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Conducting and Reporting Systematic Reviews of
Adverse Events
by
Liliane Medianeira Zorzela
A thesis submitted in partial fulfillment of the requirements for the degree of
Doctor of Philosophy
Medical Sciences - Pediatrics
University of Alberta
© Liliane Medianeira Zorzela, 2015
Abstract
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Systematic reviews (SRs) synthesize published and sometimes unpublished data and are often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.
ii
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
iii
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.
iv
Preface
This thesis is an original work by Liliane Medianeira Zorzela.
Some of the research conducted for this thesis was informed by an international research
group, The PRISMA Harms Group: with David Moher at Ottawa Health Research Institute
(OHRI); Doug Altman at University of Oxford; Jan Vandenbroucke at Leiden University; John P.
Ioannidis at Stanford University; Lina Santaguida at McMaster University; Yoon Loke at
University of East Anglia; Su Golder at University of York; and Sunita Vohra at University of
Alberta as the group lead. As part of this thesis work, L. Zorzela developed an extension for the
PRISMA statement, the PRISMA Harms. L. Zorzela collected the data, analysed the results and
wrote the review basis for the development of PRISMA Harms (chapter 2, published at BMJ
2014;348:f7668 doi: 10.1136/bmj.f7668); developed, employed and analysed the results for the
Delphi process and wrote the manuscript (chapter 3); organized and participated in the face to
face meeting and composed the manuscript “PRISMA Harms” (chapter 4). All the PRISMA
Harms related chapters were revised by the PRISMA Harms Group and by L. Zorzela’s thesis
committee group.
The development of the PRISMA Harms (chapters 2, 3 and 4) which is part of this thesis,
received research ethics approval from the University of Alberta Research Ethics Board, Project
name “PRISMA Harms Extension”, Pro 00021294, May 27, 2011. The PRISMA Harms received
partial funding support from “Alberta Innovates: Health Solutions”.
L. Zorzela developed the protocol for the review in chapter 5 (appendix 1), published at the
Cochrane Database of Systematic Reviews Volume (4), 2012, under title “Propofol infusion for
paediatric sedation”. L. Zorzela was the lead person for data screening, data collection, data
analysis and manuscript elaboration for the final Cochrane review (chapter 5). The protocol and
final review were revised by L. Zorzela’s thesis supervisor, thesis steering committee group and
all the co-‐authors.
v
Dedication
I would like to dedicate this work to my new family, my beloved daughter Isabel and my life
partner, Robert.
vi
Acknowledgments
First of all I would like to thank my parents, Ivo and Laureci, without them this work would not
be possible.
I would like to thank my thesis steering committee members, Lisa Hartling, Ari Joffe and Yoon
Loke for their expertise, guidance and treasured support during all these years.
I would like to thank the PRISMA Harms Group, Sunita Vohra, David Moher, Doug Altman, John
P. Ioannidis, Lina Santaguida, Yoon Loke, Jan Vandenbroucke and Su Golder for their expertise
and guidance on the development of the PRISMA Harms. I also would like to thank all the 25
PRISMA Harms meeting participants that came to Banff-‐ Alberta to discuss and help in the
development of the PRISMA Harms.
I would like to thank Katherine Pohlman, Yali Liu and Salima Punja for their persistence and help
during the systematic review’s development.
I would like to thank my daughter, Isabel, for her good behavior in utero and during her first
months of life, allowing me to complete this work.
Mainly, I would like to thank my supervisor, Dr. Sunita Vohra, for her patience, teaching and
support, but foremost for transforming me into a research believer. I learned how research can
be exciting and fulfilling when done with ethics and passion.
vii
Table of Contents
Chapter 1
Thesis Background ....................................................................................................................................... 2
Systematic reviews .................................................................................................................................. 2
The need to improve knowledge synthesis of harms .............................................................................. 2
Improving reporting in systematic reviews ............................................................................................. 3
Why a PRISMA Harms extension is important ......................................................................................... 3
Clinical context ........................................................................................................................................ 4
Goal of this doctoral thesis .......................................................................................................................... 4
Thesis Outline .............................................................................................................................................. 5
Improving the report of adverse events in systematic reviews ............................................................... 5
Improving the estimate of adverse events .............................................................................................. 5
Manuscript based thesis chapters ............................................................................................................... 5
Chapter 2: Quality of reporting in systematic reviews of adverse events: systematic review ................ 5
Chapter 3: The development of PRISMA Harms using a modified Delphi technique .............................. 6
Chapter 4: PRISMA Harms ....................................................................................................................... 6
Chapter 5: Propofol infusion for paediatric sedation .............................................................................. 6
References ................................................................................................................................................... 7
Chapter 2
Quality of reporting in systematic reviews of adverse events: systematic review .................................... 11
Abstract ................................................................................................................................................. 12
Introduction ............................................................................................................................................... 13
Methods .................................................................................................................................................... 14
Development of the checklist items ...................................................................................................... 14
Search strategy ...................................................................................................................................... 14
Eligibility criteria .................................................................................................................................... 15
Screening and data extraction ............................................................................................................... 15
Outcome ................................................................................................................................................ 16
Data analysis .......................................................................................................................................... 16
Results ....................................................................................................................................................... 17
Titles and abstracts ............................................................................................................................ 18
viii
Introduction and rationale ................................................................................................................. 18
Methods ............................................................................................................................................ 18
Results ............................................................................................................................................... 19
Discussion .............................................................................................................................................. 20
Principal findings ................................................................................................................................ 20
Conclusions ............................................................................................................................................ 23
What this paper adds ......................................................................................................................... 25
What is already known on this topic ................................................................................................. 25
References ............................................................................................................................................. 25
Table 1.Glossary ................................................................................................................................. 29
Table 2. Definition of Reporting Items. .............................................................................................. 30
Table 3 Summary of Findings ............................................................................................................. 33
Chapter 3
The development of PRISMA Harms using a modified Delphi technique .............................................. 41
Abstract ............................................................................................................................................. 41
Introduction ....................................................................................................................................... 42
Methods ............................................................................................................................................ 43
Results ............................................................................................................................................... 45
Discussion .......................................................................................................................................... 47
Conclusion ......................................................................................................................................... 49
References ......................................................................................................................................... 49
Chapter 4
PRISMA Harms: improving harms reporting in systematic reviews ...................................................... 64
Abstract ............................................................................................................................................. 64
Introduction ....................................................................................................................................... 65
Development of PRISMA Harms ........................................................................................................ 66
Discussion .......................................................................................................................................... 93
Conclusion ............................................................................................................................................. 94
Examples references: ......................................................................................................................... 94
References ......................................................................................................................................... 97
Chapter 5
Propofol infusion for paediatric sedation. A systematic review of serious adverse events. .............. 106
ix
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