 were considered in the systematic review and 3 in the meta-analysis (total sample: 796 patients). The studies were published between 2009 and 2017. All eligible studies had a low risk of bias. The meta-analysis revealed that the risk of VAP was 24% lower in patients receiving chlorhexidine combined with toothbrushing than in those receiving chlorhexidine alone (RR: 0.76; 95% confidence interval: 0.55-1.06), with moderate certainty of evidence and without statistical significance.

In conclusion, considering the limitations of this study, a standard protocol for the prevention of VAP is not yet recommended. More studies with larger sample sizes are needed to draw strong conclusions. However, considering that toothbrushing is a simple intervention, it should be a common practice in mechanically ventilated patients, especially among patients with coronavirus disease.

Chlorhexidine; COVID-19; Tooth Brushing; Ventilator-Associated Pneumonia


INTRODUCTION

Ventilator-associated pneumonia (VAP) is defined as pneumonia occurring more than 48h after the onset of mechanical ventilation (11. Grossman RF, Fein A. Evidence-based assessment of diagnostic tests for ventilator-associated pneumonia. Executive summary. Chest. 2000;117(4 Suppl 2):177S-181S. https://doi.org/10.1378/chest.117.4_suppl_2.177S
https://doi.org/10.1378/chest.117.4_supp...
). It affects 10%-20% of patients who receive mechanical ventilation for more than 48h. VAP is diagnosed based on the following criteria: presence of purulent sputum, fever (>38°C) or hypothermia (<35.5°C), leukocytosis (>10,000 mm3) or leukopenia (<4,000 mm3), positive bacterial culture of respiratory secretions (>106 cfu/mL), and radiography showing additional or progressive pulmonary infiltrates (22. Lorente L, Lecuona M, Jiménez A, Palmero S, Pastor E, Lafuente N, et al. Ventilator-associated pneumonia with or without toothbrushing: a randomized controlled trial. Eur J Clin Microbiol Infect Dis. 2012;31(10):2621-9. https://doi.org/10.1007/s10096-012-1605-y
https://doi.org/10.1007/s10096-012-1605-...
).

Several risk factors are associated with VAP, such as older age, male sex, increased time on mechanical ventilation, sedation, heart and lung disease, regurgitation, aspiration, prior antibiotic therapy, and invasive operations (33. Wu D, Wu C, Zhang S, Zhong Y. Risk Factors of Ventilator-Associated Pneumonia in Critically III Patients. Front Pharmacol. 2019;10:482. https://doi.org/10.3389/fphar.2019.00482
https://doi.org/10.3389/fphar.2019.00482...
). Burns are also a risk factor of VAP through pulmonary inflammation resulting from direct lung injury or systemic immune dysfunction (44. Sen S, Johnston C, Greenhalgh D, Palmieri T. Ventilator-Associated Pneumonia Prevention Bundle Significantly Reduces the Risk of Ventilator-Associated Pneumonia in Critically Ill Burn Patients. J Burn Care Res. 2016;37(3):166-71. https://doi.org/10.1097/BCR.0000000000000228
https://doi.org/10.1097/BCR.000000000000...
). Genetic polymorphisms related to inflammatory mediators may also increase the risk of developing VAP, possibly because of an ineffective response to bacteria (55. Kotsaki A, Raftogiannis M, Routsi C, Baziaka F, Kotanidou A, Antonopoulou A, et al. Genetic polymorphisms within tumor necrosis factor gene promoter region: a role for susceptibility to ventilator-associated pneumonia. Cytokine. 2012;59(2):358-63. https://doi.org/10.1016/j.cyto.2012.04.040
https://doi.org/10.1016/j.cyto.2012.04.0...
).

Currently, the global pandemic against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a higher frequency of patients requiring invasive mechanical ventilation (66. François B, Laterre PF, Luyt CE, Chastre J. The challenge of ventilator-associated pneumonia diagnosis in COVID-19 patients. Crit Care. 2020;24(1):289.). Likewise, prone positioning, heavy sedation, and treatment with neuromuscular blockers, in addition to clear evidence of prolonged immunosuppression, including deep lymphopenia, represent a risk for acquiring secondary infections, including VAP (66. François B, Laterre PF, Luyt CE, Chastre J. The challenge of ventilator-associated pneumonia diagnosis in COVID-19 patients. Crit Care. 2020;24(1):289.,77. Tan L, Wang Q, Zhang D, Ding J, Huang Q, Tang YQ, et al. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Signal Transduct Target Ther. 2020;5(1):33. https://doi.org/10.1038/s41392-020-0148-4
https://doi.org/10.1038/s41392-020-0148-...
). VAP is a complication in patients hospitalized for coronavirus disease (COVID-19) (88. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475-81. https://doi.org/10.1016/S2213-2600(20)30079-5
https://doi.org/10.1016/S2213-2600(20)30...
9. Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, et al. Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure. Cell Host Microbe. 2020;27(6):992-1000.e3. https://doi.org/10.1016/j.chom.2020.04.009
https://doi.org/10.1016/j.chom.2020.04.0...
-1010 https://doi.org/10. Zhou Z, Ren L, Zhang L, Zhong J, Xiao Y, Jia Z, et al. Heightened Innate Immune Responses in the Respiratory Tract of COVID-19 Patients. Cell Host Microbe. 2020;27(6):883-90.e2. https://doi.org/10.1016/j.chom.2020.04.017
https://doi.org/10....
).

Oral hygiene using a variety of procedures is an important measure to prevent VAP (1111. Wise MP, Williams DW. Oral care and pulmonary infection - the importance of plaque scoring. Crit Care. 2013;17(1):101. https://doi.org/10.1186/cc11896
https://doi.org/10.1186/cc11896...
). For instance, aspiration of secretions, toothbrushing, or dental and mucosal cleansing with chlorhexidine (CHX) may reduce the risk of VAP (1212. Hua F, Xie H, Worthington HV, Furness S, Zhang Q, Li C. Oral hygiene care for critically ill patients to prevent ventilator-associated pneumonia. Cochrane Database Syst Rev. 2016;10(10):CD008367. https://doi.org/10.1002/14651858.CD008367.pub3
https://doi.org/10.1002/14651858.CD00836...
). CHX is a cationic biguanide that binds to the bacterial cell walls, thus impairing and even perforating phospholipid membranes (1313. Septimus EJ, Schweizer ML. Decolonization in Prevention of Health Care-Associated Infections. Clin Microbiol Rev. 2016;29(2):201-22. https://doi.org/10.1128/CMR.00049-15
https://doi.org/10.1128/CMR.00049-15...
,1414. Hugo WB, Longworth AR. Some aspects of the mode of action of chlorhexidine. J Pharm Pharmacol. 1964;16:655-62. https://doi.org/10.1111/j.2042-7158.1964.tb07384.x
https://doi.org/10.1111/j.2042-7158.1964...
). The effect may be bacteriostatic or bactericidal depending on the concentration of the product (1515. Kumar SB. Chlorhexidine Mouthwash- A Review. J Pharm Sci Res. 2017;9(9):1450-2.). Its use for oral hygiene in patients under mechanical ventilation reduces the risk of VAP (1616. Munro CL, Grap MJ, Jones DJ, McClish DK, Sessler CN. Chlorhexidine, toothbrushing, and preventing ventilator-associated pneumonia in critically ill adults. Am J Crit Care. 2009;18(5):428-37. https://doi.org/10.4037/ajcc2009792
https://doi.org/10.4037/ajcc2009792...
17. Meinberg MC, Cheade Mde F, Miranda AL, Fachini MM, Lobo SM. The use of 2% chlorhexidine gel and toothbrushing for oral hygiene of patients receiving mechanical ventilation: effects on ventilator-associated pneumonia. Rev Bras Ter Intensiva. 2012;24(4):369-74. https://doi.org/10.1590/S0103-507X2012000400013
https://doi.org/10.1590/S0103-507X201200...
18. Sebastian MR, Lodha R, Kapil A, Kabra SK. Oral mucosal decontamination with chlorhexidine for the prevention of ventilator-associated pneumonia in children - a randomized, controlled trial. Pediatr Crit Care Med. 2012;13(5):e305-https://doi.org/10. https://doi.org/10.1097/PCC.0b013e31824ea119
https://doi.org/10....
-1919. Cabov T, Macan D, Husedzinović I, Skrlin-Subić J, Bosnjak D, Sestan-Crnek S, et al. The impact of oral health and 0.2% chlorhexidine oral gel on the prevalence of nosocomial infections in surgical intensive-care patients: a randomized placebo-controlled study. Wien Klin Wochenschr. 2010;122(13-14):397-404. https://doi.org/10.1007/s00508-010-1397-y
https://doi.org/10.1007/s00508-010-1397-...
). As a mouthwash, CHX reduces bacterial colonization in the oral cavity (2020. Ellepola AN, Joseph BK, Khan ZU. Changes in the cell surface hydrophobicity of oral Candida albicans from smokers, diabetics, asthmatics, and healthy individuals following limited exposure to chlorhexidine gluconate. Med Princ Pract. 2013;22(3):250-4. https://doi.org/10.1159/000345641
https://doi.org/10.1159/000345641...
,2121. Jackson L, Owens M. Does oral care with chlorhexidine reduce ventilator-associated pneumonia in mechanically ventilated adults? Br J Nurs. 2019;28(11):682-9. https://doi.org/10.12968/bjon.2019.28.11.682
https://doi.org/10.12968/bjon.2019.28.11...
). However, the presence of a biofilm on the surface of the teeth limits the action of any mouthwash (2222. ten Cate JM. Biofilms, a new approach to the microbiology of dental plaque. Odontology. 2006;94(1):1-9. https://doi.org/10.1007/s10266-006-0063-3
https://doi.org/10.1007/s10266-006-0063-...
). Thus, prior mechanical disruption of dental biofilms through toothbrushing improves the effect of CHX (2323. Chacko R, Rajan A, Lionel P, Thilagavathi M, Yadav B, Premkumar J. Oral decontamination techniques and ventilator-associated pneumonia. Br J Nurs. 2017;26(11):594-9. https://doi.org/10.12968/bjon.2017.26.11.594
https://doi.org/10.12968/bjon.2017.26.11...
24. Kishimoto H, Urade M. Mechanical tooth cleaning before chlorhexidine application. Am J Respir Crit Care Med. 2007;175(4):418. https://doi.org/10.1164/ajrccm.175.4.418a
https://doi.org/10.1164/ajrccm.175.4.418...
-2525. Mori H, Hirasawa H, Oda S, Shiga H, Matsuda K, Nakamura M. Oral care reduces incidence of ventilator-associated pneumonia in ICU populations. Intensive Care Med. 2006;32(2):230-6. https://doi.org/10.1007/s00134-005-0014-4
https://doi.org/10.1007/s00134-005-0014-...
) and, hence, prevents VAP (2525. Mori H, Hirasawa H, Oda S, Shiga H, Matsuda K, Nakamura M. Oral care reduces incidence of ventilator-associated pneumonia in ICU populations. Intensive Care Med. 2006;32(2):230-6. https://doi.org/10.1007/s00134-005-0014-4
https://doi.org/10.1007/s00134-005-0014-...
26. Hutchins K, Karras G, Erwin J, Sullivan KL. Ventilator-associated pneumonia and oral care: a successful quality improvement project. Am J Infect Control. 2009;37(7):590-7. https://doi.org/10.1016/j.ajic.2008.12.007
https://doi.org/10.1016/j.ajic.2008.12.0...
-2727. Sona CS, Zack JE, Schallom ME, McSweeney M, McMullen K, Thomas J, et al. The impact of a simple, low-cost oral care protocol on ventilator-associated pneumonia rates in a surgical intensive care unit. J Intensive Care Med. 2009;24(1):54-62. https://doi.org/10.1177/0885066608326972
https://doi.org/10.1177/0885066608326972...
).

High CHX concentrations have been associated with adverse effects (2828. Ferretti GA, Brown AT, Raybould TP, Lillich TT. Oral antimicrobial agents--chlorhexidine. NCI Monogr. 1990;(9):51-5.). Dental discoloration and oral mucosa irritation were attributed to the use of 0.2% and 2% CHX (2929. Zand F, Zahed L, Mansouri P, Dehghanrad F, Bahrani M, Ghorbani M. The effects of oral rinse with 0.2% and 2% chlorhexidine on oropharyngeal colonization and ventilator associated pneumonia in adults' intensive care units. J Crit Care. 2017;40:318-22. https://doi.org/10.1016/j.jcrc.2017.02.029
https://doi.org/10.1016/j.jcrc.2017.02.0...
). Lesions in the oral mucosa, such as erosive lesions, ulcerations, white/yellow plaque formation, and mucosal bleeding, have been observed in patients admitted in the intensive care units (3030. Plantinga NL, Wittekamp BHJ, Leleu K, Depuydt P, Van den Abeele AM, Brun-Buisson C, et al. Oral mucosal adverse events with chlorhexidine 2% mouthwash in ICU. Intensive Care Med. 2016;42(4):620-1. https://doi.org/10.1007/s00134-016-4217-7
https://doi.org/10.1007/s00134-016-4217-...
). By contrast, when 0.12% CHX was applied, it was effective in preventing VAP in surgical patients (3131. Nicolosi LN, del Carmen Rubio M, Martinez CD, González NN, Cruz ME. Effect of oral hygiene and 0.12% chlorhexidine gluconate oral rinse in preventing ventilator-associated pneumonia after cardiovascular surgery. Respir Care. 2014;59(4):504-9. https://doi.org/10.4187/respcare.02666
https://doi.org/10.4187/respcare.02666...
).

This study aimed to compare the reduction in the risk of VAP between the use of oral 0.12% CHX combined with toothbrushing and use of 0.12% CHX alone in the prevention of VAP through systematic review and meta-analysis.

METHODS

Protocol and registration

This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations (3232. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. https://doi.org/10.1371/journal.pmed.1000097
https://doi.org/10.1371/journal.pmed.100...
) and Cochrane guidelines (3333. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. https://doi.org/10.1136/bmj.d5928
https://doi.org/10.1136/bmj.d5928...
). It was recorded in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42020168844) (https://www.crd.york.ac.uk/PROSPERO/).

Study design and eligibility criteria

This systematic review with meta-analysis was conducted based on the patient, intervention, comparison, outcome strategy and aimed at answering the following review question: “Is toothbrushing combined with the use of 0.12% CHX (intervention) more effective in preventing VAP (outcome) among patients under mechanical ventilation (population) than using CHX alone (comparison)?”

Randomized controlled trials that compared oral hygiene using 0.12% CHX with or without toothbrushing in adult patients (aged >18 years) under invasive (tracheal) mechanical ventilation were included in the study. There were no restrictions on the year, language, or publication status (published, accepted/ahead of print articles). Studies not related to the objective of the present study, non-original works (review articles, editorials, and books/book chapters), or papers with insufficient data (letters, personal opinions, and conference abstracts) were excluded.

Sources of information and search

The primary sources of studies were PubMed (including MedLine), Scopus, Embase, Scientific Electronic Library Online, Web of Science, Latin-American and Caribbean Health Sciences Literature, Cochrane, and LIVIVO databases. The Open Access Thesis and Dissertations and OpenGrey databases allowed access to the “gray literature” to avoid bias regarding the lack of published negative results (Figure 1). The sources of search descriptors were the Medical Subject Headings, Health Sciences Descriptors, and Emtree. Several combinations of the Boolean operators “AND” and “OR” enhanced the search strategy, as detailed in Table 1. The search terms were adapted to each database. Bibliographic research was performed until November 2019. The results obtained were imported to the software EndNote Web™ (Thomson Reuters, Toronto, Canada) and then into Microsoft Word™ 2010 (Microsoft™ Ltd., Washington, USA) for the automatic and conventional removal of duplicates, respectively.

Figure 1
Flow chart of the study selection process.


Table 1
Electronic databases and applied search strategy.

Study selection

Two independent reviewers (PUJS and DMS) previously calibrated 20% of the studies and reached an acceptable inter-examiner agreement (kappa>0.81). Then, these reviewers independently performed the eligibility review, with disagreements resolved by discussion with a third reviewer (LRP) until consensus was reached.

The study selection was performed in two stages. First, the analysis of the titles and abstracts (when available) led to the exclusion of articles not related to the topic of the present review. The second stage involved the evaluation of the full text of the remaining studies to verify their adherence to the eligibility criteria. In both stages, the reviewers had access to the names of the authors and journals. A thorough verification of the references of the eligible articles was performed to identify studies overlooked in the initial search. The excluded studies were registered separately, along with the reasons for exclusion. If any article could not be recovered, other study centers were contacted to retrieve the articles in their libraries. In the case of studies published in languages other than English or Portuguese, the full text was translated.

Data collection

Two reviewers (PUJS and DMS) examined the selected papers to collect the following information: identification (author, year, and country of the research), sample features (number of patients, sex distribution, mean age, and Acute Physiology and Chronic Health Evaluation score) (3434. Wang Y, Xiao QM, Qi HN, Li W, Zhu BY, Liu YJ, et al. [Value of APACHE.II score and DIC score in predicting the death of patients with heat stroke]. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2019;37(1):43-5.,3535. Fortis S, O'Shea AMJ, Beck BF, Nair R, Goto M, Kaboli PJ, et al. An automated computerized critical illness severity scoring system derived from APACHE III: modified APACHE. J Crit Care. 2018;48:237-42. https://doi.org/10.1016/j.jcrc.2018.09.005
https://doi.org/10.1016/j.jcrc.2018.09.0...
), and the main results (ventilation time, microbiota assessment, VAP incidence, mortality, and conclusions). The corresponding authors were contacted by email (up to three times over two weeks) to obtain relevant information on missing or unclear data.

To ensure consistency, the reviewers (PUJS and DMS) extracted the information jointly from an eligible study. These reviewers discussed to resolve initial discrepancies, and a third reviewer (LRP) made a final decision in case of persistent disagreement.

Risk of individual bias of the studies

The Joanna Briggs Institute (JBI) Critical Appraisal Tools for use in JBI Systematic Reviews for randomized controlled trials (3636. Aromataris E, Munn Z. Joanna Briggs Institute Reviewer‘s Manual [Internet]. Adelaide: Joanna Briggs Institute; 2017. [cited 2020 Jun 16]; Available from: https://reviewersmanual.joannabriggs.org/
https://reviewersmanual.joannabriggs.org...
) were utilized to assess the risk of bias and individual quality of the selected studies. Two reviewers (PUJS and DMS) independently judged each domain regarding their potential risk of bias, as recommended by the PRISMA statement (3232. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. https://doi.org/10.1371/journal.pmed.1000097
https://doi.org/10.1371/journal.pmed.100...
). The percentage of “yes” answers to the questions on the assessment tool used in each study was rated as follows: the risk of bias was high, moderate, or low when the study obtained 49%, 50%-68%, or more than 69% “yes” answers, respectively.

Summary measures and synthesis of results (meta-analysis)

The statistical analyses included eligible studies that provided sufficient data to calculate the relative risk (RR) of VAP in patients who received 0.12% CHX combined with toothbrushing compared with those who received 0.12% CHX alone. A meta-analysis using a random-effects model estimated the combined RRs. Three measures of heterogeneity were estimated: the τ2 statistic is related to the between-study variance, I2 reflects the percentage of variability caused by heterogeneity excluding sampling error, and H2 indicates the between-study level of heterogeneity (H2=1 indicating homogeneity). The statistical significance level was 5%.

Certainty of evidence

The Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) tool with GRADE Pro GDT software (http://gdt.guidelinedevelopment.org) (3737. Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64(4):401-6. https://doi.org/10.1016/j.jclinepi.2010.07.015
https://doi.org/10.1016/j.jclinepi.2010....
) was used to assess the certainty of evidence and strength of recommendation. The basis for this assessment was the study design, risk of bias, inconsistency, indirect evidence, imprecision, and publication bias. The level of certainty among the identified evidence was characterized as high, moderate, low, or very low (3737. Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64(4):401-6. https://doi.org/10.1016/j.jclinepi.2010.07.015
https://doi.org/10.1016/j.jclinepi.2010....
).

RESULTS

Study selection

The first phase of the study selection revealed a total of 2,337 works. The “gray literature” did not disclose any studies related to the objective of this systematic review. After discarding duplicates, 1,071 papers remained for title and abstract screening. After a detailed analysis, only four studies were eligible for full-text review. The references from these studies did not reveal additional articles of interest; after reading the full text, the qualitative analysis did not exclude any of the four selected studies. Figure 1 presents the process of search, identification, inclusion, and exclusion of studies.

Study characteristics of eligible studies

The studies were published between 2009 and 2017, and the patients from the United States (1616. Munro CL, Grap MJ, Jones DJ, McClish DK, Sessler CN. Chlorhexidine, toothbrushing, and preventing ventilator-associated pneumonia in critically ill adults. Am J Crit Care. 2009;18(5):428-37. https://doi.org/10.4037/ajcc2009792
https://doi.org/10.4037/ajcc2009792...
), Spain (22. Lorente L, Lecuona M, Jiménez A, Palmero S, Pastor E, Lafuente N, et al. Ventilator-associated pneumonia with or without toothbrushing: a randomized controlled trial. Eur J Clin Microbiol Infect Dis. 2012;31(10):2621-9. https://doi.org/10.1007/s10096-012-1605-y
https://doi.org/10.1007/s10096-012-1605-...
,3838. Pobo A, Lisboa T, Rodriguez A, Sole R, Magret M, Trefler S, et al. A randomized trial of dental brushing for preventing ventilator-associated pneumonia. Chest. 2009;136(2):433-9. https://doi.org/10.1378/chest.09-0706
https://doi.org/10.1378/chest.09-0706...
), and Brazil (3939. de Lacerda Vidal CF, Vidal AK, Monteiro JG Jr, Cavalcanti A, Henriques APC, Oliveira M, et al. Impact of oral hygiene involving toothbrushing versus chlorhexidine in the prevention of ventilator-associated pneumonia: a randomized study. BMC Infect Dis. 2017;17(1):112. https://doi.org/10.1186/s12879-017-2188-0
https://doi.org/10.1186/s12879-017-2188-...
) were included in these studies. Overall, 988 patients were included in the analysis. Sources of information on the demographic and clinical characteristics of the population are presented in Table 2. The Ethics Committee of their respective institution or hospital approved all selected studies, which also provided informed consent before patient recruitment. None of the studies followed the Consolidated Standards of Reporting Trials statement. Half of the selected studies reported calibration among nurses (3838. Pobo A, Lisboa T, Rodriguez A, Sole R, Magret M, Trefler S, et al. A randomized trial of dental brushing for preventing ventilator-associated pneumonia. Chest. 2009;136(2):433-9. https://doi.org/10.1378/chest.09-0706
https://doi.org/10.1378/chest.09-0706...
) and dentists (3939. de Lacerda Vidal CF, Vidal AK, Monteiro JG Jr, Cavalcanti A, Henriques APC, Oliveira M, et al. Impact of oral hygiene involving toothbrushing versus chlorhexidine in the prevention of ventilator-associated pneumonia: a randomized study. BMC Infect Dis. 2017;17(1):112. https://doi.org/10.1186/s12879-017-2188-0
https://doi.org/10.1186/s12879-017-2188-...
) who performed oral hygiene procedures. Two studies (3838. Pobo A, Lisboa T, Rodriguez A, Sole R, Magret M, Trefler S, et al. A randomized trial of dental brushing for preventing ventilator-associated pneumonia. Chest. 2009;136(2):433-9. https://doi.org/10.1378/chest.09-0706
https://doi.org/10.1378/chest.09-0706...
,3939. de Lacerda Vidal CF, Vidal AK, Monteiro JG Jr, Cavalcanti A, Henriques APC, Oliveira M, et al. Impact of oral hygiene involving toothbrushing versus chlorhexidine in the prevention of ventilator-associated pneumonia: a randomized study. BMC Infect Dis. 2017;17(1):112. https://doi.org/10.1186/s12879-017-2188-0
https://doi.org/10.1186/s12879-017-2188-...
) presented the registration number of randomized controlled clinical trials.

Table 2
Summary of the main characteristics of the eligible studies (all were randomized clinical trials with previous ethical clearance and application of informed consent, with patients receiving mechanical ventilation for more than 48 hours without pneumonia at baseline).

Risk of individual bias

Table 3 shows the risk of bias and individual quality of the selected studies (22. Lorente L, Lecuona M, Jiménez A, Palmero S, Pastor E, Lafuente N, et al. Ventilator-associated pneumonia with or without toothbrushing: a randomized controlled trial. Eur J Clin Microbiol Infect Dis. 2012;31(10):2621-9. https://doi.org/10.1007/s10096-012-1605-y
https://doi.org/10.1007/s10096-012-1605-...
,1616. Munro CL, Grap MJ, Jones DJ, McClish DK, Sessler CN. Chlorhexidine, toothbrushing, and preventing ventilator-associated pneumonia in critically ill adults. Am J Crit Care. 2009;18(5):428-37. https://doi.org/10.4037/ajcc2009792
https://doi.org/10.4037/ajcc2009792...
,3838. Pobo A, Lisboa T, Rodriguez A, Sole R, Magret M, Trefler S, et al. A randomized trial of dental brushing for preventing ventilator-associated pneumonia. Chest. 2009;136(2):433-9. https://doi.org/10.1378/chest.09-0706
https://doi.org/10.1378/chest.09-0706...
,3939. de Lacerda Vidal CF, Vidal AK, Monteiro JG Jr, Cavalcanti A, Henriques APC, Oliveira M, et al. Impact of oral hygiene involving toothbrushing versus chlorhexidine in the prevention of ventilator-associated pneumonia: a randomized study. BMC Infect Dis. 2017;17(1):112. https://doi.org/10.1186/s12879-017-2188-0
https://doi.org/10.1186/s12879-017-2188-...
). One study (22. Lorente L, Lecuona M, Jiménez A, Palmero S, Pastor E, Lafuente N, et al. Ventilator-associated pneumonia with or without toothbrushing: a randomized controlled trial. Eur J Clin Microbiol Infect Dis. 2012;31(10):2621-9. https://doi.org/10.1007/s10096-012-1605-y
https://doi.org/10.1007/s10096-012-1605-...
) did not provide details regarding the randomization procedure. None of study was blinded because the participants were admitted to the intensive care units under invasive mechanical ventilation in an unconscious state. Questions 5 and 6 were answered as “unclear” in three studies (22. Lorente L, Lecuona M, Jiménez A, Palmero S, Pastor E, Lafuente N, et al. Ventilator-associated pneumonia with or without toothbrushing: a randomized controlled trial. Eur J Clin Microbiol Infect Dis. 2012;31(10):2621-9. https://doi.org/10.1007/s10096-012-1605-y
https://doi.org/10.1007/s10096-012-1605-...
,1616. Munro CL, Grap MJ, Jones DJ, McClish DK, Sessler CN. Chlorhexidine, toothbrushing, and preventing ventilator-associated pneumonia in critically ill adults. Am J Crit Care. 2009;18(5):428-37. https://doi.org/10.4037/ajcc2009792
https://doi.org/10.4037/ajcc2009792...
,3838. Pobo A, Lisboa T, Rodriguez A, Sole R, Magret M, Trefler S, et al. A randomized trial of dental brushing for preventing ventilator-associated pneumonia. Chest. 2009;136(2):433-9. https://doi.org/10.1378/chest.09-0706
https://doi.org/10.1378/chest.09-0706...
) because it was not clear if those applying the treatment were aware of the allocation of the participants. The answer to question 7 was considered “no” in two studies (1616. Munro CL, Grap MJ, Jones DJ, McClish DK, Sessler CN. Chlorhexidine, toothbrushing, and preventing ventilator-associated pneumonia in critically ill adults. Am J Crit Care. 2009;18(5):428-37. https://doi.org/10.4037/ajcc2009792
https://doi.org/10.4037/ajcc2009792...
,3939. de Lacerda Vidal CF, Vidal AK, Monteiro JG Jr, Cavalcanti A, Henriques APC, Oliveira M, et al. Impact of oral hygiene involving toothbrushing versus chlorhexidine in the prevention of ventilator-associated pneumonia: a randomized study. BMC Infect Dis. 2017;17(1):112. https://doi.org/10.1186/s12879-017-2188-0
https://doi.org/10.1186/s12879-017-2188-...
) because the groups were not treated identically according to the intervention of interest.

Table 3
Risk of bias assessed by the Joanna Briggs Institute Critical Appraisal Tools for use in JBI Systematic Reviews for randomized clinical trial studies.

Outcomes of each study

Three studies reported the VAP incidence rate and average number of days of ventilation (22. Lorente L, Lecuona M, Jiménez A, Palmero S, Pastor E, Lafuente N, et al. Ventilator-associated pneumonia with or without toothbrushing: a randomized controlled trial. Eur J Clin Microbiol Infect Dis. 2012;31(10):2621-9. https://doi.org/10.1007/s10096-012-1605-y
https://doi.org/10.1007/s10096-012-1605-...
,3838. Pobo A, Lisboa T, Rodriguez A, Sole R, Magret M, Trefler S, et al. A randomized trial of dental brushing for preventing ventilator-associated pneumonia. Chest. 2009;136(2):433-9. https://doi.org/10.1378/chest.09-0706
https://doi.org/10.1378/chest.09-0706...
,3939. de Lacerda Vidal CF, Vidal AK, Monteiro JG Jr, Cavalcanti A, Henriques APC, Oliveira M, et al. Impact of oral hygiene involving toothbrushing versus chlorhexidine in the prevention of ventilator-associated pneumonia: a randomized study. BMC Infect Dis. 2017;17(1):112. https://doi.org/10.1186/s12879-017-2188-0
https://doi.org/10.1186/s12879-017-2188-...
). None of the studies found a significant difference between CHX+toothbrushing and CHX alone in preventing VAP, except one study (1616. Munro CL, Grap MJ, Jones DJ, McClish DK, Sessler CN. Chlorhexidine, toothbrushing, and preventing ventilator-associated pneumonia in critically ill adults. Am J Crit Care. 2009;18(5):428-37. https://doi.org/10.4037/ajcc2009792
https://doi.org/10.4037/ajcc2009792...
) that compared groups with inadequate answers to the present question. Table 4 shows other outcomes common to two or more studies. All studies (22. Lorente L, Lecuona M, Jiménez A, Palmero S, Pastor E, Lafuente N, et al. Ventilator-associated pneumonia with or without toothbrushing: a randomized controlled trial. Eur J Clin Microbiol Infect Dis. 2012;31(10):2621-9. https://doi.org/10.1007/s10096-012-1605-y
https://doi.org/10.1007/s10096-012-1605-...
,1616. Munro CL, Grap MJ, Jones DJ, McClish DK, Sessler CN. Chlorhexidine, toothbrushing, and preventing ventilator-associated pneumonia in critically ill adults. Am J Crit Care. 2009;18(5):428-37. https://doi.org/10.4037/ajcc2009792
https://doi.org/10.4037/ajcc2009792...
,3838. Pobo A, Lisboa T, Rodriguez A, Sole R, Magret M, Trefler S, et al. A randomized trial of dental brushing for preventing ventilator-associated pneumonia. Chest. 2009;136(2):433-9. https://doi.org/10.1378/chest.09-0706
https://doi.org/10.1378/chest.09-0706...
,3939. de Lacerda Vidal CF, Vidal AK, Monteiro JG Jr, Cavalcanti A, Henriques APC, Oliveira M, et al. Impact of oral hygiene involving toothbrushing versus chlorhexidine in the prevention of ventilator-associated pneumonia: a randomized study. BMC Infect Dis. 2017;17(1):112. https://doi.org/10.1186/s12879-017-2188-0
https://doi.org/10.1186/s12879-017-2188-...
) reported positive results on microbiological tests for VAP identification. Moreover, none of the studies reported mortality rates.

Table 4
Summary of the outcomes of the eligible studies.

Synthesis of meta-analysis

The meta-analysis did not include one of the four eligible studies in the systematic review due to the lack of comparison between the intervention and control groups (1616. Munro CL, Grap MJ, Jones DJ, McClish DK, Sessler CN. Chlorhexidine, toothbrushing, and preventing ventilator-associated pneumonia in critically ill adults. Am J Crit Care. 2009;18(5):428-37. https://doi.org/10.4037/ajcc2009792
https://doi.org/10.4037/ajcc2009792...
). As shown in Figure 2, there was a 24% reduction in the RR of VAP in patients who underwent CHX + toothbrushing, although this effect was not considered significant (RR: 0.76; 95% confidence interval: 0.55-1.06). The heterogeneity between the studies was low (I2=0%, τ2=0%, H2=1.00).

Figure 2
Forest plot comparing the CHX 0.12% + toothbrushing and CHX 0.12% alone groups.

Certainty of evidence collection

The certainty of evidence from the outcome evaluated by the GRADE approach (3737. Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64(4):401-6. https://doi.org/10.1016/j.jclinepi.2010.07.015
https://doi.org/10.1016/j.jclinepi.2010....
) was assessed as “moderate,” which means that the true effect is likely to be close to the estimated the effect, although there is a possibility that it is substantially different. Table 5 shows more details regarding the evaluation of each GRADE tool domain.

Table 5
Grading of the Recommendations Assessment, Development, and Evaluation (GRADE) Summary of Findings Table for the Outcomes of the Systematic Review and Meta-Analysis.

DISCUSSION

This systematic review of the literature compared the performance of 0.12% CHX alone and 0.12% CHX with toothbrushing in the prevention of VAP in adults requiring mechanical ventilation in intensive care units. The results of the meta-analysis revealed a non-significant 24% reduction in the frequency of VAP in the CHX + toothbrushing group as opposed to the group that exclusively used CHX. This reduction in the incidence of VAP suggests the protective effect of toothbrushing associated with CHX, but must be interpreted with caution due to the lack of significant results.

The oral cavity microbiota is highly diverse and dynamic, mainly due to the wide variety of microbial habitats in the mouth and changes that can arise in these environments due to the adjustment in diet, salivary flow, and oral hygiene interventions (4040. Dennesen P, van der Ven A, Vlasveld M, Lokker L, Ramsay G, Kessels A, et al. Inadequate salivary flow and poor oral mucosal status in intubated intensive care unit patients. Crit Care Med. 2003;31(3):781-6. https://doi.org/10.1097/01.CCM.0000053646.04085.29
https://doi.org/10.1097/01.CCM.000005364...
41. Marsh PD. Controlling the oral biofilm with antimicrobials. J Dent. 2010;38 Suppl 1:S11-5. https://doi.org/10.1016/S0300-5712(10)70005-1
https://doi.org/10.1016/S0300-5712(10)70...
42. Tada A, Hanada N. Opportunistic respiratory pathogens in the oral cavity of the elderly. FEMS Immunol Med Microbiol. 2010;60(1):1-17. https://doi.org/10.1111/j.1574-695X.2010.00709.x
https://doi.org/10.1111/j.1574-695X.2010...
43. Wade WG. The oral microbiome in health and disease. Pharmacol Res. 2013;69(1):137-43. https://doi.org/10.1016/j.phrs.2012.11.006
https://doi.org/10.1016/j.phrs.2012.11.0...
-4444. Wise MP, Cole JM, Williams DW, Lewis MA, Frost PJ. Efficacy of oral chlorhexidine in critical care. Crit Care. 2008;12(3):419; author reply 419. https://doi.org/10.1186/cc6886
https://doi.org/10.1186/cc6886...
). The oral cavity directly connects to the lower airways; therefore, there is an alleged association between oral microbiology and respiratory infections (4545. Sands KM, Wilson MJ, Lewis MAO, Wise MP, Palmer N, Hayes AJ, et al. Respiratory pathogen colonization of dental plaque, the lower airways, and endotracheal tube biofilms during mechanical ventilation. J Crit Care. 2017;37:30-7. https://doi.org/10.1016/j.jcrc.2016.07.019
https://doi.org/10.1016/j.jcrc.2016.07.0...
). Carrilho-Neto et al. (4646. Carrilho Neto A, De Paula Ramos S, Sant'ana AC, Passanezi E. Oral health status among hospitalized patients. Int J Dent Hyg. 2011;9(1):21-9. https://doi.org/10.1111/j.1601-5037.2009.00423.x
https://doi.org/10.1111/j.1601-5037.2009...
) showed a reduction in oral hygiene in most hospitalized patients, and reported a positive correlation between the dental plaque index and gingival inflammation index (4646. Carrilho Neto A, De Paula Ramos S, Sant'ana AC, Passanezi E. Oral health status among hospitalized patients. Int J Dent Hyg. 2011;9(1):21-9. https://doi.org/10.1111/j.1601-5037.2009.00423.x
https://doi.org/10.1111/j.1601-5037.2009...
). In intubated patients, gingival inflammation caused by inadequate oral hygiene has also been associated with lung inflammation (4646. Carrilho Neto A, De Paula Ramos S, Sant'ana AC, Passanezi E. Oral health status among hospitalized patients. Int J Dent Hyg. 2011;9(1):21-9. https://doi.org/10.1111/j.1601-5037.2009.00423.x
https://doi.org/10.1111/j.1601-5037.2009...
47. Eddens T, Kolls JK. Host defenses against bacterial lower respiratory tract infection. Curr Opin Immunol. 2012;24(4):424-30. https://doi.org/10.1016/j.coi.2012.07.005
https://doi.org/10.1016/j.coi.2012.07.00...
-4848. Hunter JD. Ventilator associated pneumonia. Postgrad Med J. 2006;82(965):172-8. https://doi.org/10.1136/pgmj.2005.036905
https://doi.org/10.1136/pgmj.2005.036905...
).

Dental plaque accumulation and colonization of microorganisms in the mouth were significantly higher from day four of intubation, conferring a higher risk of VAP (4949. Munro CL, Grap MJ, Elswick RK Jr, McKinney J, Sessler CN, Hummel RS 3rd. Oral health status and development of ventilator-associated pneumonia: a descriptive study. Am J Crit Care. 2006;15(5):453-60. https://doi.org/10.4037/ajcc2006.15.5.453
https://doi.org/10.4037/ajcc2006.15.5.45...
). Sands et al. (4545. Sands KM, Wilson MJ, Lewis MAO, Wise MP, Palmer N, Hayes AJ, et al. Respiratory pathogen colonization of dental plaque, the lower airways, and endotracheal tube biofilms during mechanical ventilation. J Crit Care. 2017;37:30-7. https://doi.org/10.1016/j.jcrc.2016.07.019
https://doi.org/10.1016/j.jcrc.2016.07.0...
) revealed that in one-third of mechanically ventilated patients, dental plaque is presumed to be a reservoir of certain respiratory pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa (4545. Sands KM, Wilson MJ, Lewis MAO, Wise MP, Palmer N, Hayes AJ, et al. Respiratory pathogen colonization of dental plaque, the lower airways, and endotracheal tube biofilms during mechanical ventilation. J Crit Care. 2017;37:30-7. https://doi.org/10.1016/j.jcrc.2016.07.019
https://doi.org/10.1016/j.jcrc.2016.07.0...
). In one of the eligible studies, S. aureus and Haemophilus influenzae, organisms connected with respiratory infections, were abundant in dental plaque (5050. Sands KM, Twigg JA, Lewis MAO, Wise MP, Marchesi JR, Smith A, et al. Microbial profiling of dental plaque from mechanically ventilated patients. J Med Microbiol. 2016;65(2):147-59. https://doi.org/10.1099/jmm.0.000212
https://doi.org/10.1099/jmm.0.000212...
,5151. King P. Haemophilus influenzae and the lung (Haemophilus and the lung). Clin Transl Med. 2012;1(1):https://doi.org/10. https://doi.org/10.1186/2001-1326-1-10
https://doi.org/10....
).

In 2020, the COVID-19 pandemic scenario contributed to the need for prolonged mechanical ventilation in infected patients, since intubation is frequent in those with more severe cases, also increasing the incidence of COVID-19-related pneumonia (5252. World Health Organization. Naming the coronavirus disease (COVID-19) and the virus that causes it. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it [cited June 16th, 2020]
https://www.who.int/emergencies/diseases...
). The clinical presentation of COVID-19 pneumonia is homogeneous, which greatly overlaps with that of VAP. This situation hinders the use of empiric antibiotics due to the increased risk of multi-drug resistance (66. François B, Laterre PF, Luyt CE, Chastre J. The challenge of ventilator-associated pneumonia diagnosis in COVID-19 patients. Crit Care. 2020;24(1):289.). SARS-CoV-2 infection induces increased cytokine production, causing immune dysregulation and the development of hyperinflammation and defects in lymphoid function (99. Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, et al. Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure. Cell Host Microbe. 2020;27(6):992-1000.e3. https://doi.org/10.1016/j.chom.2020.04.009
https://doi.org/10.1016/j.chom.2020.04.0...
,1010 https://doi.org/10. Zhou Z, Ren L, Zhang L, Zhong J, Xiao Y, Jia Z, et al. Heightened Innate Immune Responses in the Respiratory Tract of COVID-19 Patients. Cell Host Microbe. 2020;27(6):883-90.e2. https://doi.org/10.1016/j.chom.2020.04.017
https://doi.org/10....
). In addition, the virus has the ability to infect hair cells in the alveoli, decreasing the airway clearance capacity and evolving to respiratory distress syndrome (5353. Perico L, Benigni A, Remuzzi G. Should COVID-19 Concern Nephrologists? Why and to What Extent? The Emerging Impasse of Angiotensin Blockade. Nephron. 2020;144(5):213-21. https://doi.org/10.1159/000507305
https://doi.org/10.1159/000507305...
). This complication observed in patients hospitalized with COVID-19 is managed by mechanical ventilation (5454. World Health Organization. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected: interim guidance.; Available from: https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratoryinfection-when-novel-coronavirus-(ncov)-infection-is-suspected [cited June 16th, 2020]
https://www.who.int/publications-detail/...
). There are still serious risks of bacterial infections related to VAP in patients with COVID-19. Coinfection can worsen the clinical picture and increase the mortality of patients with COVID-19, as well as prolong and increase hospitalization costs. When VAP cannot be prevented in patients with COVID-19, this infection must be identified early to increase the chances of successful treatment (5555. Póvoa HCC, Chianca GC, Iorio NLPP. COVID-19: An Alert to Ventilator-Associated Bacterial Pneumonia. Infect Dis Ther. 2020;9(3):417-20. https://doi.org/10.1007/s40121-020-00306-5
https://doi.org/10.1007/s40121-020-00306...
).

CHX has been recognized as the gold standard in oral hygiene care and maintenance for over 20 years (5656. Jones CG. Chlorhexidine: is it still the gold standard? Periodontol 2000. 1997;15:55-62. https://doi.org/10.1111/j.1600-0757.1997.tb00105.x
https://doi.org/10.1111/j.1600-0757.1997...
,5757. Van der Weijden FA, Van der Sluijs E, Ciancio SG, Slot DE. Can Chemical Mouthwash Agents Achieve Plaque/Gingivitis Control? Dent Clin North Am. 2015;59(4):799-829. https://doi.org/10.1016/j.cden.2015.06.002
https://doi.org/10.1016/j.cden.2015.06.0...
). It is an effective ally in the control of plaque and treatment of gum disease, when associated with brushing (5757. Van der Weijden FA, Van der Sluijs E, Ciancio SG, Slot DE. Can Chemical Mouthwash Agents Achieve Plaque/Gingivitis Control? Dent Clin North Am. 2015;59(4):799-829. https://doi.org/10.1016/j.cden.2015.06.002
https://doi.org/10.1016/j.cden.2015.06.0...
,5858. Lindhe J, Lang NP, Berglundh T, Giannobile WV, Sanz M. Clinical periodontology and implant dentistry. 6th ed. Hoboken, NJ: Wiley; 2015.), in addition to diseases such as alveolar osteitis and bacteremia after tooth extractions (5959. Canullo L, Laino L, Longo F, Filetici P, D'Onofrio I, Troiano G. Does chlorhexidine Prevent Complications in Extractive, Periodontal, and Implant Surgery? A Systematic Review and Meta-analysis with Trial Sequential Analysis. Int J Oral Maxillofac Implants. 2020;35(6):1149-58. https://doi.org/10.11607/jomi.8216
https://doi.org/10.11607/jomi.8216...
). Its use was also considered safe in patients who received implants because it has excellent resistance to titanium corrosion (6060. Quaranta A, Ronconi LF, Di Carlo F, Vozza I, Quaranta M. Electrochemical behaviour of titanium in ammine and stannous fluoride and chlorhexidine 0.2 percent mouthwashes. Int J Immunopathol Pharmacol. 2010;23(1):335-43. https://doi.org/10.1177/039463201002300132
https://doi.org/10.1177/0394632010023001...
).

CHX is a cationic biguanide with lipophilic groups that can bind to bacterial cell walls and alter their osmotic balance (1313. Septimus EJ, Schweizer ML. Decolonization in Prevention of Health Care-Associated Infections. Clin Microbiol Rev. 2016;29(2):201-22. https://doi.org/10.1128/CMR.00049-15
https://doi.org/10.1128/CMR.00049-15...
,1414. Hugo WB, Longworth AR. Some aspects of the mode of action of chlorhexidine. J Pharm Pharmacol. 1964;16:655-62. https://doi.org/10.1111/j.2042-7158.1964.tb07384.x
https://doi.org/10.1111/j.2042-7158.1964...
). This effect inhibits bacterial growth and can even prevent the death of patients; the mechanism of action depends on the concentration of the substance (1515. Kumar SB. Chlorhexidine Mouthwash- A Review. J Pharm Sci Res. 2017;9(9):1450-2.). In addition to CHX, toothbrushing has shown promising effects on VAP (6161. Russell AD. Chlorhexidine: antibacterial action and bacterial resistance. Infection. 1986;14(5):212-5. https://doi.org/10.1007/BF01644264
https://doi.org/10.1007/BF01644264...
,6262. Roberts N, Moule P. Chlorhexidine and tooth-brushing as prevention strategies in reducing ventilator-associated pneumonia rates. Nurs Crit Care. 2011;16(6):295-302. https://doi.org/10.1111/j.1478-5153.2011.00465.x
https://doi.org/10.1111/j.1478-5153.2011...
). Disorganization of plaque or biofilm adherent to the dental surface can be performed mechanically and chemically (6363. Teles RP, Teles FR. Antimicrobial agents used in the control of periodontal biofilms: effective adjuncts to mechanical plaque control? Braz Oral Res. 2009;23 Suppl 1:39-48. https://doi.org/10.1590/S1806-83242009000500007
https://doi.org/10.1590/S1806-8324200900...
). Brushing assists in the removal of biofilm through the brush bristles, as mechanical contact can break plaque that is adherent to the tooth surface (6464. Chandki R, Banthia P, Banthia R. Biofilms: A microbial home. J Indian Soc Periodontol. 2011;15(2):111-4. https://doi.org/10.4103/0972-124X.84377
https://doi.org/10.4103/0972-124X.84377...
,6565. Verkaik MJ, Busscher HJ, Rustema-Abbing M, Slomp AM, Abbas F, van der Mei HC. Oral biofilm models for mechanical plaque removal. Clin Oral Investig. 2010;14(4):403-9. https://doi.org/10.1007/s00784-009-0309-x
https://doi.org/10.1007/s00784-009-0309-...
). Disruption of dental plaque through toothbrushing facilitates the action of CHX on residual biofilms.

Meinberg et al. (1717. Meinberg MC, Cheade Mde F, Miranda AL, Fachini MM, Lobo SM. The use of 2% chlorhexidine gel and toothbrushing for oral hygiene of patients receiving mechanical ventilation: effects on ventilator-associated pneumonia. Rev Bras Ter Intensiva. 2012;24(4):369-74. https://doi.org/10.1590/S0103-507X2012000400013
https://doi.org/10.1590/S0103-507X201200...
) conducted a clinical trial using CHX (2%) with and without toothbrushing and observed that 55.8% of patients developed VAP (1717. Meinberg MC, Cheade Mde F, Miranda AL, Fachini MM, Lobo SM. The use of 2% chlorhexidine gel and toothbrushing for oral hygiene of patients receiving mechanical ventilation: effects on ventilator-associated pneumonia. Rev Bras Ter Intensiva. 2012;24(4):369-74. https://doi.org/10.1590/S0103-507X2012000400013
https://doi.org/10.1590/S0103-507X201200...
). All studies included in the present review showed reduced VAP incidence rates (22. Lorente L, Lecuona M, Jiménez A, Palmero S, Pastor E, Lafuente N, et al. Ventilator-associated pneumonia with or without toothbrushing: a randomized controlled trial. Eur J Clin Microbiol Infect Dis. 2012;31(10):2621-9. https://doi.org/10.1007/s10096-012-1605-y
https://doi.org/10.1007/s10096-012-1605-...
,3838. Pobo A, Lisboa T, Rodriguez A, Sole R, Magret M, Trefler S, et al. A randomized trial of dental brushing for preventing ventilator-associated pneumonia. Chest. 2009;136(2):433-9. https://doi.org/10.1378/chest.09-0706
https://doi.org/10.1378/chest.09-0706...
,3939. de Lacerda Vidal CF, Vidal AK, Monteiro JG Jr, Cavalcanti A, Henriques APC, Oliveira M, et al. Impact of oral hygiene involving toothbrushing versus chlorhexidine in the prevention of ventilator-associated pneumonia: a randomized study. BMC Infect Dis. 2017;17(1):112. https://doi.org/10.1186/s12879-017-2188-0
https://doi.org/10.1186/s12879-017-2188-...
). This result supports the use of 0.12% CHX in VAP prevention care in mechanically ventilated patients. Additionally, the use of CHX at high concentrations presumably causes adverse effects, such as oral mucosal irritation (6666. Tantipong H, Morkchareonpong C, Jaiyindee S, Thamlikitkul V. Randomized controlled trial and meta-analysis of oral decontamination with 2% chlorhexidine solution for the prevention of ventilator-associated pneumonia. Infect Control Hosp Epidemiol. 2008;29(2):131-6. https://doi.org/10.1086/526438
https://doi.org/10.1086/526438...
) and the development of respiratory distress syndrome (RDS) due to the ingestion of CHX (6767. Hirata K, Kurokawa A. Chlorhexidine gluconate ingestion resulting in fatal respiratory distress syndrome. Vet Hum Toxicol. 2002;44(2):89-91.). RDS is associated with diffuse alveolar and endothelial lesions (6868. Cutts S, Talboys R, Paspula C, Prempeh EM, Fanous R, Ail D. Adult respiratory distress syndrome. Ann R Coll Surg Engl. 2017;99(1):12-6. https://doi.org/10.1308/rcsann.2016.0238
https://doi.org/10.1308/rcsann.2016.0238...
), which can be fatal in fragile patients (6969. Ferreira CR, de Souza DF, Cunha TM, Tavares M, Reis SS, Pedroso RS, et al. The effectiveness of a bundle in the prevention of ventilator-associated pneumonia. Braz J Infect Dis. 2016;20(3):267-71. https://doi.org/10.1016/j.bjid.2016.03.004
https://doi.org/10.1016/j.bjid.2016.03.0...
).

Other adverse effects caused by the mechanism of action of CHX, as well as its prolonged use, include changes in taste (7070. Cortellini P, Labriola A, Zambelli R, Prato GP, Nieri M, Tonetti MS. Chlorhexidine with an anti discoloration system after periodontal flap surgery: a cross-over, randomized, triple-blind clinical trial. J Clin Periodontol. 2008;35(7):614-20. https://doi.org/10.1111/j.1600-051X.2008.01238.x
https://doi.org/10.1111/j.1600-051X.2008...
) and pigmentation in the enamel, tongue, and composite resin fillings (7171. Guerra F, Pasqualotto D, Rinaldo F, Mazur M, Corridore D, Nofroni I, et al. Therapeutic efficacy of chlorhexidine-based mouthwashes and its adverse events: Performance-related evaluation of mouthwashes added with Anti-Discoloration System and cetylpyridinium chloride. Int J Dent Hyg. 2019;17(3):229-36. https://doi.org/10.1111/idh.12371
https://doi.org/10.1111/idh.12371...
). In an attempt to minimize or to eradicate such effects, researchers have sought changes in the use of this molecule. Guerra et al. (7171. Guerra F, Pasqualotto D, Rinaldo F, Mazur M, Corridore D, Nofroni I, et al. Therapeutic efficacy of chlorhexidine-based mouthwashes and its adverse events: Performance-related evaluation of mouthwashes added with Anti-Discoloration System and cetylpyridinium chloride. Int J Dent Hyg. 2019;17(3):229-36. https://doi.org/10.1111/idh.12371
https://doi.org/10.1111/idh.12371...
) demonstrated that the decrease in the concentration of CHX with cetylpyridinium chloride maintains a protective effect without changes in flavor perceived by the patient (7171. Guerra F, Pasqualotto D, Rinaldo F, Mazur M, Corridore D, Nofroni I, et al. Therapeutic efficacy of chlorhexidine-based mouthwashes and its adverse events: Performance-related evaluation of mouthwashes added with Anti-Discoloration System and cetylpyridinium chloride. Int J Dent Hyg. 2019;17(3):229-36. https://doi.org/10.1111/idh.12371
https://doi.org/10.1111/idh.12371...
). In a pilot study by Ripari et al. (7272. Ripari F, Cera A, Freda M, Zumbo G, Zara F, Vozza I. Tea Tree Oil versus Chlorhexidine Mouthwash in Treatment of Gingivitis: A Pilot Randomized, Double Blinded Clinical Trial. Eur J Dent. 2020;14(1):55-62. https://doi.org/10.1055/s-0040-1703999
https://doi.org/10.1055/s-0040-1703999...
), the efficacy of CHX mouthwash and tea tree oil was compared in the treatment of gingivitis; results suggest that tea tree oil may be advantageous in cases where patients spend little time brushing their teeth (7272. Ripari F, Cera A, Freda M, Zumbo G, Zara F, Vozza I. Tea Tree Oil versus Chlorhexidine Mouthwash in Treatment of Gingivitis: A Pilot Randomized, Double Blinded Clinical Trial. Eur J Dent. 2020;14(1):55-62. https://doi.org/10.1055/s-0040-1703999
https://doi.org/10.1055/s-0040-1703999...
).

VAP increases the period of mechanical ventilation, which has been related to high patient morbidity and mortality rates, as well as increased hospital costs (6969. Ferreira CR, de Souza DF, Cunha TM, Tavares M, Reis SS, Pedroso RS, et al. The effectiveness of a bundle in the prevention of ventilator-associated pneumonia. Braz J Infect Dis. 2016;20(3):267-71. https://doi.org/10.1016/j.bjid.2016.03.004
https://doi.org/10.1016/j.bjid.2016.03.0...
,7373. Heyland DK, Cook DJ, Griffith L, Keenan SP, Brun-Buisson C. The attributable morbidity and mortality of ventilator-associated pneumonia in the critically ill patient. The Canadian Critical Trials Group. Am J Respir Crit Care Med. 1999;159(4 Pt 1):1249-56. https://doi.org/10.1164/ajrccm.159.4.9807050
https://doi.org/10.1164/ajrccm.159.4.980...
). In any of the eligible studies in the present systematic review, the comparison between toothbrushing combined with CHX (0.12%) and CHX (0.12%) alone did not reveal a significant reduction in the number of days of mechanical ventilation (22. Lorente L, Lecuona M, Jiménez A, Palmero S, Pastor E, Lafuente N, et al. Ventilator-associated pneumonia with or without toothbrushing: a randomized controlled trial. Eur J Clin Microbiol Infect Dis. 2012;31(10):2621-9. https://doi.org/10.1007/s10096-012-1605-y
https://doi.org/10.1007/s10096-012-1605-...
,3838. Pobo A, Lisboa T, Rodriguez A, Sole R, Magret M, Trefler S, et al. A randomized trial of dental brushing for preventing ventilator-associated pneumonia. Chest. 2009;136(2):433-9. https://doi.org/10.1378/chest.09-0706
https://doi.org/10.1378/chest.09-0706...
). This result may show that the hospital length of stay associated with mechanical ventilation is a risk factor that overlaps with the VAP prevention protocol. One of the eligible studies observed this relationship, in which the majority of VAP cases occurred after day four of mechanical ventilation (3939. de Lacerda Vidal CF, Vidal AK, Monteiro JG Jr, Cavalcanti A, Henriques APC, Oliveira M, et al. Impact of oral hygiene involving toothbrushing versus chlorhexidine in the prevention of ventilator-associated pneumonia: a randomized study. BMC Infect Dis. 2017;17(1):112. https://doi.org/10.1186/s12879-017-2188-0
https://doi.org/10.1186/s12879-017-2188-...
).

Among the included articles, it is possible to recognize that toothbrushing alone is not superior in inhibiting VAP over 0.12% CHX alone (1717. Meinberg MC, Cheade Mde F, Miranda AL, Fachini MM, Lobo SM. The use of 2% chlorhexidine gel and toothbrushing for oral hygiene of patients receiving mechanical ventilation: effects on ventilator-associated pneumonia. Rev Bras Ter Intensiva. 2012;24(4):369-74. https://doi.org/10.1590/S0103-507X2012000400013
https://doi.org/10.1590/S0103-507X201200...
,3838. Pobo A, Lisboa T, Rodriguez A, Sole R, Magret M, Trefler S, et al. A randomized trial of dental brushing for preventing ventilator-associated pneumonia. Chest. 2009;136(2):433-9. https://doi.org/10.1378/chest.09-0706
https://doi.org/10.1378/chest.09-0706...
). Manual brushing with CHX does not help prevent VAP among patients receiving intensive mechanical ventilation therapy (22. Lorente L, Lecuona M, Jiménez A, Palmero S, Pastor E, Lafuente N, et al. Ventilator-associated pneumonia with or without toothbrushing: a randomized controlled trial. Eur J Clin Microbiol Infect Dis. 2012;31(10):2621-9. https://doi.org/10.1007/s10096-012-1605-y
https://doi.org/10.1007/s10096-012-1605-...
). However, although not significant, the meta-analysis conducted in our study showed a 24% reduction in the incidence of VAP in the CHX (0.12%) + toothbrushing group. This result may demonstrate the protective role of brushing in preventing VAP; however, due to the lack of statistical power, this did not reach the significance level. This also corroborates the study of Yao et al. (7474. Yao LY, Chang CK, Maa SH, Wang C, Chen CC. Brushing teeth with purified water to reduce ventilator-associated pneumonia. J Nurs Res. 2011;19(4):289-97. https://doi.org/10.1097/JNR.0b013e318236d05f
https://doi.org/10.1097/JNR.0b013e318236...
), who assessed the risk of VAP using toothbrushing with purified water and revealed a VAP incidence of 34% (7474. Yao LY, Chang CK, Maa SH, Wang C, Chen CC. Brushing teeth with purified water to reduce ventilator-associated pneumonia. J Nurs Res. 2011;19(4):289-97. https://doi.org/10.1097/JNR.0b013e318236d05f
https://doi.org/10.1097/JNR.0b013e318236...
). Among the eligible studies, the incidence of VAP ranged from 10.3% (22. Lorente L, Lecuona M, Jiménez A, Palmero S, Pastor E, Lafuente N, et al. Ventilator-associated pneumonia with or without toothbrushing: a randomized controlled trial. Eur J Clin Microbiol Infect Dis. 2012;31(10):2621-9. https://doi.org/10.1007/s10096-012-1605-y
https://doi.org/10.1007/s10096-012-1605-...
) to 22.4% (3838. Pobo A, Lisboa T, Rodriguez A, Sole R, Magret M, Trefler S, et al. A randomized trial of dental brushing for preventing ventilator-associated pneumonia. Chest. 2009;136(2):433-9. https://doi.org/10.1378/chest.09-0706
https://doi.org/10.1378/chest.09-0706...
).

VAP has considerable mortality rates, although the cause of death may be associated with previous morbidity (7575. Wu D, Wu C, Zhang S, Zhong Y. Risk Factors of Ventilator-Associated Pneumonia in Critically III Patients. Front Pharmacol. 2019;10:482. https://doi.org/10.3389/fphar.2019.00482
https://doi.org/10.3389/fphar.2019.00482...
). The attributable mortality associated with VAP is approximately 10%, ranging from 3% to 22% (7676. Melsen WG, Rovers MM, Koeman M, Bonten MJ. Estimating the attributable mortality of ventilator-associated pneumonia from randomized prevention studies. Crit Care Med. 2011;39(12):2736-42. https://doi.org/10.1097/CCM.0b013e3182281f33
https://doi.org/10.1097/CCM.0b013e318228...
,7777. Corrado RE, Lee D, Lucero DE, Varma JK, Vora NM. Burden of Adult Community-acquired, Health-care-Associated, Hospital-Acquired, and Ventilator-Associated Pneumonia: New York City, 2010 to 2014. Chest. 2017;152(5):930-42. https://doi.org/10.1016/j.chest.2017.04.162
https://doi.org/10.1016/j.chest.2017.04....
). Eligible trials included in the present study did not report the VAP mortality rates, representing an important limitation of the present conclusions.

This systematic review and meta-analysis has other limitations. First, only a small number of studies were included in the review. Second, eligible studies showed lack of relevant information, such as patient mortality and overall length of stay in intensive care units. Thus, our results should be interpreted with caution, and further studies with a standardized design are warranted to examine the use of 0.12% CHX + toothbrushing in reducing the risk of VAP in patients undergoing mechanical ventilation in intensive care units. As a strength, our review had a very comprehensive search strategy, including part of the gray literature; to the best of our knowledge, this is the first meta-analysis of clinical trials to compare the CHX (0.12%) + toothbrushing and CHX (0.12%) protocols.

CONCLUSION

Considering the limitations of this study, a standard protocol for the prevention of VAP is not recommended. Healthcare professionals should be aware of the benefits of oral hygiene in intensive care unit patients, to primarily reduce the incidence of VAP. The adoption of CHX may represent an improvement in mortality rates of patients under mechanical ventilation and, consequently, an improvement in patients’ quality of life, as well as a reduction in hospital expenses. Future research should focus on a single VAP prevention protocol using CHX+toothbrushing, including large sample sizes, aspects related to length of hospital stay, and mortality.

ACKNOWLEDGMENTS

This study was funded by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil (CAPES) - Finance code 001 and by the Ministry of Science, Technology, Innovation and Communications, Ministry of Health of Brazil and National Council for Scientific and Technological Development (CNPq; award numbers: 307808/2018-1 and 401612/2020-1).

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Publication Dates

  • Publication in this collection
    11 June 2021
  • Date of issue
    2021

History

  • Received
    4 Dec 2020
  • Accepted
    15 Apr 2021
Creative Common - by 4.0
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