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Conducting and Reporting Systematic Reviews of Adverse Events Open Access


Other title
systematic reviews
adverse events
Type of item
Degree grantor
University of Alberta
Author or creator
Zorzela, Liliane Medianeira
Supervisor and department
Vohra, Sunita (Department of Pediatrics)
Examining committee member and department
Yoon Loke (Medicine & Pharmacology, University of East Anglia)
Lisa Hartling (Pediatrics, University of Alberta)
Ari Joffe (Pediatrics, University of Alberta)
Christopher Parshuram (Critical Care Medicine & Paediatrics, University of Toronto)
Linda Carroll (School of Public Health, University of Alberta)
Medical Sciences-Paediatrics

Date accepted
Graduation date
Doctor of Philosophy
Degree level
Introduction Systematic reviews (SRs) synthesize published and sometimes unpublished data and are often based on randomized controlled trials (RCTs). However, RCTs are known to be poor at identifying and reporting harms. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) Statement was published in 2009 to offer guidance on the minimum reporting standards when publishing a SR. Thus far, PRISMA has mainly focused on efficacy, but there is a need for evidence on both efficacy and harms of interventions. Propofol is an anesthetic intervention used for pediatric sedation, but there have been several case reports of ‘propofol infusion syndrome’ (PRIS), a poorly understood syndrome often leading to death. In several countries, regulatory agencies have contraindicated the use of propofol infusion in pediatric intensive care units. However, propofol is still used despite the liability concerns. The overall goals of this thesis were to improve methods of conducting and reporting systematic reviews of adverse events. More specifically, (i) to develop an extension for the PRISMA Statement, for SRs addressing adverse events (AEs): the PRISMA Harms; (ii) to identify if propofol is associated with serious AEs in children and measure if the inclusion of non-randomized studies in a SR of AEs provides further information than data from RCTs alone. Methods There were 2 distinct methods used in this doctoral thesis. The first was to develop the PRISMA Harms guideline. We followed the recommended steps for guideline development: 1) to document if there is need for the development of a guideline; 2) to employ a Delphi process to identify relevant items to be included in the reporting guideline; 3) to have an in-person consensus building meeting; and 4) to write the guideline. The second was to identify if propofol infusion is associated with serious AEs in pediatric patients and to measure if the inclusion of non-randomized studies provides more relevant data than clinical trials alone, we conducted a SR of propofol infusion in pediatric patients including both clinical trials and observational studies. Results For the PRISMA Harms development, the first step identified 309 reviews of AEs and documented weaknesses in reporting and the need for a guideline. The second step conducted three Delphi rounds sent to 352 participants, 166 responses were received. The in-person meeting had 25 participants and the final PRISMA Harms manuscript was developed after multiple revisions containing 4 mandatory items and 14 recommended items for reviews addressing harms. The propofol SR identified 91 serious AEs (PRIS or cardiac arrest) associated with propofol infusion, 21 identified in a single unpublished RCT and all the other serious AEs emerged from non-randomized studies. In the included studies, a total of 5633 children received propofol for more than 60 minutes and did not have any serious events (i.e., PRIS or cardiac arrest) associated with it. Conclusion Through this work we developed PRISMA Harms, an international reporting guideline to improve harms reporting in SRs. Further, we documented serious AEs associated with propofol infusion in children and the relevance of including non-randomized and unpublished studies in SRs of AEs, providing both clinical and methodological significant information.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Zorzela LM, Punja S, Joffe A, Hartling L, Vandermeer B, Loke Y, Vohra S. Propofol infusion for paediatric sedation. Cochrane Database of Systematic Reviews 2012, Issue 4. Art. No.: CD009813. DOI: 10.1002/14651858.CD009813Zorzela L, Golder S, Liu Y, Pilkington K, Hartling L, et all. Quality of reporting in systematic reviews of adverse events: systematic review. BMJ 2014;348:f7668 doi: 10.1136/bmj.f7668.

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