Accepted Manuscript. Commentary: The Power under Control of Meta-Analysis in the Synthesis of Clinical Knowledge. Luca Bertolaccini, MD PhD FCCP

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1 Accepted Manuscript Commentary: The Power under Control of Meta-Analysis in the Synthesis of Clinical Knowledge Luca Bertolaccini, MD PhD FCCP PII: S (19) DOI: Reference: YMTC To appear in: The Journal of Thoracic and Cardiovascular Surgery Received Date: 13 January 2019 Accepted Date: 14 January 2019 Please cite this article as: Bertolaccini L, Commentary: The Power under Control of Meta-Analysis in the Synthesis of Clinical Knowledge, The Journal of Thoracic and Cardiovascular Surgery (2019), doi: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 1 Commentary: The Power Under Control of Meta-Analysis in the Synthesis of Clinical Knowledge Luca Bertolaccini, MD PhD FCCP [1] 1. Department of Thoracic Surgery, Maggiore Teaching Hospital, Bologna (IT). Conflict of Interest Statement: No Conflict. Corresponding Author: Luca Bertolaccini, MD PhD FCCP Mailing address: Department of Thoracic Surgery Maggiore Teaching Hospital Largo Nigrisoli 2, Bologna (IT) Tel: Fax: luca.bertolaccini@gmail.com Article word count: 500 words. 20

3 21 Central Picture Legend 22 Luca Bertolaccini, MD PhD FCCP Central Message Preoperative Chlorhexidine mouthwash significantly reduces the risk of postoperative pneumonia after cardiac surgery. The results could be used in recommendations and design of future clinical trials

4 31 Even if mechanical ventilation reduces the incidence of respiratory failure and improves 32 the survival after cardiac surgery, it may lead to ventilator-associated pneumonia (VAP) 1. Shreds of evidence in medical Literature suggest that Chlorhexidine gluconate (a broad-spectrum antibacterial agent) could be used to decrease the incidence of VAP after cardiac surgery 2. Combining the results of studies analysed, the technique of meta-analysis is designed to increase the sample size and the power of the effects under investigation 3. Like many other statistical techniques, the meta-analyses are potent tools if used carefully, since most data are derived from observational studies and single-centre prospective trials and few data are derived from large-scale multicentre trials 4. In the systematic review (SR) and meta-analysis published this month in the Journal, Bardia et al. assessed the efficacy of preoperative Chlorhexidine gluconate in the reduction of postoperative pneumonia after cardiac surgery and found that the preoperative mouthwash significantly reduces this risk 5. From a pathophysiological point of view, oral decontamination by Chlorhexidine could decrease the microbial burden of the aerodigestive tract and, hence, apply a protective effect, particularly pronounced in the prevention of Gram-positive pneumonia 5. As recognised by the Authors, this SR/meta-analysis evaluated data derived only from 47 cardiac surgeries. Therefore, the generalizability to non-cardiac surgical patients is still unclear with 48 contradictory results presented in the Literature for thoracic surgery. For instance, an SR 49 recommended the perioperative oral decontamination in adult patients undergoing elective 50 thoracic non-cardiac surgery 6. On the contrary, a recent multicentre randomised controlled - 3 -

5 51 double-blind trial showed that Chlorhexidine decontamination did not decrease the incidence of 52 VAP Unfortunately, the SR/meta-analysis was not registered in the international database of prospectively recorded SR PROSPERO ( This registry provides a comprehensive listing of SR with the aim to avoid replication and decrease the opportunity for reporting bias. The registration of the SR protocol may alert guideline groups that a detailed report is being performed and offer occasions for cooperation with colleagues for implementing the findings of the investigation 8. The registration of the protocol could appear as an additional duty to SR/meta-analysis authors, but it is easy, reduces repetition of papers, and the review team could benefit from registration avoiding subsequent uncertainty 9. Nonetheless, conducting metaanalyses does not overcome inherent problems in the design and execution of the primary studies since meta-analyses do not correct publication biases. Therefore, studies reporting remarkable results are more likely to be identified, summarised, and subsequently pooled, than studies with smaller effect sizes 10. In conclusion, every meta-analysis presents some limitations in the planning, in the execution and the analysis, due to the heterogeneity in patient populations or the surgical 67 techniques, the different duration of follow-up, and the various definitions of clinical outcomes. 68 Despite these well-known caveats, the results derived from SR/meta-analysis of Bardia et al could be used to provide guidance in the design of future clinical trials and the completion of 70 recommendations about the preoperative use of Chlorhexidine for the reduction of postoperative - 4 -

6 71 pneumonia after cardiac surgery

7 REFERENCES 1. Lin YJ, Xu L, Huang XZ, et al. Reduced occurrence of ventilator-associated pneumonia after c ardiac surgery using preoperative 0.2% chlorhexidine oral rinse: results from a single-centre single-blinded randomized trial. The Journal of hospital infection. 2015;91: Nicolosi LN, del Carmen Rubio M, Martinez CD, Gonzalez NN, Cruz ME. Effect of oral hygien e and 0.12% chlorhexidine gluconate oral rinse in preventing ventilator-associated pneumo nia after cardiovascular surgery. Respiratory care. 2014;59: Walker E, Hernandez AV, Kattan MW. Meta-analysis: Its strengths and limitations. Cleveland Clinic journal of medicine. 2008;75: Yanagawa B, Tam DY, Mazine A, Tricco AC. Systematic review and meta-analysis in cardiac su rgery: a primer. Curr Opin Cardiol. 2018;33: Bardia A BD, Dai F, Hersey D, Jinadasa S, Tickoo M, Schonberger MB. Preoperative Chlorhexi dine Mouthwash to Reduce Pneumonia after Cardiac Surgery: A Systematic Review and Me ta-analysis. J Thorac Cardiovasc Surg. 2019:in press. 6. Pedersen PU, Larsen P, Hakonsen SJ. The effectiveness of systematic perioperative oral hygi ene in reduction of postoperative respiratory tract infections after elective thoracic surgery in adults: a systematic review. JBI database of systematic reviews and implementation repor ts. 2016;14: D'Journo XB, Falcoz PE, Alifano M, et al. Oropharyngeal and nasopharyngeal decontaminati on with chlorhexidine gluconate in lung cancer surgery: a randomized clinical trial. Intensive care medicine. 2018;44: Editors PLM. Best practice in systematic reviews: the importance of protocols and registrati 96 on. PLoS Med. 2011;8:e

8 97 9. Chang SM, Slutsky J. Debunking myths of protocol registration. Syst Rev. 2012;1: Garg AX, Hackam D, Tonelli M. Systematic review and meta-analysis: when one study is just not enough. Clin J Am Soc Nephrol. 2008;3:

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